Zinc(II) ion

evidence_span

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experimental_model

Recordings of tonic and phasic currents in dissociated hippocampal neurons and slices, with a kindled seizure model

exposure

Zinc with the synthetic neurosteroid ganaxolone, applied to neurons and intrahippocampally in fully kindled mice

limitations

The separation of tonic from phasic current is what makes the subunit assignment work. Zinc was given intrahippocampally at a defined dose rather than altered nutritionally.

nutrient_topic

GABA research collection; topical membership is not evidence of a direct clinical effect, and the sign of a GABA response depends on the chloride gradient of the cell it was measured in. · Gamma-aminobutyric acid

organism

Mouse

plain_language

Zinc shuts down the steroid-sensitive receptors that sit outside synapses while leaving the ones inside synapses working.

primary_references

[gb-p30471294] Zinc reduces antiseizure activity of neurosteroids by selective blockade of extrasynaptic GABA-A receptor-mediated tonic inhibition in the hippocampus. (2019). https://pubmed.ncbi.nlm.nih.gov/30471294/ DOI: 10.1016/j.neuropharm.2018.11.031

tissue_or_cell_type

Dentate gyrus granule cells and CA1 pyramidal cells

GABA: a ligand with no sign of its own, the cofactor that limits its synthesis, the barrier that keeps it out of the brain, and the immune settings where the same molecule protects and harms (2026-09-22) · lines 261–272

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Recordings of tonic and phasic currents in dissociated hippocampal neurons and slices, with a kindled seizure model · source_derived_draft · unverified_draft

### gb-zinc-blocks-only-the-tonic-receptors Zinc is an abundant trace metal in the hippocampus nerve terminals and blocked the GABA-evoked and ganaxolone-potentiated GABA-gated chloride currents in dentate gyrus granule cells and CA1 pyramidal cells in a concentration-dependent fashion similar to competitive GABA-A receptor antagonists, zinc completely blocked ganaxolone potentiation of extrasynaptic tonic currents but not synaptic phasic currents, systemic ganaxolone produced dose-dependent suppression of behavioral and electrographic seizures in fully-kindled mice with complete protection at 10 mg/kg, however the antiseizure effects were significantly prevented by intrahippocampal zinc with a median effective dose of 150 micromolar, and the response was reversible. Condition category: normal nutrient_topic: GABA research collection; topical membership is not evidence of a direct clinical effect, and the sign of a GABA response depends on the chloride gradient of the cell it was measured in. plain_language: Zinc shuts down the steroid-sensitive receptors that sit outside synapses while leaving the ones inside synapses working. organism: Mouse tissue_or_cell_type: Dentate gyrus granule cells and CA1 pyramidal cells experimental_model: Recordings of tonic and phasic currents in dissociated hippocampal neurons and slices, with a kindled seizure model limitations: The separation of tonic from phasic current is what makes the subunit assignment work. Zinc was given intrahippocampally at a defined dose rather than altered nutritionally. exposure: Zinc with the synthetic neurosteroid ganaxolone, applied to neurons and intrahippocampally in fully kindled mice evidence_span: {"source_cache": "artifacts/gaba-research/30471294.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "657923c781b7e3a3309235bce60303fde53f18d7a830cde050b268269f02747a", "start_char": 0, "end_char": 1814, "text_sha256": "657923c781b7e3a3309235bce60303fde53f18d7a830cde050b268269f02747a"} [gb-p30471294] Zinc reduces antiseizure activity of neurosteroids by selective blockade of extrasynaptic GABA-A receptor-mediated tonic inhibition in the hippocampus. (2019). https://pubmed.ncbi.nlm.nih.gov/30471294/ DOI: 10.1016/j.neuropharm.2018.11.031

evidence_span

{"source_cache": "artifacts/coq10-research/38425362.fulltext.txt", "locator": "Primary full-text span; zero-based, end-exclusive Unicode character offsets", "file_sha256": "7d25af4ecd7340649536b8fea3b8a0a308a1611bbf8c57f6a79b362f443f1cba", "start_char": 19036, "end_char": 19993, "text_sha256": "b045e1167d6b11834b57a1d07ec6cfd4a9b4419ea9a0f482e9509488bd3b3178"}

experimental_model

Purified reconstructed COQ metabolon with short-chain substrates

exposure

Enzyme combinations, methyl donors, reductants and metal additions

limitations

Ancestral proteins and CoQ1 analogues; no clinical cofactor dose or proof of nutritional rate limitation. Reaction order need not be universal across species.

nutrient_topic

Coenzyme Q10 research collection; topical membership is not evidence of a direct dietary effect. · Coenzyme Q10 / CoQ10 redox system

organism

Reconstructed ancestral tetrapod proteins

plain_language

A zinc-binding site helped a different head-group modification.

primary_references

[coq10-p38425362] In vitro construction of the COQ metabolon unveils the molecular determinants of coenzyme Q biosynthesis. (2024). https://pubmed.ncbi.nlm.nih.gov/38425362/ DOI: 10.1038/s41929-023-01087-z

tissue_or_cell_type

Stepwise CoQ head-group assembly

Coenzyme Q10: biosynthesis, electron transfer, antioxidant recycling and nutrient interactions (2026-09-17) · lines 671–682

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purified reconstructed COQ metabolon with short-chain substrates · source_derived_draft · unverified_draft

### coq10-coq4-zinc Zinc promoted COQ4 decarboxylase activity, whereas disruption of its metal-binding site eliminated detected product. Condition category: normal nutrient_topic: Coenzyme Q10 research collection; topical membership is not evidence of a direct dietary effect. plain_language: A zinc-binding site helped a different head-group modification. organism: Reconstructed ancestral tetrapod proteins tissue_or_cell_type: Stepwise CoQ head-group assembly experimental_model: Purified reconstructed COQ metabolon with short-chain substrates limitations: Ancestral proteins and CoQ1 analogues; no clinical cofactor dose or proof of nutritional rate limitation. Reaction order need not be universal across species. exposure: Enzyme combinations, methyl donors, reductants and metal additions evidence_span: {"source_cache": "artifacts/coq10-research/38425362.fulltext.txt", "locator": "Primary full-text span; zero-based, end-exclusive Unicode character offsets", "file_sha256": "7d25af4ecd7340649536b8fea3b8a0a308a1611bbf8c57f6a79b362f443f1cba", "start_char": 19036, "end_char": 19993, "text_sha256": "b045e1167d6b11834b57a1d07ec6cfd4a9b4419ea9a0f482e9509488bd3b3178"} [coq10-p38425362] In vitro construction of the COQ metabolon unveils the molecular determinants of coenzyme Q biosynthesis. (2024). https://pubmed.ncbi.nlm.nih.gov/38425362/ DOI: 10.1038/s41929-023-01087-z

evidence_access

Primary abstract

experimental_model

Purified bacterial-enzyme assays.

limitations

No safe or effective intestinal zinc intervention is established by the enzyme experiment.

nutrient_topic

L-Proline collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Proline

plain_language

A mineral can inhibit this microbial enzyme rather than serve as its cofactor.

primary_references

Analysis of proline reduction in the nosocomial pathogen Clostridium difficile. · 2006 · https://pubmed.ncbi.nlm.nih.gov/17041035/ · DOI 10.1128/JB.01370-06

L-Proline: synthesis, collagen processing, redox metabolism and cross-nutrient mechanisms (2026-09-19) · lines 422–428

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Purified bacterial-enzyme assays. · source_derived_draft · unverified_draft

## l-proline-microbial-zinc A mineral can inhibit this microbial enzyme rather than serve as its cofactor. Zinc strongly inhibited purified C. difficile D-proline reductase, which did not require added divalent cations for its measured activity. Model: Purified bacterial-enzyme assays. Limitations: No safe or effective intestinal zinc intervention is established by the enzyme experiment. Evidence access: Primary abstract Analysis of proline reduction in the nosocomial pathogen Clostridium difficile. · 2006 · https://pubmed.ncbi.nlm.nih.gov/17041035/ · DOI 10.1128/JB.01370-06

cross_nutrient

false

experimental_model

Purified recombinant human CA2; metal reconstitution, ITC and X-ray absorption spectroscopy

exposure

Zn K-edge XANES and EXAFS on isolated and zinc-reconstituted recombinant CA2.

limitations

Coordination assignment is spectroscopic; the oxygen ligand is most likely solvent-derived, not an independently measured dietary effect.

nutrient_topic

Zinc research collection; topical membership is not evidence of a direct dietary effect. · Zinc

organism

Homo sapiens

plain_language

CA2 holds zinc with three histidines and a water-derived ligand at its active site.

primary_references

[zinc-enz-ca2-coordination2012] Revisiting zinc coordination in human carbonic anhydrase II. (2012). https://pubmed.ncbi.nlm.nih.gov/23030313/ DOI: 10.1021/ic301645j

tissue_or_cell_type

Purified protein; cell-free assay

Zinc: transport, enzyme loading, deficiency and nutrient interactions (2026-09-17) · lines 651–662

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purified recombinant human CA2; metal reconstitution, ITC and X-ray absorption spectroscopy · source_derived_draft · unverified_draft

### zinc-enz-ca2-coordination X-ray absorption analysis of human CA2 supported a zinc site with three histidine nitrogen ligands and most likely one water/hydroxide oxygen ligand in both isolated and reconstituted enzyme. Condition category: normal nutrient_topic: Zinc research collection; topical membership is not evidence of a direct dietary effect. plain_language: CA2 holds zinc with three histidines and a water-derived ligand at its active site. organism: Homo sapiens tissue_or_cell_type: Purified protein; cell-free assay experimental_model: Purified recombinant human CA2; metal reconstitution, ITC and X-ray absorption spectroscopy limitations: Coordination assignment is spectroscopic; the oxygen ligand is most likely solvent-derived, not an independently measured dietary effect. exposure: Zn K-edge XANES and EXAFS on isolated and zinc-reconstituted recombinant CA2. cross_nutrient: false [zinc-enz-ca2-coordination2012] Revisiting zinc coordination in human carbonic anhydrase II. (2012). https://pubmed.ncbi.nlm.nih.gov/23030313/ DOI: 10.1021/ic301645j

cross_nutrient

false

experimental_model

Purified recombinant human CA2 expressed in E. coli; chelation, crystallography, DSC and H/D exchange

exposure

1 mM ZnCl2 added in vitro after chelation and buffer exchange.

limitations

Purified recombinant protein; chelation is not dietary deficiency. Approximately 10% zinc remained in the nominal apo preparation. The assay addition is not a supplement dose.

nutrient_topic

Zinc research collection; topical membership is not evidence of a direct dietary effect. · Zinc

organism

Homo sapiens

plain_language

Returning zinc to the depleted enzyme restored activity.

primary_references

[zinc-enz-ca2-apo2009] Apo-human carbonic anhydrase II revisited: implications of the loss of a metal in protein structure, stability, and solvent network. (2009). https://pubmed.ncbi.nlm.nih.gov/19583303/ DOI: 10.1021/bi9007512

tissue_or_cell_type

Purified protein; cell-free assay

Zinc: transport, enzyme loading, deficiency and nutrient interactions (2026-09-17) · lines 612–623

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purified recombinant human CA2 expressed in E. coli; chelation, crystallography, DSC and H/D exchange · source_derived_draft · unverified_draft

### zinc-enz-ca2-reconstitution Adding 1 mM ZnCl2 revived the activity of chelated recombinant human CA2. Condition category: normal nutrient_topic: Zinc research collection; topical membership is not evidence of a direct dietary effect. plain_language: Returning zinc to the depleted enzyme restored activity. organism: Homo sapiens tissue_or_cell_type: Purified protein; cell-free assay experimental_model: Purified recombinant human CA2 expressed in E. coli; chelation, crystallography, DSC and H/D exchange limitations: Purified recombinant protein; chelation is not dietary deficiency. Approximately 10% zinc remained in the nominal apo preparation. The assay addition is not a supplement dose. exposure: 1 mM ZnCl2 added in vitro after chelation and buffer exchange. cross_nutrient: false [zinc-enz-ca2-apo2009] Apo-human carbonic anhydrase II revisited: implications of the loss of a metal in protein structure, stability, and solvent network. (2009). https://pubmed.ncbi.nlm.nih.gov/19583303/ DOI: 10.1021/bi9007512

cross_nutrient

false

experimental_model

Purified recombinant human CA2 expressed in E. coli; chelation, crystallography, DSC and H/D exchange

exposure

Purified apo and holo proteins; DSC in 50 mM Tris-HCl pH 7.0.

limitations

Purified recombinant protein; chelation is not dietary deficiency. Approximately 10% zinc remained in the nominal apo preparation. Thermal unfolding temperature is not a body-temperature requirement.

nutrient_topic

Zinc research collection; topical membership is not evidence of a direct dietary effect. · Zinc

organism

Homo sapiens

plain_language

Bound zinc also helps CA2 resist thermal unfolding.

primary_references

[zinc-enz-ca2-apo2009] Apo-human carbonic anhydrase II revisited: implications of the loss of a metal in protein structure, stability, and solvent network. (2009). https://pubmed.ncbi.nlm.nih.gov/19583303/ DOI: 10.1021/bi9007512

tissue_or_cell_type

Purified protein; cell-free assay

Zinc: transport, enzyme loading, deficiency and nutrient interactions (2026-09-17) · lines 625–636

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purified recombinant human CA2 expressed in E. coli; chelation, crystallography, DSC and H/D exchange · source_derived_draft · unverified_draft

### zinc-enz-ca2-stability Zinc-containing CA2 unfolded at 59±0.5°C versus 51±0.5°C for the chelated preparation in differential scanning calorimetry. Condition category: normal nutrient_topic: Zinc research collection; topical membership is not evidence of a direct dietary effect. plain_language: Bound zinc also helps CA2 resist thermal unfolding. organism: Homo sapiens tissue_or_cell_type: Purified protein; cell-free assay experimental_model: Purified recombinant human CA2 expressed in E. coli; chelation, crystallography, DSC and H/D exchange limitations: Purified recombinant protein; chelation is not dietary deficiency. Approximately 10% zinc remained in the nominal apo preparation. Thermal unfolding temperature is not a body-temperature requirement. exposure: Purified apo and holo proteins; DSC in 50 mM Tris-HCl pH 7.0. cross_nutrient: false [zinc-enz-ca2-apo2009] Apo-human carbonic anhydrase II revisited: implications of the loss of a metal in protein structure, stability, and solvent network. (2009). https://pubmed.ncbi.nlm.nih.gov/19583303/ DOI: 10.1021/bi9007512

cross_nutrient

false

experimental_model

Transient expression of human SOD1 and CCS in human HEK293T cells; in-cell NMR

exposure

10 µM ZnSO4 immediately after transfection; 48 h expression before later copper manipulations.

limitations

HEK293T cells overexpressed SOD1/CCS above endogenous levels; these medium concentrations are experimental exposures, not dietary targets. Copper transfer and disulfide oxidation need not occur in a fixed coupled step in every cellular context.

nutrient_topic

Zinc research collection; topical membership is not evidence of a direct dietary effect. · Zinc

organism

Homo sapiens

plain_language

Zinc binding helps the cellular SOD1 protein reach a dimeric maturation intermediate.

primary_references

[zinc-enz-sod1-live2013] Atomic-resolution monitoring of protein maturation in live human cells by NMR. (2013). https://pubmed.ncbi.nlm.nih.gov/23455544/ DOI: 10.1038/nchembio.1202

tissue_or_cell_type

Human HEK293T cytoplasm

Zinc: transport, enzyme loading, deficiency and nutrient interactions (2026-09-17) · lines 729–740

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Transient expression of human SOD1 and CCS in human HEK293T cells; in-cell NMR · source_derived_draft · unverified_draft

### zinc-enz-sod1-zinc-binding Adding 10 µM ZnSO4 during human SOD1 expression in HEK293T cells promoted site-selective binding of one zinc ion per SOD1 subunit and the zinc-containing dimer. Condition category: normal nutrient_topic: Zinc research collection; topical membership is not evidence of a direct dietary effect. plain_language: Zinc binding helps the cellular SOD1 protein reach a dimeric maturation intermediate. organism: Homo sapiens tissue_or_cell_type: Human HEK293T cytoplasm experimental_model: Transient expression of human SOD1 and CCS in human HEK293T cells; in-cell NMR limitations: HEK293T cells overexpressed SOD1/CCS above endogenous levels; these medium concentrations are experimental exposures, not dietary targets. Copper transfer and disulfide oxidation need not occur in a fixed coupled step in every cellular context. exposure: 10 µM ZnSO4 immediately after transfection; 48 h expression before later copper manipulations. cross_nutrient: false [zinc-enz-sod1-live2013] Atomic-resolution monitoring of protein maturation in live human cells by NMR. (2013). https://pubmed.ncbi.nlm.nih.gov/23455544/ DOI: 10.1038/nchembio.1202

availability_state

machinery_impairment Imported condition classification; unverified.

cross_nutrient

false

experimental_model

Engineered chicken DT40 cells with ZnT gene disruption and transporter re-expression; TNAP activation

exposure

Genetic deficiency of the two specific secretory ZnT complexes, followed by zinc supplementation in culture; amount unreported in abstract.

limitations

Primary abstract-level evidence in engineered chicken DT40 cells with transporter complementation. Not a human dietary deficiency or supplementation trial; assay exposure amounts and mutant-specific residue effects are not inferred.

nutrient_topic

Zinc research collection; topical membership is not evidence of a direct dietary effect. · Zinc

organism

Gallus gallus

plain_language

More available zinc did not bypass missing enzyme-loading machinery.

primary_references

[zinc-enz-znt-tnap2011] Tissue nonspecific alkaline phosphatase is activated via a two-step mechanism by zinc transport complexes in the early secretory pathway. (2011). https://pubmed.ncbi.nlm.nih.gov/21402707/ DOI: 10.1074/jbc.m111.227173

tissue_or_cell_type

Chicken DT40 early secretory pathway

trigger_kind

machinery_impairment Imported condition classification; unverified.

Zinc: transport, enzyme loading, deficiency and nutrient interactions (2026-09-17) · lines 781–792

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Engineered chicken DT40 cells with ZnT gene disruption and transporter re-expression; TNAP activation · source_derived_draft · unverified_draft

### zinc-enz-zinc-cannot-bypass-znt-loss Extracellular zinc supplementation did not restore reduced TNAP activity in DT40 cells deficient in both ZnT5-ZnT6 and ZnT7 complexes. Condition category: machinery_impairment nutrient_topic: Zinc research collection; topical membership is not evidence of a direct dietary effect. plain_language: More available zinc did not bypass missing enzyme-loading machinery. organism: Gallus gallus tissue_or_cell_type: Chicken DT40 early secretory pathway experimental_model: Engineered chicken DT40 cells with ZnT gene disruption and transporter re-expression; TNAP activation limitations: Primary abstract-level evidence in engineered chicken DT40 cells with transporter complementation. Not a human dietary deficiency or supplementation trial; assay exposure amounts and mutant-specific residue effects are not inferred. exposure: Genetic deficiency of the two specific secretory ZnT complexes, followed by zinc supplementation in culture; amount unreported in abstract. cross_nutrient: false [zinc-enz-znt-tnap2011] Tissue nonspecific alkaline phosphatase is activated via a two-step mechanism by zinc transport complexes in the early secretory pathway. (2011). https://pubmed.ncbi.nlm.nih.gov/21402707/ DOI: 10.1074/jbc.m111.227173

cross_nutrient

false

experimental_model

Cultured cells expressing human ZIP4 with mutational analysis

exposure

Elevated zinc exposure; detailed concentration and cell lineage not specified in the abstract.

limitations

Abstract extraction; the region requirement does not mean every histidine acts as an independent sensor. This is zinc exposure, not demonstrated dietary deficiency.

nutrient_topic

Zinc research collection; topical membership is not evidence of a direct dietary effect. · Zinc

organism

Human protein in cultured cells

plain_language

Human ZIP4 has a zinc-triggered disposal response that is separate from removal from the surface.

primary_references

[zinc-trans-17202136] A histidine-rich cluster mediates the ubiquitination and degradation of the human zinc transporter, hZIP4, and protects against zinc cytotoxicity. (2007). https://pubmed.ncbi.nlm.nih.gov/17202136/ DOI: 10.1074/jbc.m610552200

tissue_or_cell_type

Cellular zinc-uptake machinery

Zinc: transport, enzyme loading, deficiency and nutrient interactions (2026-09-17) · lines 258–269

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Cultured cells expressing human ZIP4 with mutational analysis · source_derived_draft · unverified_draft

### zinc-trans-hzip4-degradation Elevated zinc stimulated human ZIP4 ubiquitination and degradation; a cytoplasmic histidine-rich region was required for this degradation response but dispensable for zinc-induced endocytosis. Condition category: normal nutrient_topic: Zinc research collection; topical membership is not evidence of a direct dietary effect. plain_language: Human ZIP4 has a zinc-triggered disposal response that is separate from removal from the surface. organism: Human protein in cultured cells tissue_or_cell_type: Cellular zinc-uptake machinery experimental_model: Cultured cells expressing human ZIP4 with mutational analysis limitations: Abstract extraction; the region requirement does not mean every histidine acts as an independent sensor. This is zinc exposure, not demonstrated dietary deficiency. exposure: Elevated zinc exposure; detailed concentration and cell lineage not specified in the abstract. cross_nutrient: false [zinc-trans-17202136] A histidine-rich cluster mediates the ubiquitination and degradation of the human zinc transporter, hZIP4, and protects against zinc cytotoxicity. (2007). https://pubmed.ncbi.nlm.nih.gov/17202136/ DOI: 10.1074/jbc.m610552200

cross_nutrient

true

experimental_model

Mouse ZIP14 in Xenopus oocytes

exposure

Radiolabeled ferrous iron uptake with competing zinc.

limitations

Ferrous and ferric iron are distinct. This competition does not establish in vivo dietary interactions; transport properties vary by substrate.

nutrient_topic

Zinc research collection; topical membership is not evidence of a direct dietary effect. · Zinc

organism

Mouse protein in Xenopus laevis oocytes

plain_language

Zinc interfered with ferrous iron entry through ZIP14 in the transport assay.

primary_references

[zinc-trans-21653899] Zip14 is a complex broad-scope metal-ion transporter whose functional properties support roles in the cellular uptake of zinc and nontransferrin-bound iron. (2011). https://pubmed.ncbi.nlm.nih.gov/21653899/ DOI: 10.1152/ajpcell.00479.2010

tissue_or_cell_type

Oocyte plasma membrane

Zinc: transport, enzyme loading, deficiency and nutrient interactions (2026-09-17) · lines 505–516

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Mouse ZIP14 in Xenopus oocytes · source_derived_draft · unverified_draft

### zinc-trans-zip14-zinc-inhibits-iron Zinc inhibited mouse ZIP14-mediated Fe(II) uptake in Xenopus oocytes. Condition category: normal nutrient_topic: Zinc research collection; topical membership is not evidence of a direct dietary effect. plain_language: Zinc interfered with ferrous iron entry through ZIP14 in the transport assay. organism: Mouse protein in Xenopus laevis oocytes tissue_or_cell_type: Oocyte plasma membrane experimental_model: Mouse ZIP14 in Xenopus oocytes limitations: Ferrous and ferric iron are distinct. This competition does not establish in vivo dietary interactions; transport properties vary by substrate. exposure: Radiolabeled ferrous iron uptake with competing zinc. cross_nutrient: true [zinc-trans-21653899] Zip14 is a complex broad-scope metal-ion transporter whose functional properties support roles in the cellular uptake of zinc and nontransferrin-bound iron. (2011). https://pubmed.ncbi.nlm.nih.gov/21653899/ DOI: 10.1152/ajpcell.00479.2010

availability_state

nutrient_deficiency Imported condition classification; unverified.

cross_nutrient

false

experimental_model

Dietary depletion followed by oral gavage and immunolocalization

exposure

Zinc-deficient weanlings for 10 days; 100 micromol ZnCl2/kg oral gavage with time-course localization.

limitations

Acute experimental repletion; the gavage is not a recommended human dose and internalization is distinct from later degradation.

nutrient_topic

Zinc research collection; topical membership is not evidence of a direct dietary effect. · Zinc

organism

Mus musculus

plain_language

After zinc becomes available again, intestinal cells pull ZIP4 away from their surface.

primary_references

[zinc-trans-18020946] Novel zinc-responsive post-transcriptional mechanisms reciprocally regulate expression of the mouse Slc39a4 and Slc39a5 zinc transporters (Zip4 and Zip5). (2007). https://pubmed.ncbi.nlm.nih.gov/18020946/ DOI: 10.1515/bc.2007.149

tissue_or_cell_type

Duodenal enterocytes

trigger_kind

nutrient_deficiency Imported condition classification; unverified.

Zinc: transport, enzyme loading, deficiency and nutrient interactions (2026-09-17) · lines 245–256

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Dietary depletion followed by oral gavage and immunolocalization · source_derived_draft · unverified_draft

### zinc-trans-zip4-repletion-endocytosis Oral zinc repletion caused mouse ZIP4 internalization from enterocyte apical membranes after dietary zinc deficiency. Condition category: nutrient_deficiency nutrient_topic: Zinc research collection; topical membership is not evidence of a direct dietary effect. plain_language: After zinc becomes available again, intestinal cells pull ZIP4 away from their surface. organism: Mus musculus tissue_or_cell_type: Duodenal enterocytes experimental_model: Dietary depletion followed by oral gavage and immunolocalization limitations: Acute experimental repletion; the gavage is not a recommended human dose and internalization is distinct from later degradation. exposure: Zinc-deficient weanlings for 10 days; 100 micromol ZnCl2/kg oral gavage with time-course localization. cross_nutrient: false [zinc-trans-18020946] Novel zinc-responsive post-transcriptional mechanisms reciprocally regulate expression of the mouse Slc39a4 and Slc39a5 zinc transporters (Zip4 and Zip5). (2007). https://pubmed.ncbi.nlm.nih.gov/18020946/ DOI: 10.1515/bc.2007.149

cross_nutrient

true

experimental_model

Rat ZIP8-expressing HEK293T radiotracer assay

exposure

2 micromolar labeled iron with ascorbate and tenfold unlabeled zinc excess.

limitations

The assay contains reduction chemistry and soluble ions; this is not direct evidence for the magnitude of human meal-iron inhibition.

nutrient_topic

Zinc research collection; topical membership is not evidence of a direct dietary effect. · Zinc

organism

Rat protein in human cells

plain_language

Zinc strongly reduced iron entry in this cultured transport system.

primary_references

[zinc-trans-22898811] ZIP8 is an iron and zinc transporter whose cell-surface expression is up-regulated by cellular iron loading. (2012). https://pubmed.ncbi.nlm.nih.gov/22898811/ DOI: 10.1074/jbc.m112.367284

tissue_or_cell_type

HEK293T cells

Zinc: transport, enzyme loading, deficiency and nutrient interactions (2026-09-17) · lines 453–464

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Rat ZIP8-expressing HEK293T radiotracer assay · source_derived_draft · unverified_draft

### zinc-trans-zip8-zinc-inhibits-iron A tenfold molar excess of zinc inhibited iron uptake by more than 90% in rat ZIP8-expressing HEK293T cells under the study conditions. Condition category: normal nutrient_topic: Zinc research collection; topical membership is not evidence of a direct dietary effect. plain_language: Zinc strongly reduced iron entry in this cultured transport system. organism: Rat protein in human cells tissue_or_cell_type: HEK293T cells experimental_model: Rat ZIP8-expressing HEK293T radiotracer assay limitations: The assay contains reduction chemistry and soluble ions; this is not direct evidence for the magnitude of human meal-iron inhibition. exposure: 2 micromolar labeled iron with ascorbate and tenfold unlabeled zinc excess. cross_nutrient: true [zinc-trans-22898811] ZIP8 is an iron and zinc transporter whose cell-surface expression is up-regulated by cellular iron loading. (2012). https://pubmed.ncbi.nlm.nih.gov/22898811/ DOI: 10.1074/jbc.m112.367284

cross_nutrient

calcium ion (signaling_ion); Human zinc transporter ZIP6 / SLC39A6 (upstream_transporter)

evidence_span

{"source_cache": "artifacts/zinc-signaling-sources/21422171.txt", "locator": "Results: zinc availability and TCR signaling; Figure 4e calcium time course", "file_sha256": "4d36b4fdeeff83b602b0532796814981ee45409241fe40fcd8f7bc1da8beff19"}

experimental_model

Primary human T-cell receptor signaling study

exposure

Receptor activation, extracellular zinc availability and ZIP6 suppression comparisons.

limitations

Culture zinc availability and local signals cannot be mapped directly to oral doses or plasma thresholds. Calcium fluorescence tracks the signal rather than proving one specific calcium channel mechanism.

nutrient_topic

Zinc research collection; topical membership is not evidence of a direct dietary effect. · Zinc

organism

Homo sapiens

plain_language

Zinc availability affected how long the calcium signal lasted.

primary_references

[zn-sig-21422171] Regulation of T cell receptor signaling by activation-induced zinc influx. (2011). https://pubmed.ncbi.nlm.nih.gov/21422171/ DOI: 10.1084/jem.20100031

tissue_or_cell_type

CD4 T cells at the receptor-contact region

Zinc: transport, enzyme loading, deficiency and nutrient interactions (2026-09-17) · lines 1055–1067

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Primary human T-cell receptor signaling study · source_derived_draft · unverified_draft

### zn-sig-zinc-calcium-signal Higher extracellular zinc sustained the cytoplasmic calcium signal after T-cell activation; initial calcium rises were similar, then the signals diverged. Condition category: normal nutrient_topic: Zinc research collection; topical membership is not evidence of a direct dietary effect. plain_language: Zinc availability affected how long the calcium signal lasted. organism: Homo sapiens tissue_or_cell_type: CD4 T cells at the receptor-contact region experimental_model: Primary human T-cell receptor signaling study limitations: Culture zinc availability and local signals cannot be mapped directly to oral doses or plasma thresholds. Calcium fluorescence tracks the signal rather than proving one specific calcium channel mechanism. exposure: Receptor activation, extracellular zinc availability and ZIP6 suppression comparisons. cross_nutrient: calcium ion (signaling_ion); Human zinc transporter ZIP6 / SLC39A6 (upstream_transporter) evidence_span: {"source_cache": "artifacts/zinc-signaling-sources/21422171.txt", "locator": "Results: zinc availability and TCR signaling; Figure 4e calcium time course", "file_sha256": "4d36b4fdeeff83b602b0532796814981ee45409241fe40fcd8f7bc1da8beff19"} [zn-sig-21422171] Regulation of T cell receptor signaling by activation-induced zinc influx. (2011). https://pubmed.ncbi.nlm.nih.gov/21422171/ DOI: 10.1084/jem.20100031

cross_nutrient

Human metal-regulatory transcription factor 1 / MTF1 (human_protein); Mouse metal-regulatory transcription factor 1 / Mtf1 (mouse_protein)

evidence_span

{"source_cache": "artifacts/zinc-signaling-sources/9507026-abstract.txt", "locator": "Primary indexed abstract", "file_sha256": "ecd19e16b15909d46328c2c5dcd9f9536422db7bb12b9dfd9d91763fafe164bd"}

experimental_model

Human and mouse cell extracts and recombinant MTF1

exposure

Zinc versus other tested transition metals; DNA-binding assays.

limitations

In-vitro metal specificity does not mean all cellular metal responses are mediated by direct MTF1 binding.

nutrient_topic

Zinc research collection; topical membership is not evidence of a direct dietary effect. · Zinc

organism

Homo sapiens; Mus musculus

plain_language

Zinc acted as a specific input to this metal-responsive transcription factor.

primary_references

[zn-sig-9507026] The DNA binding activity of metal response element-binding transcription factor-1 is activated in vivo and in vitro by zinc, but not by other transition metals. (1998). https://pubmed.ncbi.nlm.nih.gov/9507026/ DOI: 10.1074/jbc.273.12.7127

tissue_or_cell_type

Cell extracts and recombinant protein

Zinc: transport, enzyme loading, deficiency and nutrient interactions (2026-09-17) · lines 873–885

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human and mouse cell extracts and recombinant MTF1 · source_derived_draft · unverified_draft

### zn-sig-zinc-mtf1-binding Recombinant human and mouse MTF1 required added zinc for DNA binding; among the tested transition metals, only zinc activated recombinant MTF1 binding. Condition category: normal nutrient_topic: Zinc research collection; topical membership is not evidence of a direct dietary effect. plain_language: Zinc acted as a specific input to this metal-responsive transcription factor. organism: Homo sapiens; Mus musculus tissue_or_cell_type: Cell extracts and recombinant protein experimental_model: Human and mouse cell extracts and recombinant MTF1 limitations: In-vitro metal specificity does not mean all cellular metal responses are mediated by direct MTF1 binding. exposure: Zinc versus other tested transition metals; DNA-binding assays. cross_nutrient: Human metal-regulatory transcription factor 1 / MTF1 (human_protein); Mouse metal-regulatory transcription factor 1 / Mtf1 (mouse_protein) evidence_span: {"source_cache": "artifacts/zinc-signaling-sources/9507026-abstract.txt", "locator": "Primary indexed abstract", "file_sha256": "ecd19e16b15909d46328c2c5dcd9f9536422db7bb12b9dfd9d91763fafe164bd"} [zn-sig-9507026] The DNA binding activity of metal response element-binding transcription factor-1 is activated in vivo and in vitro by zinc, but not by other transition metals. (1998). https://pubmed.ncbi.nlm.nih.gov/9507026/ DOI: 10.1074/jbc.273.12.7127

cross_nutrient

Human SHP-1 / PTPN6 (affected_protein); Human zinc transporter ZIP6 / SLC39A6 (upstream_transporter)

evidence_span

{"source_cache": "artifacts/zinc-signaling-sources/21422171-abstract.txt", "locator": "Primary indexed abstract", "file_sha256": "e3b0e519eb5c44185655c0195cb81c713f2b005d70a982466e3e041e997fae59"}

experimental_model

Primary human T-cell receptor signaling study

exposure

Receptor activation, extracellular zinc availability and ZIP6 suppression comparisons.

limitations

Culture zinc availability and local signals cannot be mapped directly to oral doses or plasma thresholds. Calcium fluorescence tracks the signal rather than proving one specific calcium channel mechanism.

nutrient_topic

Zinc research collection; topical membership is not evidence of a direct dietary effect. · Zinc

organism

Homo sapiens

plain_language

The zinc signal reduced recruitment of an inhibitory phosphatase.

primary_references

[zn-sig-21422171] Regulation of T cell receptor signaling by activation-induced zinc influx. (2011). https://pubmed.ncbi.nlm.nih.gov/21422171/ DOI: 10.1084/jem.20100031

tissue_or_cell_type

CD4 T cells at the receptor-contact region

Zinc: transport, enzyme loading, deficiency and nutrient interactions (2026-09-17) · lines 1027–1039

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Primary human T-cell receptor signaling study · source_derived_draft · unverified_draft

### zn-sig-zinc-shp1 Increased zinc influx reduced recruitment of SHP-1 to the T-cell receptor activation complex. Condition category: normal nutrient_topic: Zinc research collection; topical membership is not evidence of a direct dietary effect. plain_language: The zinc signal reduced recruitment of an inhibitory phosphatase. organism: Homo sapiens tissue_or_cell_type: CD4 T cells at the receptor-contact region experimental_model: Primary human T-cell receptor signaling study limitations: Culture zinc availability and local signals cannot be mapped directly to oral doses or plasma thresholds. Calcium fluorescence tracks the signal rather than proving one specific calcium channel mechanism. exposure: Receptor activation, extracellular zinc availability and ZIP6 suppression comparisons. cross_nutrient: Human SHP-1 / PTPN6 (affected_protein); Human zinc transporter ZIP6 / SLC39A6 (upstream_transporter) evidence_span: {"source_cache": "artifacts/zinc-signaling-sources/21422171-abstract.txt", "locator": "Primary indexed abstract", "file_sha256": "e3b0e519eb5c44185655c0195cb81c713f2b005d70a982466e3e041e997fae59"} [zn-sig-21422171] Regulation of T cell receptor signaling by activation-induced zinc influx. (2011). https://pubmed.ncbi.nlm.nih.gov/21422171/ DOI: 10.1084/jem.20100031

cross_nutrient

Human ZAP70 (affected_kinase); Human zinc transporter ZIP6 / SLC39A6 (upstream_transporter)

evidence_span

{"source_cache": "artifacts/zinc-signaling-sources/21422171-abstract.txt", "locator": "Primary indexed abstract", "file_sha256": "e3b0e519eb5c44185655c0195cb81c713f2b005d70a982466e3e041e997fae59"}

experimental_model

Primary human T-cell receptor signaling study

exposure

Receptor activation, extracellular zinc availability and ZIP6 suppression comparisons.

limitations

Culture zinc availability and local signals cannot be mapped directly to oral doses or plasma thresholds. Calcium fluorescence tracks the signal rather than proving one specific calcium channel mechanism.

nutrient_topic

Zinc research collection; topical membership is not evidence of a direct dietary effect. · Zinc

organism

Homo sapiens

plain_language

A local zinc signal strengthened this receptor-associated kinase response.

primary_references

[zn-sig-21422171] Regulation of T cell receptor signaling by activation-induced zinc influx. (2011). https://pubmed.ncbi.nlm.nih.gov/21422171/ DOI: 10.1084/jem.20100031

tissue_or_cell_type

CD4 T cells at the receptor-contact region

Zinc: transport, enzyme loading, deficiency and nutrient interactions (2026-09-17) · lines 1041–1053

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Primary human T-cell receptor signaling study · source_derived_draft · unverified_draft

### zn-sig-zinc-zap70 Greater activation-associated zinc influx augmented ZAP70 phosphorylation in the human T-cell study. Condition category: normal nutrient_topic: Zinc research collection; topical membership is not evidence of a direct dietary effect. plain_language: A local zinc signal strengthened this receptor-associated kinase response. organism: Homo sapiens tissue_or_cell_type: CD4 T cells at the receptor-contact region experimental_model: Primary human T-cell receptor signaling study limitations: Culture zinc availability and local signals cannot be mapped directly to oral doses or plasma thresholds. Calcium fluorescence tracks the signal rather than proving one specific calcium channel mechanism. exposure: Receptor activation, extracellular zinc availability and ZIP6 suppression comparisons. cross_nutrient: Human ZAP70 (affected_kinase); Human zinc transporter ZIP6 / SLC39A6 (upstream_transporter) evidence_span: {"source_cache": "artifacts/zinc-signaling-sources/21422171-abstract.txt", "locator": "Primary indexed abstract", "file_sha256": "e3b0e519eb5c44185655c0195cb81c713f2b005d70a982466e3e041e997fae59"} [zn-sig-21422171] Regulation of T cell receptor signaling by activation-induced zinc influx. (2011). https://pubmed.ncbi.nlm.nih.gov/21422171/ DOI: 10.1084/jem.20100031

evidence_span

{"source_cache": "artifacts/citrulline-research/10409685.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "c320fb6f3fd659a2e7df4a8ddd3467a902a07b84380075d429040eaf244ccf6b", "start_char": 0, "end_char": 942, "text_sha256": "c320fb6f3fd659a2e7df4a8ddd3467a902a07b84380075d429040eaf244ccf6b"}

experimental_model

Crystal structures of zinc-free and zinc-bound heme domains

exposure

Zinc-free versus zinc-tetrathiolate-containing structures

limitations

Direct structure is NOS2; similarity to NOS3 does not justify silently treating the proteins as identical.

nutrient_topic

Citrulline research collection; topical membership is not evidence of a direct dietary effect. · L-Citrulline

organism

Human NOS2

plain_language

The structural metal and the pterin-binding region are connected.

primary_references

[citrulline-p10409685] Crystal structures of zinc-free and -bound heme domain of human inducible nitric-oxide synthase. Implications for dimer stability and comparison with endothelial nitric-oxide synthase. (1999). https://pubmed.ncbi.nlm.nih.gov/10409685/ DOI: 10.1074/jbc.274.30.21276

tissue_or_cell_type

NOS dimer interface and pterin-binding region

Citrulline: arginine recycling, nitrogen disposal and nutrient connections (2026-09-17) · lines 606–617

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Crystal structures of zinc-free and zinc-bound heme domains · source_derived_draft · unverified_draft

### citrulline-inos-zinc-interface The NOS2 zinc-tetrathiolate center supported intersubunit contacts and integrity of the BH4-binding site. Condition category: normal nutrient_topic: Citrulline research collection; topical membership is not evidence of a direct dietary effect. plain_language: The structural metal and the pterin-binding region are connected. organism: Human NOS2 tissue_or_cell_type: NOS dimer interface and pterin-binding region experimental_model: Crystal structures of zinc-free and zinc-bound heme domains limitations: Direct structure is NOS2; similarity to NOS3 does not justify silently treating the proteins as identical. exposure: Zinc-free versus zinc-tetrathiolate-containing structures evidence_span: {"source_cache": "artifacts/citrulline-research/10409685.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "c320fb6f3fd659a2e7df4a8ddd3467a902a07b84380075d429040eaf244ccf6b", "start_char": 0, "end_char": 942, "text_sha256": "c320fb6f3fd659a2e7df4a8ddd3467a902a07b84380075d429040eaf244ccf6b"} [citrulline-p10409685] Crystal structures of zinc-free and -bound heme domain of human inducible nitric-oxide synthase. Implications for dimer stability and comparison with endothelial nitric-oxide synthase. (1999). https://pubmed.ncbi.nlm.nih.gov/10409685/ DOI: 10.1074/jbc.274.30.21276

evidence_span

{"source_cache": "artifacts/citrulline-research/10608822.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "1600b193cc63f30b204285729710bb81f34bc2918a8ca7f97aa97bc4acd998fd", "start_char": 0, "end_char": 2100, "text_sha256": "1600b193cc63f30b204285729710bb81f34bc2918a8ca7f97aa97bc4acd998fd"}

experimental_model

Purified recombinant enzyme activity and cofactor analysis

exposure

Arginine substrate; BH4, FAD, FMN, heme, iron and zinc measurements

limitations

Biochemical cofactor findings do not show that extra dietary cofactors increase NO in healthy people.

nutrient_topic

Citrulline research collection; topical membership is not evidence of a direct dietary effect. · L-Citrulline

organism

Human NOS3 expressed in yeast

plain_language

Zinc is a structural component measured in the enzyme, not an automatic reason for high-dose zinc.

primary_references

[citrulline-p10608822] Characterization of recombinant human endothelial nitric-oxide synthase purified from the yeast Pichia pastoris. (1999). https://pubmed.ncbi.nlm.nih.gov/10608822/ DOI: 10.1074/jbc.274.53.37658

tissue_or_cell_type

Endothelial NOS enzyme preparation

Citrulline: arginine recycling, nitrogen disposal and nutrient connections (2026-09-17) · lines 567–578

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purified recombinant enzyme activity and cofactor analysis · source_derived_draft · unverified_draft

### citrulline-nos-zinc Metal analysis detected approximately 0.43 zinc equivalents per human eNOS subunit. Condition category: normal nutrient_topic: Citrulline research collection; topical membership is not evidence of a direct dietary effect. plain_language: Zinc is a structural component measured in the enzyme, not an automatic reason for high-dose zinc. organism: Human NOS3 expressed in yeast tissue_or_cell_type: Endothelial NOS enzyme preparation experimental_model: Purified recombinant enzyme activity and cofactor analysis limitations: Biochemical cofactor findings do not show that extra dietary cofactors increase NO in healthy people. exposure: Arginine substrate; BH4, FAD, FMN, heme, iron and zinc measurements evidence_span: {"source_cache": "artifacts/citrulline-research/10608822.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "1600b193cc63f30b204285729710bb81f34bc2918a8ca7f97aa97bc4acd998fd", "start_char": 0, "end_char": 2100, "text_sha256": "1600b193cc63f30b204285729710bb81f34bc2918a8ca7f97aa97bc4acd998fd"} [citrulline-p10608822] Characterization of recombinant human endothelial nitric-oxide synthase purified from the yeast Pichia pastoris. (1999). https://pubmed.ncbi.nlm.nih.gov/10608822/ DOI: 10.1074/jbc.274.53.37658

cross_nutrient

Zn inhibition of a Mn enzyme was structurally measured in purified protein; no dietary threshold.

experimental_model

Metal-substitution crystallography and kinetics of purified human ARG1

exposure

Non-native metal reconstitution or added zinc

limitations

Primary experimental scope only; no human dietary threshold, clinical treatment rule, or universal metal substitution is established.

nutrient_topic

Manganese research collection; topical membership is not evidence of a direct dietary effect. · Manganese

organism

Homo sapiens protein

plain_language

Zinc can inhibit purified manganese-loaded ARG1 at an additional site.

primary_references

[mn-enz-23061982] Structure and function of non-native metal clusters in human arginase I. (2012). https://pubmed.ncbi.nlm.nih.gov/23061982/ DOI: 10.1021/bi301145n

tissue_or_cell_type

Purified enzyme

Manganese: enzyme cofactors, glycosylation, transport and nutrient interactions (2026-09-17) · lines 559–570

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Metal-substitution crystallography and kinetics of purified human ARG1 · source_derived_draft · unverified_draft

### mn-enz-arg1-zinc-inhibition Added Zn(II) bound the H141/E277 region of manganese-loaded human ARG1, revealing a structural basis for zinc inhibition. Condition category: normal nutrient_topic: Manganese research collection; topical membership is not evidence of a direct dietary effect. plain_language: Zinc can inhibit purified manganese-loaded ARG1 at an additional site. organism: Homo sapiens protein tissue_or_cell_type: Purified enzyme experimental_model: Metal-substitution crystallography and kinetics of purified human ARG1 limitations: Primary experimental scope only; no human dietary threshold, clinical treatment rule, or universal metal substitution is established. exposure: Non-native metal reconstitution or added zinc cross_nutrient: Zn inhibition of a Mn enzyme was structurally measured in purified protein; no dietary threshold. [mn-enz-23061982] Structure and function of non-native metal clusters in human arginase I. (2012). https://pubmed.ncbi.nlm.nih.gov/23061982/ DOI: 10.1021/bi301145n

cross_nutrient

true

experimental_model

Mouse ZIP14 in RNA-injected Xenopus laevis oocytes

exposure

2 micromolar radiolabeled Mn(II) with candidate inhibitor metal at 20 micromolar and 1 mM L-ascorbic acid; Figure 9B.

limitations

A tenfold molar competitor in a heterologous system is not a dietary competition threshold.

nutrient_topic

Manganese research collection; topical membership is not evidence of a direct dietary effect. · Manganese

organism

Mouse protein in Xenopus laevis oocytes

plain_language

Zn(II) competed with manganese entry through ZIP14 in this assay.

primary_references

[mn-trans-21653899] Zip14 is a complex broad-scope metal-ion transporter whose functional properties support roles in the cellular uptake of zinc and nontransferrin-bound iron. (2011). https://pubmed.ncbi.nlm.nih.gov/21653899/ DOI: 10.1152/ajpcell.00479.2010

tissue_or_cell_type

Oocyte plasma membrane

Manganese: enzyme cofactors, glycosylation, transport and nutrient interactions (2026-09-17) · lines 318–329

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Mouse ZIP14 in RNA-injected Xenopus laevis oocytes · source_derived_draft · unverified_draft

### mn-trans-zip14-zn-inhibits-mn Zn(II) inhibited mouse ZIP14-mediated Mn(II) uptake in Xenopus oocytes under the tested competition conditions. Condition category: normal nutrient_topic: Manganese research collection; topical membership is not evidence of a direct dietary effect. plain_language: Zn(II) competed with manganese entry through ZIP14 in this assay. organism: Mouse protein in Xenopus laevis oocytes tissue_or_cell_type: Oocyte plasma membrane experimental_model: Mouse ZIP14 in RNA-injected Xenopus laevis oocytes limitations: A tenfold molar competitor in a heterologous system is not a dietary competition threshold. exposure: 2 micromolar radiolabeled Mn(II) with candidate inhibitor metal at 20 micromolar and 1 mM L-ascorbic acid; Figure 9B. cross_nutrient: true [mn-trans-21653899] Zip14 is a complex broad-scope metal-ion transporter whose functional properties support roles in the cellular uptake of zinc and nontransferrin-bound iron. (2011). https://pubmed.ncbi.nlm.nih.gov/21653899/ DOI: 10.1152/ajpcell.00479.2010

evidence_span

{"source_cache": "artifacts/glutathione-research/9218781.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "e00867a8f693a2a0e6506a87d162a52ce4aa75ac846c7b0495dcf6ad7c9330e1", "start_char": 0, "end_char": 1251, "text_sha256": "e00867a8f693a2a0e6506a87d162a52ce4aa75ac846c7b0495dcf6ad7c9330e1"}

experimental_model

Human GLO1 crystal structure

exposure

S-benzyl-GSH complex

limitations

The essential zinc site is biochemical evidence; neither zinc nor GSH supplementation was tested.

nutrient_topic

Glutathione research collection; topical membership is not evidence of a direct dietary effect. · GSH

organism

Human

plain_language

Zinc-dependent enzyme machinery connects to this glutathione pathway.

primary_references

[glutathione-p9218781] Crystal structure of human glyoxalase I--evidence for gene duplication and 3D domain swapping. (1997). https://pubmed.ncbi.nlm.nih.gov/9218781/ DOI: 10.1093/emboj/16.12.3386

tissue_or_cell_type

Purified dimeric enzyme

Glutathione: metabolism, signaling and nutrient connections (2026-09-17) · lines 892–903

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human GLO1 crystal structure · source_derived_draft · unverified_draft

### glutathione-glo1-zinc The human GLO1 active site contained an essential zinc ion with ligands contributed across the dimer interface. Condition category: normal nutrient_topic: Glutathione research collection; topical membership is not evidence of a direct dietary effect. plain_language: Zinc-dependent enzyme machinery connects to this glutathione pathway. organism: Human tissue_or_cell_type: Purified dimeric enzyme experimental_model: Human GLO1 crystal structure limitations: The essential zinc site is biochemical evidence; neither zinc nor GSH supplementation was tested. exposure: S-benzyl-GSH complex evidence_span: {"source_cache": "artifacts/glutathione-research/9218781.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "e00867a8f693a2a0e6506a87d162a52ce4aa75ac846c7b0495dcf6ad7c9330e1", "start_char": 0, "end_char": 1251, "text_sha256": "e00867a8f693a2a0e6506a87d162a52ce4aa75ac846c7b0495dcf6ad7c9330e1"} [glutathione-p9218781] Crystal structure of human glyoxalase I--evidence for gene duplication and 3D domain swapping. (1997). https://pubmed.ncbi.nlm.nih.gov/9218781/ DOI: 10.1093/emboj/16.12.3386

cross_nutrient

Iron and zinc are not interchangeable RPE65 cofactors in the tested preparation.

experimental_model

Metal-rescue comparison

limitations

Does not test systemic zinc status or other zinc-dependent visual functions.

nutrient_topic

Vitamin A research collection; topical membership is not evidence of a direct dietary effect. · Vitamin A

organism

Bos taurus

plain_language

Zinc could not replace iron in this enzyme assay.

primary_references

[moiseyev-2006] RPE65 is an iron(II)-dependent isomerohydrolase in the retinoid visual cycle (2006). https://pubmed.ncbi.nlm.nih.gov/16319067/ DOI: 10.1074/jbc.M508903200

tissue_or_cell_type

RPE microsomes

Vitamin A: forms, mechanisms, deficiency and excess (2026-09-17) · lines 689–699

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Metal-rescue comparison · source_derived_draft · unverified_draft

### a-vision-rpe65-zinc-not-substitute ZnCl2 did not restore isomerohydrolase activity after metal chelation in the bovine RPE assay, whereas FeSO4 did. Condition category: normal nutrient_topic: Vitamin A research collection; topical membership is not evidence of a direct dietary effect. plain_language: Zinc could not replace iron in this enzyme assay. organism: Bos taurus tissue_or_cell_type: RPE microsomes experimental_model: Metal-rescue comparison limitations: Does not test systemic zinc status or other zinc-dependent visual functions. cross_nutrient: Iron and zinc are not interchangeable RPE65 cofactors in the tested preparation. [moiseyev-2006] RPE65 is an iron(II)-dependent isomerohydrolase in the retinoid visual cycle (2006). https://pubmed.ncbi.nlm.nih.gov/16319067/ DOI: 10.1074/jbc.M508903200

evidence_span

{"source_cache": "artifacts/inositol-research/8110188.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "c05bb5272b443bde4f99d4af375d31988a4812150450d6c4462059a59aa8a09e", "start_char": 0, "end_char": 940, "text_sha256": "c05bb5272b443bde4f99d4af375d31988a4812150450d6c4462059a59aa8a09e"}

experimental_model

Purification and kinetics of placental PI synthase

exposure

Substrate and ion titrations

limitations

Assay optima and inhibitory concentrations are not dietary advice or proof of in vivo nutrient competition.

nutrient_topic

Inositol research collection; topical membership is not evidence of a direct dietary effect. · Inositol (stereoisomer family)

organism

Homo sapiens

plain_language

The same mineral can have different effects on different enzymes.

primary_references

[ino-p8110188] Purification and characterization of phosphatidylinositol synthase from human placenta. (1994). https://pubmed.ncbi.nlm.nih.gov/8110188/ DOI: 10.1042/bj2970517

tissue_or_cell_type

Placental microsomal enzyme

Inositol: synthesis, signaling, mineral interactions and conditional deficiency (2026-09-17) · lines 548–559

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purification and kinetics of placental PI synthase · source_derived_draft · unverified_draft

### ino-cdipt-zinc Zn2+ inhibited purified human placental PI synthase in the tested conditions. Condition category: normal nutrient_topic: Inositol research collection; topical membership is not evidence of a direct dietary effect. plain_language: The same mineral can have different effects on different enzymes. organism: Homo sapiens tissue_or_cell_type: Placental microsomal enzyme experimental_model: Purification and kinetics of placental PI synthase limitations: Assay optima and inhibitory concentrations are not dietary advice or proof of in vivo nutrient competition. exposure: Substrate and ion titrations evidence_span: {"source_cache": "artifacts/inositol-research/8110188.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "c05bb5272b443bde4f99d4af375d31988a4812150450d6c4462059a59aa8a09e", "start_char": 0, "end_char": 940, "text_sha256": "c05bb5272b443bde4f99d4af375d31988a4812150450d6c4462059a59aa8a09e"} [ino-p8110188] Purification and characterization of phosphatidylinositol synthase from human placenta. (1994). https://pubmed.ncbi.nlm.nih.gov/8110188/ DOI: 10.1042/bj2970517

evidence_span

{"source_cache": "artifacts/inositol-research/28450399.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "a7b18249458f30cd8f1147710856a6bf7f87ca1b045e97290a04ce7c7cbfbb78", "start_char": 0, "end_char": 1555, "text_sha256": "a7b18249458f30cd8f1147710856a6bf7f87ca1b045e97290a04ce7c7cbfbb78"}

experimental_model

Mouse enzyme crystallography and functional analysis

exposure

Structure with substrates and zinc-site characterization

limitations

Mouse protein; intracellular InsP6 synthesis is distinct from intestinal exposure to dietary phytate.

nutrient_topic

Inositol research collection; topical membership is not evidence of a direct dietary effect. · Inositol (stereoisomer family)

organism

Mus musculus protein

plain_language

Zinc is part of the architecture of this mouse inositol-phosphate enzyme; dietary benefit was not tested.

primary_references

[ino-p28450399] The crystal structure of mammalian inositol 1,3,4,5,6-pentakisphosphate 2-kinase reveals a new zinc-binding site and key features for protein function. (2017). https://pubmed.ncbi.nlm.nih.gov/28450399/ DOI: 10.1074/jbc.m117.780395

tissue_or_cell_type

Purified Ippk

Inositol: synthesis, signaling, mineral interactions and conditional deficiency (2026-09-17) · lines 756–767

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Mouse enzyme crystallography and functional analysis · source_derived_draft · unverified_draft

### ino-ippk-zinc The mouse Ippk structure identified a zinc-binding site involved in maintaining the enzyme’s structural organization. Condition category: normal nutrient_topic: Inositol research collection; topical membership is not evidence of a direct dietary effect. plain_language: Zinc is part of the architecture of this mouse inositol-phosphate enzyme; dietary benefit was not tested. organism: Mus musculus protein tissue_or_cell_type: Purified Ippk experimental_model: Mouse enzyme crystallography and functional analysis limitations: Mouse protein; intracellular InsP6 synthesis is distinct from intestinal exposure to dietary phytate. exposure: Structure with substrates and zinc-site characterization evidence_span: {"source_cache": "artifacts/inositol-research/28450399.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "a7b18249458f30cd8f1147710856a6bf7f87ca1b045e97290a04ce7c7cbfbb78", "start_char": 0, "end_char": 1555, "text_sha256": "a7b18249458f30cd8f1147710856a6bf7f87ca1b045e97290a04ce7c7cbfbb78"} [ino-p28450399] The crystal structure of mammalian inositol 1,3,4,5,6-pentakisphosphate 2-kinase reveals a new zinc-binding site and key features for protein function. (2017). https://pubmed.ncbi.nlm.nih.gov/28450399/ DOI: 10.1074/jbc.m117.780395

evidence_span

{"source_cache": "artifacts/inositol-research/15024000.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "5ab3a8eda77989c3e4a681b4a971fb7e969c285d3e5c8e41bc31713a7f88c9ac", "start_char": 0, "end_char": 1427, "text_sha256": "5ab3a8eda77989c3e4a681b4a971fb7e969c285d3e5c8e41bc31713a7f88c9ac"}

experimental_model

Recombinant human enzyme and complementation of yeast ino1 deletion

exposure

Substrate, NAD+, cation and valproate experiments

limitations

Purified-enzyme and yeast results do not establish supplement effects or a human dietary deficiency threshold.

nutrient_topic

Inositol research collection; topical membership is not evidence of a direct dietary effect. · Inositol (stereoisomer family)

organism

Human protein expressed in bacteria and yeast

plain_language

A mineral can inhibit one enzyme even while supporting many other functions.

primary_references

[ino-p15024000] Human 1-D-myo-inositol-3-phosphate synthase is functional in yeast. (2004). https://pubmed.ncbi.nlm.nih.gov/15024000/ DOI: 10.1074/jbc.m312078200

tissue_or_cell_type

Purified enzyme; yeast cultures

Inositol: synthesis, signaling, mineral interactions and conditional deficiency (2026-09-17) · lines 210–221

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Recombinant human enzyme and complementation of yeast ino1 deletion · source_derived_draft · unverified_draft

### ino-isyna-zinc Zn2+ strongly inhibited purified human ISYNA1 in the cation comparison. Condition category: normal nutrient_topic: Inositol research collection; topical membership is not evidence of a direct dietary effect. plain_language: A mineral can inhibit one enzyme even while supporting many other functions. organism: Human protein expressed in bacteria and yeast tissue_or_cell_type: Purified enzyme; yeast cultures experimental_model: Recombinant human enzyme and complementation of yeast ino1 deletion limitations: Purified-enzyme and yeast results do not establish supplement effects or a human dietary deficiency threshold. exposure: Substrate, NAD+, cation and valproate experiments evidence_span: {"source_cache": "artifacts/inositol-research/15024000.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "5ab3a8eda77989c3e4a681b4a971fb7e969c285d3e5c8e41bc31713a7f88c9ac", "start_char": 0, "end_char": 1427, "text_sha256": "5ab3a8eda77989c3e4a681b4a971fb7e969c285d3e5c8e41bc31713a7f88c9ac"} [ino-p15024000] Human 1-D-myo-inositol-3-phosphate synthase is functional in yeast. (2004). https://pubmed.ncbi.nlm.nih.gov/15024000/ DOI: 10.1074/jbc.m312078200

cross_nutrient

Zinc-folate: molecular catalytic-site dependency; dietary zinc deficiency was not tested.

experimental_model

Recombinant human GCPII crystallography

exposure

Glutamate, phosphate and inhibitor-bound structures

limitations

Structural cofactor evidence does not establish zinc intake thresholds.

nutrient_topic

Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. · Folate (vitamin B9)

organism

Homo sapiens

plain_language

The folate-processing enzyme contains a two-zinc catalytic site.

primary_references

[mesters2006] Structure of glutamate carboxypeptidase II, a drug target in neuronal damage and prostate cancer (2006). https://pubmed.ncbi.nlm.nih.gov/16467855/ DOI: 10.1038/sj.emboj.7600969

tissue_or_cell_type

Purified recombinant protein

Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 118–129

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Recombinant human GCPII crystallography · source_derived_draft · unverified_draft

### folate-gcpii-zinc-catalytic-center Human GCPII crystal structures resolved two zinc ions at the catalytic center, bridged by water or hydroxide and Asp387. Condition category: normal nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: The folate-processing enzyme contains a two-zinc catalytic site. organism: Homo sapiens tissue_or_cell_type: Purified recombinant protein experimental_model: Recombinant human GCPII crystallography limitations: Structural cofactor evidence does not establish zinc intake thresholds. exposure: Glutamate, phosphate and inhibitor-bound structures cross_nutrient: Zinc-folate: molecular catalytic-site dependency; dietary zinc deficiency was not tested. [mesters2006] Structure of glutamate carboxypeptidase II, a drug target in neuronal damage and prostate cancer (2006). https://pubmed.ncbi.nlm.nih.gov/16467855/ DOI: 10.1038/sj.emboj.7600969

cross_nutrient

Zinc supports parallel remethylation.

experimental_model

Recombinant human BHMT and human liver-derived BHMT.

limitations

Demetallation is not dietary zinc deficiency.

nutrient_topic

Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. · Folate (vitamin B9)

organism

Homo sapiens

plain_language

The betaine route requires a zinc-containing enzyme.

primary_references

[millian-1998] Human betaine-homocysteine methyltransferase is a zinc metalloenzyme (1998). https://pubmed.ncbi.nlm.nih.gov/9681996/ DOI: 10.1006/abbi.1998.0757

tissue_or_cell_type

Purified protein

Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 622–632

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Recombinant human BHMT and human liver-derived BHMT. · source_derived_draft · unverified_draft

### folate-methyl-bhmt-zinc Chemical zinc removal inactivated human BHMT; zinc reconstitution restored its activity and metal content. Condition category: normal nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: The betaine route requires a zinc-containing enzyme. organism: Homo sapiens tissue_or_cell_type: Purified protein experimental_model: Recombinant human BHMT and human liver-derived BHMT. limitations: Demetallation is not dietary zinc deficiency. cross_nutrient: Zinc supports parallel remethylation. [millian-1998] Human betaine-homocysteine methyltransferase is a zinc metalloenzyme (1998). https://pubmed.ncbi.nlm.nih.gov/9681996/ DOI: 10.1006/abbi.1998.0757

evidence_access

Primary full text, metal incorporation and kinetics

experimental_model

Human enzyme expression, metal analysis, kinetics and crystallography.

limitations

Copper-substituted protein was used for spectroscopy; this does not make copper its preferred physiological cofactor.

nutrient_topic

Tryptophan collection; molecular form, preparation, species, exposure and manipulation remain explicit. · L-Tryptophan

plain_language

The enzyme needs properly incorporated zinc, not simply zinc added later.

primary_references

Human α-amino-β-carboxymuconate-ε-semialdehyde decarboxylase (ACMSD): a structural and mechanistic unveiling. · 2015 · https://pubmed.ncbi.nlm.nih.gov/25392945/ · DOI 10.1002/prot.24722

Tryptophan: transport, protein synthesis, neuroactive metabolites, NAD and microbial pathways (2026-09-19) · lines 218–224

AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Human enzyme expression, metal analysis, kinetics and crystallography. · source_derived_draft · unverified_draft

## tryptophan-acmsd-zinc The enzyme needs properly incorporated zinc, not simply zinc added later. Recombinant human ACMSD activity increased with incorporated zinc; adding free metal to purified enzyme did not restore or increase activity. Model: Human enzyme expression, metal analysis, kinetics and crystallography. Limitations: Copper-substituted protein was used for spectroscopy; this does not make copper its preferred physiological cofactor. Evidence access: Primary full text, metal incorporation and kinetics Human α-amino-β-carboxymuconate-ε-semialdehyde decarboxylase (ACMSD): a structural and mechanistic unveiling. · 2015 · https://pubmed.ncbi.nlm.nih.gov/25392945/ · DOI 10.1002/prot.24722

cross_nutrient

A protein associated with Mg homeostasis regulates a Zn-permeable channel in culture; nutritional co-dependence was not tested.

evidence-system

Coexpression, TRPM7 knockout and pore-inactivation tests

experimental_model

Coexpression, TRPM7 knockout and pore-inactivation tests

limitations

Zinc is a divalent-flux reporter here; this does not establish CNNM2 as a magnesium pore or dietary Mg-to-Zn dependence.

nutrient_topic

Magnesium research collection; topical membership is not evidence of a direct dietary effect. · Magnesium

organism

Human proteins and human-derived cells

plain_language

CNNM2 can regulate entry through a separate channel whose pore carries the ion.

primary_references

[bai-2021-cnnm-trpm7] CNNM proteins selectively bind to the TRPM7 channel to stimulate divalent cation entry into cells (2021). https://pmc.ncbi.nlm.nih.gov/articles/PMC8726484/ DOI: 10.1371/journal.pbio.3001496

tissue

HEK293-family cells; supporting HAP1 cells

tissue_or_cell_type

HEK293-family cells; supporting HAP1 cells

Magnesium: cross-nutrient mechanisms and deficiency (2026-09-17) · lines 1151–1163

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Coexpression, TRPM7 knockout and pore-inactivation tests · source_derived_draft · unverified_draft

### cnnm2-stimulates-trpm7-zinc-influx CNNM2 coexpression increased TRPM7-dependent zinc influx, and the TRPM7 E1047K pore mutant prevented this increase. Condition category: normal nutrient_topic: Magnesium research collection; topical membership is not evidence of a direct dietary effect. plain_language: CNNM2 can regulate entry through a separate channel whose pore carries the ion. organism: Human proteins and human-derived cells tissue_or_cell_type: HEK293-family cells; supporting HAP1 cells experimental_model: Coexpression, TRPM7 knockout and pore-inactivation tests limitations: Zinc is a divalent-flux reporter here; this does not establish CNNM2 as a magnesium pore or dietary Mg-to-Zn dependence. cross_nutrient: A protein associated with Mg homeostasis regulates a Zn-permeable channel in culture; nutritional co-dependence was not tested. evidence-system: Coexpression, TRPM7 knockout and pore-inactivation tests tissue: HEK293-family cells; supporting HAP1 cells [bai-2021-cnnm-trpm7] CNNM proteins selectively bind to the TRPM7 channel to stimulate divalent cation entry into cells (2021). https://pmc.ncbi.nlm.nih.gov/articles/PMC8726484/ DOI: 10.1371/journal.pbio.3001496

availability_state

machinery_impairment Imported condition classification; unverified.

cross_nutrient

Shared intestinal TRPM7 machinery links zinc and magnesium availability; Mg deficiency as the cause of Zn deficiency was not demonstrated.

evidence-system

Conditional intestinal knockout and mineral phenotyping

experimental_model

Conditional intestinal knockout and mineral phenotyping

limitations

Not evidence that magnesium supplementation universally increases zinc absorption.

nutrient_topic

Magnesium research collection; topical membership is not evidence of a direct dietary effect. · Magnesium

organism

Mouse

plain_language

A single epithelial machinery defect depleted zinc along with magnesium.

primary_references

[mittermeier-2019-trpm7] TRPM7 is the central gatekeeper of intestinal mineral absorption essential for postnatal survival (2019). https://pubmed.ncbi.nlm.nih.gov/30770447/ DOI: 10.1073/pnas.1810633116

tissue

Intestine; serum

tissue_or_cell_type

Intestine; serum

trigger_kind

machinery_impairment Imported condition classification; unverified.

Magnesium: cross-nutrient mechanisms and deficiency (2026-09-17) · lines 1002–1014

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Conditional intestinal knockout and mineral phenotyping · source_derived_draft · unverified_draft

### intestinal-trpm7-loss-zinc Intestinal Trpm7 deletion reduced circulating zinc in early postnatal mice. Condition category: machinery_impairment nutrient_topic: Magnesium research collection; topical membership is not evidence of a direct dietary effect. plain_language: A single epithelial machinery defect depleted zinc along with magnesium. organism: Mouse tissue_or_cell_type: Intestine; serum experimental_model: Conditional intestinal knockout and mineral phenotyping limitations: Not evidence that magnesium supplementation universally increases zinc absorption. cross_nutrient: Shared intestinal TRPM7 machinery links zinc and magnesium availability; Mg deficiency as the cause of Zn deficiency was not demonstrated. evidence-system: Conditional intestinal knockout and mineral phenotyping tissue: Intestine; serum [mittermeier-2019-trpm7] TRPM7 is the central gatekeeper of intestinal mineral absorption essential for postnatal survival (2019). https://pubmed.ncbi.nlm.nih.gov/30770447/ DOI: 10.1073/pnas.1810633116

cross_nutrient

Calcium/Mg substitution at one enzyme site, not whole-body interchangeability.

experimental_model

Recombinant enzyme comparison. Activity was measured using artificial pNPP substrate.

limitations

Site-specific substitution is not evidence that dietary calcium replaces magnesium requirements. This assay does not quantify physiological pyrophosphate turnover or mineral deposition.

nutrient_topic

Magnesium research collection; topical membership is not evidence of a direct dietary effect. · Magnesium

organism

Homo sapiens

plain_language

Calcium can occupy this magnesium site, but gives a different enzyme response.

primary_references

[mg-hoylaerts2015] Functional significance of calcium binding to tissue-nonspecific alkaline phosphatase (2015). https://pubmed.ncbi.nlm.nih.gov/25775211/ DOI: 10.1371/journal.pone.0119874

tissue_or_cell_type

Recombinant human TNAP; cell-free p-nitrophenyl phosphate (pNPP) hydrolysis assay

Magnesium: cross-nutrient mechanisms and deficiency (2026-09-17) · lines 1479–1489

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Recombinant enzyme comparison. Activity was measured using artificial pNPP substrate. · source_derived_draft · unverified_draft

### mg-alpl-calcium-partial-substitution Calcium at TNAP site M3 supported about 40% of the activity of Mg/Zn-TNAP at pH 7.4 and 9.8. Condition category: normal nutrient_topic: Magnesium research collection; topical membership is not evidence of a direct dietary effect. plain_language: Calcium can occupy this magnesium site, but gives a different enzyme response. organism: Homo sapiens tissue_or_cell_type: Recombinant human TNAP; cell-free p-nitrophenyl phosphate (pNPP) hydrolysis assay experimental_model: Recombinant enzyme comparison. Activity was measured using artificial pNPP substrate. limitations: Site-specific substitution is not evidence that dietary calcium replaces magnesium requirements. This assay does not quantify physiological pyrophosphate turnover or mineral deposition. cross_nutrient: Calcium/Mg substitution at one enzyme site, not whole-body interchangeability. [mg-hoylaerts2015] Functional significance of calcium binding to tissue-nonspecific alkaline phosphatase (2015). https://pubmed.ncbi.nlm.nih.gov/25775211/ DOI: 10.1371/journal.pone.0119874

cross_nutrient

Calcium/Zn/Mg interaction depends on site occupancy and local conditions.

experimental_model

Purified TNAP concentration/pH experiment. Activity was measured using artificial pNPP substrate.

limitations

Local experimental concentrations cannot be converted to dietary dose cutoffs. This assay does not quantify physiological pyrophosphate turnover or mineral deposition.

nutrient_topic

Magnesium research collection; topical membership is not evidence of a direct dietary effect. · Magnesium

organism

Homo sapiens

plain_language

The same calcium ion can activate one site and interfere with another.

primary_references

[mg-hoylaerts2015] Functional significance of calcium binding to tissue-nonspecific alkaline phosphatase (2015). https://pubmed.ncbi.nlm.nih.gov/25775211/ DOI: 10.1371/journal.pone.0119874

tissue_or_cell_type

Recombinant human TNAP; cell-free p-nitrophenyl phosphate (pNPP) hydrolysis assay

Magnesium: cross-nutrient mechanisms and deficiency (2026-09-17) · lines 1491–1501

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purified TNAP concentration/pH experiment. Activity was measured using artificial pNPP substrate. · source_derived_draft · unverified_draft

### mg-alpl-high-calcium-zinc-displacement Very high calcium displaced or competed with Zn at TNAP M1/M2 sites and reduced activity; concentrations depended on pH. Condition category: normal nutrient_topic: Magnesium research collection; topical membership is not evidence of a direct dietary effect. plain_language: The same calcium ion can activate one site and interfere with another. organism: Homo sapiens tissue_or_cell_type: Recombinant human TNAP; cell-free p-nitrophenyl phosphate (pNPP) hydrolysis assay experimental_model: Purified TNAP concentration/pH experiment. Activity was measured using artificial pNPP substrate. limitations: Local experimental concentrations cannot be converted to dietary dose cutoffs. This assay does not quantify physiological pyrophosphate turnover or mineral deposition. cross_nutrient: Calcium/Zn/Mg interaction depends on site occupancy and local conditions. [mg-hoylaerts2015] Functional significance of calcium binding to tissue-nonspecific alkaline phosphatase (2015). https://pubmed.ncbi.nlm.nih.gov/25775211/ DOI: 10.1371/journal.pone.0119874

cross_nutrient

Zinc -> magnesium availability; calcium intake recorded as context.

experimental_model

Adult men; three dietary calcium strata.

exposure

142 mg Zn/day as sulfate; calcium 230, 500 or 800 mg/day. Only the 500-mg stratum individually significant; pooled groups significant.

limitations

142 mg zinc/day is a high experimental exposure; ordinary food zinc effects and a shared transporter were not established.

nutrient_topic

Magnesium research collection; topical membership is not evidence of a direct dietary effect. · Magnesium

organism

Homo sapiens

plain_language

Large zinc exposure can interfere with magnesium uptake.

primary_references

[mg-spencer1994] Inhibitory effects of zinc on magnesium balance and magnesium absorption in man (1994). https://pubmed.ncbi.nlm.nih.gov/7836627/ DOI: 10.1080/07315724.1994.10718438

tissue_or_cell_type

Human intestinal absorption and metabolic balance

Magnesium: cross-nutrient mechanisms and deficiency (2026-09-17) · lines 1577–1588

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Adult men; three dietary calcium strata. · source_derived_draft · unverified_draft

### mg-high-zinc-lowers-absorption High-dose supplemental zinc reduced measured Mg absorption in the pooled metabolic-balance groups. Condition category: normal nutrient_topic: Magnesium research collection; topical membership is not evidence of a direct dietary effect. plain_language: Large zinc exposure can interfere with magnesium uptake. organism: Homo sapiens tissue_or_cell_type: Human intestinal absorption and metabolic balance experimental_model: Adult men; three dietary calcium strata. limitations: 142 mg zinc/day is a high experimental exposure; ordinary food zinc effects and a shared transporter were not established. cross_nutrient: Zinc -> magnesium availability; calcium intake recorded as context. exposure: 142 mg Zn/day as sulfate; calcium 230, 500 or 800 mg/day. Only the 500-mg stratum individually significant; pooled groups significant. [mg-spencer1994] Inhibitory effects of zinc on magnesium balance and magnesium absorption in man (1994). https://pubmed.ncbi.nlm.nih.gov/7836627/ DOI: 10.1080/07315724.1994.10718438

cross_nutrient

Zinc/Mg intake balance; exposure-dependent.

experimental_model

Same adult metabolic-balance experiment.

limitations

Not a molecular transporter competition assay or evidence that every zinc dose depletes Mg.

nutrient_topic

Magnesium research collection; topical membership is not evidence of a direct dietary effect. · Magnesium

organism

Homo sapiens

plain_language

Absorption interference was accompanied by a change in net magnesium balance.

primary_references

[mg-spencer1994] Inhibitory effects of zinc on magnesium balance and magnesium absorption in man (1994). https://pubmed.ncbi.nlm.nih.gov/7836627/ DOI: 10.1080/07315724.1994.10718438

tissue_or_cell_type

Human intestinal absorption and metabolic balance

Magnesium: cross-nutrient mechanisms and deficiency (2026-09-17) · lines 1590–1600

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Same adult metabolic-balance experiment. · source_derived_draft · unverified_draft

### mg-high-zinc-lowers-balance The pooled high-zinc groups also had lower Mg balance. Condition category: normal nutrient_topic: Magnesium research collection; topical membership is not evidence of a direct dietary effect. plain_language: Absorption interference was accompanied by a change in net magnesium balance. organism: Homo sapiens tissue_or_cell_type: Human intestinal absorption and metabolic balance experimental_model: Same adult metabolic-balance experiment. limitations: Not a molecular transporter competition assay or evidence that every zinc dose depletes Mg. cross_nutrient: Zinc/Mg intake balance; exposure-dependent. [mg-spencer1994] Inhibitory effects of zinc on magnesium balance and magnesium absorption in man (1994). https://pubmed.ncbi.nlm.nih.gov/7836627/ DOI: 10.1080/07315724.1994.10718438

cross_nutrient

Magnesium + zinc -> ALPL; connects to calcium/phosphate mineralization.

experimental_model

Recombinant TNAP metal-reconstitution assay. Activity was measured using artificial pNPP substrate.

limitations

Not an oral supplementation synergy trial. This assay does not quantify physiological pyrophosphate turnover or mineral deposition.

nutrient_topic

Magnesium research collection; topical membership is not evidence of a direct dietary effect. · Magnesium

organism

Homo sapiens

plain_language

This mineralization enzyme needs the right metals in different sites.

primary_references

[mg-hoylaerts2015] Functional significance of calcium binding to tissue-nonspecific alkaline phosphatase (2015). https://pubmed.ncbi.nlm.nih.gov/25775211/ DOI: 10.1371/journal.pone.0119874

tissue_or_cell_type

Recombinant human TNAP; cell-free p-nitrophenyl phosphate (pNPP) hydrolysis assay

Magnesium: cross-nutrient mechanisms and deficiency (2026-09-17) · lines 1467–1477

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Recombinant TNAP metal-reconstitution assay. Activity was measured using artificial pNPP substrate. · source_derived_draft · unverified_draft

### mg-zinc-alpl-reconstitution Combined Mg and Zn reconstituted demetalated TNAP activity; neither metal alone restored the same activity. Condition category: normal nutrient_topic: Magnesium research collection; topical membership is not evidence of a direct dietary effect. plain_language: This mineralization enzyme needs the right metals in different sites. organism: Homo sapiens tissue_or_cell_type: Recombinant human TNAP; cell-free p-nitrophenyl phosphate (pNPP) hydrolysis assay experimental_model: Recombinant TNAP metal-reconstitution assay. Activity was measured using artificial pNPP substrate. limitations: Not an oral supplementation synergy trial. This assay does not quantify physiological pyrophosphate turnover or mineral deposition. cross_nutrient: Magnesium + zinc -> ALPL; connects to calcium/phosphate mineralization. [mg-hoylaerts2015] Functional significance of calcium binding to tissue-nonspecific alkaline phosphatase (2015). https://pubmed.ncbi.nlm.nih.gov/25775211/ DOI: 10.1371/journal.pone.0119874

evidence_access

Primary full text, pathway and enzyme results

experimental_model

Human recombinant enzyme biochemistry.

limitations

Not evidence that zinc intake universally lowers NAD or that inhibiting this branch is always desirable.

nutrient_topic

Tryptophan collection; molecular form, preparation, species, exposure and manipulation remain explicit. · L-Tryptophan

plain_language

A branch enzyme diverts material away from the quinolinate-to-NAD route.

primary_references

Human α-amino-β-carboxymuconate-ε-semialdehyde decarboxylase (ACMSD): a structural and mechanistic unveiling. · 2015 · https://pubmed.ncbi.nlm.nih.gov/25392945/ · DOI 10.1002/prot.24722

Tryptophan: transport, protein synthesis, neuroactive metabolites, NAD and microbial pathways (2026-09-19) · lines 226–232

AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Human recombinant enzyme biochemistry. · source_derived_draft · unverified_draft

## tryptophan-acmsd-diversion A branch enzyme diverts material away from the quinolinate-to-NAD route. Human ACMSD decarboxylates unstable ACMS, competing with its spontaneous conversion toward quinolinate in the NAD synthesis pathway. Model: Human recombinant enzyme biochemistry. Limitations: Not evidence that zinc intake universally lowers NAD or that inhibiting this branch is always desirable. Evidence access: Primary full text, pathway and enzyme results Human α-amino-β-carboxymuconate-ε-semialdehyde decarboxylase (ACMSD): a structural and mechanistic unveiling. · 2015 · https://pubmed.ncbi.nlm.nih.gov/25392945/ · DOI 10.1002/prot.24722

cross_nutrient

false

experimental_model

Purified recombinant human CA2 expressed in E. coli; chelation, crystallography, DSC and H/D exchange

exposure

Chelated CA2 crystallography at 1.26 Å resolution.

limitations

Purified recombinant protein; chelation is not dietary deficiency. Approximately 10% zinc remained in the nominal apo preparation.

nutrient_topic

Zinc research collection; topical membership is not evidence of a direct dietary effect. · Zinc

organism

Homo sapiens

plain_language

An enzyme can lose activity before its entire shape collapses.

primary_references

[zinc-enz-ca2-apo2009] Apo-human carbonic anhydrase II revisited: implications of the loss of a metal in protein structure, stability, and solvent network. (2009). https://pubmed.ncbi.nlm.nih.gov/19583303/ DOI: 10.1021/bi9007512

tissue_or_cell_type

Purified protein; cell-free assay

Zinc: transport, enzyme loading, deficiency and nutrient interactions (2026-09-17) · lines 638–649

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purified recombinant human CA2 expressed in E. coli; chelation, crystallography, DSC and H/D exchange · source_derived_draft · unverified_draft

### zinc-enz-ca2-fold-preserved The chelated human CA2 structure retained the overall protein fold relative to zinc-containing CA2. Condition category: normal nutrient_topic: Zinc research collection; topical membership is not evidence of a direct dietary effect. plain_language: An enzyme can lose activity before its entire shape collapses. organism: Homo sapiens tissue_or_cell_type: Purified protein; cell-free assay experimental_model: Purified recombinant human CA2 expressed in E. coli; chelation, crystallography, DSC and H/D exchange limitations: Purified recombinant protein; chelation is not dietary deficiency. Approximately 10% zinc remained in the nominal apo preparation. exposure: Chelated CA2 crystallography at 1.26 Å resolution. cross_nutrient: false [zinc-enz-ca2-apo2009] Apo-human carbonic anhydrase II revisited: implications of the loss of a metal in protein structure, stability, and solvent network. (2009). https://pubmed.ncbi.nlm.nih.gov/19583303/ DOI: 10.1021/bi9007512

cross_nutrient

false

experimental_model

Purified recombinant human CA2 expressed in E. coli; chelation, crystallography, DSC and H/D exchange

exposure

100 mM pyridine-2,6-dicarboxylic acid, 25 mM MOPS pH 7.0, 20°C for 8 h; chelator removed by buffer exchange.

limitations

Purified recombinant protein; chelation is not dietary deficiency. Approximately 10% zinc remained in the nominal apo preparation.

nutrient_topic

Zinc research collection; topical membership is not evidence of a direct dietary effect. · Zinc

organism

Homo sapiens

plain_language

Removing the bound zinc largely disables CA2, even though the protein is still present.

primary_references

[zinc-enz-ca2-apo2009] Apo-human carbonic anhydrase II revisited: implications of the loss of a metal in protein structure, stability, and solvent network. (2009). https://pubmed.ncbi.nlm.nih.gov/19583303/ DOI: 10.1021/bi9007512

tissue_or_cell_type

Purified protein; cell-free assay

Zinc: transport, enzyme loading, deficiency and nutrient interactions (2026-09-17) · lines 599–610

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purified recombinant human CA2 expressed in E. coli; chelation, crystallography, DSC and H/D exchange · source_derived_draft · unverified_draft

### zinc-enz-ca2-removal Chelating zinc from recombinant human CA2 reduced catalytic activity; the apo preparation retained about 10% residual zinc. Condition category: normal nutrient_topic: Zinc research collection; topical membership is not evidence of a direct dietary effect. plain_language: Removing the bound zinc largely disables CA2, even though the protein is still present. organism: Homo sapiens tissue_or_cell_type: Purified protein; cell-free assay experimental_model: Purified recombinant human CA2 expressed in E. coli; chelation, crystallography, DSC and H/D exchange limitations: Purified recombinant protein; chelation is not dietary deficiency. Approximately 10% zinc remained in the nominal apo preparation. exposure: 100 mM pyridine-2,6-dicarboxylic acid, 25 mM MOPS pH 7.0, 20°C for 8 h; chelator removed by buffer exchange. cross_nutrient: false [zinc-enz-ca2-apo2009] Apo-human carbonic anhydrase II revisited: implications of the loss of a metal in protein structure, stability, and solvent network. (2009). https://pubmed.ncbi.nlm.nih.gov/19583303/ DOI: 10.1021/bi9007512

cross_nutrient

false

experimental_model

Human CA6 purified from pooled saliva or breast milk; stopped-flow enzymology

exposure

Stopped-flow CO2 hydration assay of proteins purified from pooled human saliva and milk.

limitations

Protein kinetic measurements; no test of dietary zinc treatment or infant health outcomes. Table values characterize the isolated preparations.

nutrient_topic

Zinc research collection; topical membership is not evidence of a direct dietary effect. · Zinc

organism

Homo sapiens

plain_language

Secreted CA6 accelerates conversion of carbon dioxide and water into bicarbonate.

primary_references

[zinc-enz-ca6-2022] Biochemical and Biophysical Characterization of Carbonic Anhydrase VI from Human Milk and Saliva. (2022). https://pubmed.ncbi.nlm.nih.gov/35947329/ DOI: 10.1007/s10930-022-10070-9

tissue_or_cell_type

Human saliva and breast milk; purified enzyme assay

Zinc: transport, enzyme loading, deficiency and nutrient interactions (2026-09-17) · lines 664–675

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human CA6 purified from pooled saliva or breast milk; stopped-flow enzymology · source_derived_draft · unverified_draft

### zinc-enz-ca6-hydration Purified human salivary and milk CA6 catalyzed CO2 hydration, with reported kcat values of 3.3×10^5 and 2.3×10^5 s−1, respectively. Condition category: normal nutrient_topic: Zinc research collection; topical membership is not evidence of a direct dietary effect. plain_language: Secreted CA6 accelerates conversion of carbon dioxide and water into bicarbonate. organism: Homo sapiens tissue_or_cell_type: Human saliva and breast milk; purified enzyme assay experimental_model: Human CA6 purified from pooled saliva or breast milk; stopped-flow enzymology limitations: Protein kinetic measurements; no test of dietary zinc treatment or infant health outcomes. Table values characterize the isolated preparations. exposure: Stopped-flow CO2 hydration assay of proteins purified from pooled human saliva and milk. cross_nutrient: false [zinc-enz-ca6-2022] Biochemical and Biophysical Characterization of Carbonic Anhydrase VI from Human Milk and Saliva. (2022). https://pubmed.ncbi.nlm.nih.gov/35947329/ DOI: 10.1007/s10930-022-10070-9

cross_nutrient

false

experimental_model

Human CA6 purified from pooled saliva or breast milk; stopped-flow enzymology

exposure

Inhibitor dilution series in stopped-flow enzymology; not oral treatment.

limitations

Assay inhibition does not measure nutrient deficiency or treatment efficacy.

nutrient_topic

Zinc research collection; topical membership is not evidence of a direct dietary effect. · Zinc

organism

Homo sapiens

plain_language

A carbonic anhydrase inhibitor blocked the purified secreted enzyme.

primary_references

[zinc-enz-ca6-2022] Biochemical and Biophysical Characterization of Carbonic Anhydrase VI from Human Milk and Saliva. (2022). https://pubmed.ncbi.nlm.nih.gov/35947329/ DOI: 10.1007/s10930-022-10070-9

tissue_or_cell_type

Purified human saliva and milk CA6

Zinc: transport, enzyme loading, deficiency and nutrient interactions (2026-09-17) · lines 677–688

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human CA6 purified from pooled saliva or breast milk; stopped-flow enzymology · source_derived_draft · unverified_draft

### zinc-enz-ca6-inhibition Acetazolamide inhibited salivary and milk human CA6 with reported Ki values of 16 and 23 nM in the enzyme assay. Condition category: normal nutrient_topic: Zinc research collection; topical membership is not evidence of a direct dietary effect. plain_language: A carbonic anhydrase inhibitor blocked the purified secreted enzyme. organism: Homo sapiens tissue_or_cell_type: Purified human saliva and milk CA6 experimental_model: Human CA6 purified from pooled saliva or breast milk; stopped-flow enzymology limitations: Assay inhibition does not measure nutrient deficiency or treatment efficacy. exposure: Inhibitor dilution series in stopped-flow enzymology; not oral treatment. cross_nutrient: false [zinc-enz-ca6-2022] Biochemical and Biophysical Characterization of Carbonic Anhydrase VI from Human Milk and Saliva. (2022). https://pubmed.ncbi.nlm.nih.gov/35947329/ DOI: 10.1007/s10930-022-10070-9

cross_nutrient

true

experimental_model

Purified human SOD1 and full-length, mutant or truncated human CCS; ESI-MS and NMR

exposure

Human CCS domain constructs and SOD1; ESI-MS and NMR.

limitations

Reconstituted human proteins studied in vitro; domain contributions do not imply CCS carries zinc to SOD1 or that zinc supplementation completes copper loading.

nutrient_topic

Zinc research collection; topical membership is not evidence of a direct dietary effect. · Zinc

organism

Homo sapiens

plain_language

SOD1 needs copper delivery as well as zinc binding.

primary_references

[zinc-enz-ccs-2012] Human superoxide dismutase 1 (hSOD1) maturation through interaction with human copper chaperone for SOD1 (hCCS). (2012). https://pubmed.ncbi.nlm.nih.gov/22869735/ DOI: 10.1073/pnas.1207493109

tissue_or_cell_type

Purified protein; cell-free assay

Zinc: transport, enzyme loading, deficiency and nutrient interactions (2026-09-17) · lines 690–701

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purified human SOD1 and full-length, mutant or truncated human CCS; ESI-MS and NMR · source_derived_draft · unverified_draft

### zinc-enz-ccs-copper In the purified human protein system, CCS domain 1 was necessary for loading SOD1 with Cu(I). Condition category: normal nutrient_topic: Zinc research collection; topical membership is not evidence of a direct dietary effect. plain_language: SOD1 needs copper delivery as well as zinc binding. organism: Homo sapiens tissue_or_cell_type: Purified protein; cell-free assay experimental_model: Purified human SOD1 and full-length, mutant or truncated human CCS; ESI-MS and NMR limitations: Reconstituted human proteins studied in vitro; domain contributions do not imply CCS carries zinc to SOD1 or that zinc supplementation completes copper loading. exposure: Human CCS domain constructs and SOD1; ESI-MS and NMR. cross_nutrient: true [zinc-enz-ccs-2012] Human superoxide dismutase 1 (hSOD1) maturation through interaction with human copper chaperone for SOD1 (hCCS). (2012). https://pubmed.ncbi.nlm.nih.gov/22869735/ DOI: 10.1073/pnas.1207493109

cross_nutrient

true

experimental_model

Purified human SOD1 and full-length, mutant or truncated human CCS; ESI-MS and NMR

exposure

Human CCS mutants/domain constructs examined by ESI-MS and NMR.

limitations

Reconstituted human proteins studied in vitro; domain contributions do not imply CCS carries zinc to SOD1 or that zinc supplementation completes copper loading.

nutrient_topic

Zinc research collection; topical membership is not evidence of a direct dietary effect. · Zinc

organism

Homo sapiens

plain_language

SOD1 maturation also requires forming a specific internal disulfide bond.

primary_references

[zinc-enz-ccs-2012] Human superoxide dismutase 1 (hSOD1) maturation through interaction with human copper chaperone for SOD1 (hCCS). (2012). https://pubmed.ncbi.nlm.nih.gov/22869735/ DOI: 10.1073/pnas.1207493109

tissue_or_cell_type

Purified protein; cell-free assay

Zinc: transport, enzyme loading, deficiency and nutrient interactions (2026-09-17) · lines 716–727

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purified human SOD1 and full-length, mutant or truncated human CCS; ESI-MS and NMR · source_derived_draft · unverified_draft

### zinc-enz-ccs-disulfide Human CCS domain 3 catalyzed formation of the SOD1 Cys57-Cys146 disulfide through a transfer mechanism involving CCS Cys244 and Cys246. Condition category: normal nutrient_topic: Zinc research collection; topical membership is not evidence of a direct dietary effect. plain_language: SOD1 maturation also requires forming a specific internal disulfide bond. organism: Homo sapiens tissue_or_cell_type: Purified protein; cell-free assay experimental_model: Purified human SOD1 and full-length, mutant or truncated human CCS; ESI-MS and NMR limitations: Reconstituted human proteins studied in vitro; domain contributions do not imply CCS carries zinc to SOD1 or that zinc supplementation completes copper loading. exposure: Human CCS mutants/domain constructs examined by ESI-MS and NMR. cross_nutrient: true [zinc-enz-ccs-2012] Human superoxide dismutase 1 (hSOD1) maturation through interaction with human copper chaperone for SOD1 (hCCS). (2012). https://pubmed.ncbi.nlm.nih.gov/22869735/ DOI: 10.1073/pnas.1207493109

cross_nutrient

true

experimental_model

Purified human SOD1 and full-length, mutant or truncated human CCS; ESI-MS and NMR

exposure

Full-length and domain-truncated human CCS with human SOD1.

limitations

Reconstituted human proteins studied in vitro; domain contributions do not imply CCS carries zinc to SOD1 or that zinc supplementation completes copper loading.

nutrient_topic

Zinc research collection; topical membership is not evidence of a direct dietary effect. · Zinc

organism

Homo sapiens

plain_language

The copper-delivery protein first has to engage SOD1.

primary_references

[zinc-enz-ccs-2012] Human superoxide dismutase 1 (hSOD1) maturation through interaction with human copper chaperone for SOD1 (hCCS). (2012). https://pubmed.ncbi.nlm.nih.gov/22869735/ DOI: 10.1073/pnas.1207493109

tissue_or_cell_type

Purified protein; cell-free assay

Zinc: transport, enzyme loading, deficiency and nutrient interactions (2026-09-17) · lines 703–714

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purified human SOD1 and full-length, mutant or truncated human CCS; ESI-MS and NMR · source_derived_draft · unverified_draft

### zinc-enz-ccs-recognition Human CCS domain 2 promoted the CCS-SOD1 heterodimer interaction required for copper loading in the in-vitro study. Condition category: normal nutrient_topic: Zinc research collection; topical membership is not evidence of a direct dietary effect. plain_language: The copper-delivery protein first has to engage SOD1. organism: Homo sapiens tissue_or_cell_type: Purified protein; cell-free assay experimental_model: Purified human SOD1 and full-length, mutant or truncated human CCS; ESI-MS and NMR limitations: Reconstituted human proteins studied in vitro; domain contributions do not imply CCS carries zinc to SOD1 or that zinc supplementation completes copper loading. exposure: Full-length and domain-truncated human CCS with human SOD1. cross_nutrient: true [zinc-enz-ccs-2012] Human superoxide dismutase 1 (hSOD1) maturation through interaction with human copper chaperone for SOD1 (hCCS). (2012). https://pubmed.ncbi.nlm.nih.gov/22869735/ DOI: 10.1073/pnas.1207493109

cross_nutrient

true

experimental_model

Transient expression of human SOD1 and CCS in human HEK293T cells; in-cell NMR

exposure

10 µM ZnSO4 in expression medium; 100 µM CuCl2 added after 48 h and incubated 24 h.

limitations

HEK293T cells overexpressed SOD1/CCS above endogenous levels; these medium concentrations are experimental exposures, not dietary targets. Copper transfer and disulfide oxidation need not occur in a fixed coupled step in every cellular context.

nutrient_topic

Zinc research collection; topical membership is not evidence of a direct dietary effect. · Zinc

organism

Homo sapiens

plain_language

The copper chaperone increased copper loading into zinc-containing SOD1.

primary_references

[zinc-enz-sod1-live2013] Atomic-resolution monitoring of protein maturation in live human cells by NMR. (2013). https://pubmed.ncbi.nlm.nih.gov/23455544/ DOI: 10.1038/nchembio.1202

tissue_or_cell_type

Human HEK293T cytoplasm

Zinc: transport, enzyme loading, deficiency and nutrient interactions (2026-09-17) · lines 742–753

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Transient expression of human SOD1 and CCS in human HEK293T cells; in-cell NMR · source_derived_draft · unverified_draft

### zinc-enz-sod1-copper-loading Coexpression of CCS increased Cu(I) incorporation into SOD1 after Cu(II) exposure in zinc-supplemented HEK293T cells; at higher expression the Cu(I),Zn-SOD1:E,Zn-SOD1 ratio reached about 1:1. Condition category: normal nutrient_topic: Zinc research collection; topical membership is not evidence of a direct dietary effect. plain_language: The copper chaperone increased copper loading into zinc-containing SOD1. organism: Homo sapiens tissue_or_cell_type: Human HEK293T cytoplasm experimental_model: Transient expression of human SOD1 and CCS in human HEK293T cells; in-cell NMR limitations: HEK293T cells overexpressed SOD1/CCS above endogenous levels; these medium concentrations are experimental exposures, not dietary targets. Copper transfer and disulfide oxidation need not occur in a fixed coupled step in every cellular context. exposure: 10 µM ZnSO4 in expression medium; 100 µM CuCl2 added after 48 h and incubated 24 h. cross_nutrient: true [zinc-enz-sod1-live2013] Atomic-resolution monitoring of protein maturation in live human cells by NMR. (2013). https://pubmed.ncbi.nlm.nih.gov/23455544/ DOI: 10.1038/nchembio.1202

cross_nutrient

true

experimental_model

Transient expression of human SOD1 and CCS in human HEK293T cells; in-cell NMR

exposure

10 µM ZnSO4 and SOD1/CCS coexpression; no added CuCl2 in this comparison.

limitations

HEK293T cells overexpressed SOD1/CCS above endogenous levels; these medium concentrations are experimental exposures, not dietary targets. Copper transfer and disulfide oxidation need not occur in a fixed coupled step in every cellular context. This is not proof that all copper is absent from the cell.

nutrient_topic

Zinc research collection; topical membership is not evidence of a direct dietary effect. · Zinc

organism

Homo sapiens

plain_language

CCS can help form the SOD1 disulfide before copper is inserted.

primary_references

[zinc-enz-sod1-live2013] Atomic-resolution monitoring of protein maturation in live human cells by NMR. (2013). https://pubmed.ncbi.nlm.nih.gov/23455544/ DOI: 10.1038/nchembio.1202

tissue_or_cell_type

Human HEK293T cytoplasm

Zinc: transport, enzyme loading, deficiency and nutrient interactions (2026-09-17) · lines 755–766

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Transient expression of human SOD1 and CCS in human HEK293T cells; in-cell NMR · source_derived_draft · unverified_draft

### zinc-enz-sod1-disulfide-independent In zinc-supplemented HEK293T cells, CCS coexpression promoted SOD1 disulfide oxidation without detectable additional SOD1 copper loading. Condition category: normal nutrient_topic: Zinc research collection; topical membership is not evidence of a direct dietary effect. plain_language: CCS can help form the SOD1 disulfide before copper is inserted. organism: Homo sapiens tissue_or_cell_type: Human HEK293T cytoplasm experimental_model: Transient expression of human SOD1 and CCS in human HEK293T cells; in-cell NMR limitations: HEK293T cells overexpressed SOD1/CCS above endogenous levels; these medium concentrations are experimental exposures, not dietary targets. Copper transfer and disulfide oxidation need not occur in a fixed coupled step in every cellular context. This is not proof that all copper is absent from the cell. exposure: 10 µM ZnSO4 and SOD1/CCS coexpression; no added CuCl2 in this comparison. cross_nutrient: true [zinc-enz-sod1-live2013] Atomic-resolution monitoring of protein maturation in live human cells by NMR. (2013). https://pubmed.ncbi.nlm.nih.gov/23455544/ DOI: 10.1038/nchembio.1202

cross_nutrient

true

experimental_model

Recombinant human TNAP and M4 mutants; cell-free enzyme activity and metal reconstitution

exposure

Recombinant TNAP M4-site mutants and metal-dependent activity comparisons at pH 7.4 and 9.8.

limitations

This record states the authors’ mechanistic interpretation; existing M3 calcium substitution and Mg/Zn reconstitution claims remain unchanged. It does not imply dietary calcium is a zinc substitute.

nutrient_topic

Zinc research collection; topical membership is not evidence of a direct dietary effect. · Zinc

organism

Homo sapiens

plain_language

TNAP metal sites do different jobs: its peripheral calcium site was interpreted as structural.

primary_references

[zinc-enz-tnap-metals2015] Functional significance of calcium binding to tissue-nonspecific alkaline phosphatase. (2015). https://pubmed.ncbi.nlm.nih.gov/25775211/ DOI: 10.1371/journal.pone.0119874

tissue_or_cell_type

Purified protein; cell-free assay

Zinc: transport, enzyme loading, deficiency and nutrient interactions (2026-09-17) · lines 820–831

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Recombinant human TNAP and M4 mutants; cell-free enzyme activity and metal reconstitution · source_derived_draft · unverified_draft

### zinc-enz-tnap-m4-not-catalytic The recombinant TNAP mutant study attributed effects of disrupting calcium site M4 to protein structure rather than direct catalysis by M4-bound calcium. Condition category: normal nutrient_topic: Zinc research collection; topical membership is not evidence of a direct dietary effect. plain_language: TNAP metal sites do different jobs: its peripheral calcium site was interpreted as structural. organism: Homo sapiens tissue_or_cell_type: Purified protein; cell-free assay experimental_model: Recombinant human TNAP and M4 mutants; cell-free enzyme activity and metal reconstitution limitations: This record states the authors’ mechanistic interpretation; existing M3 calcium substitution and Mg/Zn reconstitution claims remain unchanged. It does not imply dietary calcium is a zinc substitute. exposure: Recombinant TNAP M4-site mutants and metal-dependent activity comparisons at pH 7.4 and 9.8. cross_nutrient: true [zinc-enz-tnap-metals2015] Functional significance of calcium binding to tissue-nonspecific alkaline phosphatase. (2015). https://pubmed.ncbi.nlm.nih.gov/25775211/ DOI: 10.1371/journal.pone.0119874

availability_state

machinery_impairment Imported condition classification; unverified.

cross_nutrient

false

experimental_model

Engineered chicken DT40 cells with ZnT gene disruption and transporter re-expression; TNAP activation

exposure

Transport-incompetent ZnT5 variant with ZnT6, compared with functional loading machinery.

limitations

Primary abstract-level evidence in engineered chicken DT40 cells with transporter complementation. Not a human dietary deficiency or supplementation trial; assay exposure amounts and mutant-specific residue effects are not inferred.

nutrient_topic

Zinc research collection; topical membership is not evidence of a direct dietary effect. · Zinc

organism

Gallus gallus cell model with human proteins

plain_language

Protecting the enzyme protein is insufficient when the complex cannot deliver zinc.

primary_references

[zinc-enz-znt-tnap2011] Tissue nonspecific alkaline phosphatase is activated via a two-step mechanism by zinc transport complexes in the early secretory pathway. (2011). https://pubmed.ncbi.nlm.nih.gov/21402707/ DOI: 10.1074/jbc.m111.227173

tissue_or_cell_type

Chicken DT40 early secretory pathway

trigger_kind

machinery_impairment Imported condition classification; unverified.

Zinc: transport, enzyme loading, deficiency and nutrient interactions (2026-09-17) · lines 807–818

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Engineered chicken DT40 cells with ZnT gene disruption and transporter re-expression; TNAP activation · source_derived_draft · unverified_draft

### zinc-enz-znt-mutant-no-activity Reconstitution of ZnT5-ZnT6 with transport-incompetent ZnT5 did not restore TNAP activity. Condition category: machinery_impairment nutrient_topic: Zinc research collection; topical membership is not evidence of a direct dietary effect. plain_language: Protecting the enzyme protein is insufficient when the complex cannot deliver zinc. organism: Gallus gallus cell model with human proteins tissue_or_cell_type: Chicken DT40 early secretory pathway experimental_model: Engineered chicken DT40 cells with ZnT gene disruption and transporter re-expression; TNAP activation limitations: Primary abstract-level evidence in engineered chicken DT40 cells with transporter complementation. Not a human dietary deficiency or supplementation trial; assay exposure amounts and mutant-specific residue effects are not inferred. exposure: Transport-incompetent ZnT5 variant with ZnT6, compared with functional loading machinery. cross_nutrient: false [zinc-enz-znt-tnap2011] Tissue nonspecific alkaline phosphatase is activated via a two-step mechanism by zinc transport complexes in the early secretory pathway. (2011). https://pubmed.ncbi.nlm.nih.gov/21402707/ DOI: 10.1074/jbc.m111.227173

availability_state

machinery_impairment Imported condition classification; unverified.

cross_nutrient

false

experimental_model

Engineered chicken DT40 cells with ZnT gene disruption and transporter re-expression; TNAP activation

exposure

Transport-incompetent ZnT5 variant reconstituted with ZnT6 in DT40 cells.

limitations

Primary abstract-level evidence in engineered chicken DT40 cells with transporter complementation. Not a human dietary deficiency or supplementation trial; assay exposure amounts and mutant-specific residue effects are not inferred.

nutrient_topic

Zinc research collection; topical membership is not evidence of a direct dietary effect. · Zinc

organism

Gallus gallus cell model with human proteins

plain_language

The transporter complex can protect the unfinished protein even when zinc transport fails.

primary_references

[zinc-enz-znt-tnap2011] Tissue nonspecific alkaline phosphatase is activated via a two-step mechanism by zinc transport complexes in the early secretory pathway. (2011). https://pubmed.ncbi.nlm.nih.gov/21402707/ DOI: 10.1074/jbc.m111.227173

tissue_or_cell_type

Chicken DT40 early secretory pathway; human transporter complementation

trigger_kind

machinery_impairment Imported condition classification; unverified.

Zinc: transport, enzyme loading, deficiency and nutrient interactions (2026-09-17) · lines 794–805

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Engineered chicken DT40 cells with ZnT gene disruption and transporter re-expression; TNAP activation · source_derived_draft · unverified_draft

### zinc-enz-znt-mutant-stabilizes A transport-incompetent ZnT5 variant expressed with ZnT6 stabilized TNAP protein as the apo form despite failing to restore enzyme activity. Condition category: machinery_impairment nutrient_topic: Zinc research collection; topical membership is not evidence of a direct dietary effect. plain_language: The transporter complex can protect the unfinished protein even when zinc transport fails. organism: Gallus gallus cell model with human proteins tissue_or_cell_type: Chicken DT40 early secretory pathway; human transporter complementation experimental_model: Engineered chicken DT40 cells with ZnT gene disruption and transporter re-expression; TNAP activation limitations: Primary abstract-level evidence in engineered chicken DT40 cells with transporter complementation. Not a human dietary deficiency or supplementation trial; assay exposure amounts and mutant-specific residue effects are not inferred. exposure: Transport-incompetent ZnT5 variant reconstituted with ZnT6 in DT40 cells. cross_nutrient: false [zinc-enz-znt-tnap2011] Tissue nonspecific alkaline phosphatase is activated via a two-step mechanism by zinc transport complexes in the early secretory pathway. (2011). https://pubmed.ncbi.nlm.nih.gov/21402707/ DOI: 10.1074/jbc.m111.227173

cross_nutrient

false

experimental_model

Engineered chicken DT40 cells with ZnT gene disruption and transporter re-expression; TNAP activation

exposure

ZnT gene disruption and transporter re-expression comparisons.

limitations

Primary abstract-level evidence in engineered chicken DT40 cells with transporter complementation. Not a human dietary deficiency or supplementation trial; assay exposure amounts and mutant-specific residue effects are not inferred.

nutrient_topic

Zinc research collection; topical membership is not evidence of a direct dietary effect. · Zinc

organism

Gallus gallus cell model with human proteins

plain_language

Specific transporter complexes deliver zinc while TNAP matures.

primary_references

[zinc-enz-znt-tnap2011] Tissue nonspecific alkaline phosphatase is activated via a two-step mechanism by zinc transport complexes in the early secretory pathway. (2011). https://pubmed.ncbi.nlm.nih.gov/21402707/ DOI: 10.1074/jbc.m111.227173

tissue_or_cell_type

Chicken DT40 early secretory pathway; human transporter complementation

Zinc: transport, enzyme loading, deficiency and nutrient interactions (2026-09-17) · lines 768–779

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Engineered chicken DT40 cells with ZnT gene disruption and transporter re-expression; TNAP activation · source_derived_draft · unverified_draft

### zinc-enz-znt-specific-maturation The ZnT5-ZnT6 and ZnT7 complexes support TNAP conversion from apoenzyme to zinc-loaded active enzyme in the early secretory pathway. Condition category: normal nutrient_topic: Zinc research collection; topical membership is not evidence of a direct dietary effect. plain_language: Specific transporter complexes deliver zinc while TNAP matures. organism: Gallus gallus cell model with human proteins tissue_or_cell_type: Chicken DT40 early secretory pathway; human transporter complementation experimental_model: Engineered chicken DT40 cells with ZnT gene disruption and transporter re-expression; TNAP activation limitations: Primary abstract-level evidence in engineered chicken DT40 cells with transporter complementation. Not a human dietary deficiency or supplementation trial; assay exposure amounts and mutant-specific residue effects are not inferred. exposure: ZnT gene disruption and transporter re-expression comparisons. cross_nutrient: false [zinc-enz-znt-tnap2011] Tissue nonspecific alkaline phosphatase is activated via a two-step mechanism by zinc transport complexes in the early secretory pathway. (2011). https://pubmed.ncbi.nlm.nih.gov/21402707/ DOI: 10.1074/jbc.m111.227173

availability_state

machinery_impairment Imported condition classification; unverified.

cross_nutrient

false

experimental_model

Conditional intestinal knockout with tissue elemental analysis

exposure

Induced enterocyte deletion on zinc-adequate chow.

limitations

This measured redistribution supports but does not directly quantify the proposed blood-to-enterocyte-to-lumen excretion route.

nutrient_topic

Zinc research collection; topical membership is not evidence of a direct dietary effect. · Zinc

organism

Mus musculus

plain_language

Removing intestinal ZIP5 changed where zinc accumulated, increasing the pancreatic pool.

primary_references

[zinc-trans-24303081] The zinc transporter Zip5 (Slc39a5) regulates intestinal zinc excretion and protects the pancreas against zinc toxicity. (2013). https://pubmed.ncbi.nlm.nih.gov/24303081/ DOI: 10.1371/journal.pone.0082149

tissue_or_cell_type

Intestinal enterocytes; pancreatic zinc endpoint

trigger_kind

machinery_impairment Imported condition classification; unverified.

Zinc: transport, enzyme loading, deficiency and nutrient interactions (2026-09-17) · lines 388–399

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Conditional intestinal knockout with tissue elemental analysis · source_derived_draft · unverified_draft

### zinc-trans-intestinal-zip5-pancreas-zinc Enterocyte-specific Zip5 deletion increased pancreatic zinc in mice eating a zinc-adequate diet. Condition category: machinery_impairment nutrient_topic: Zinc research collection; topical membership is not evidence of a direct dietary effect. plain_language: Removing intestinal ZIP5 changed where zinc accumulated, increasing the pancreatic pool. organism: Mus musculus tissue_or_cell_type: Intestinal enterocytes; pancreatic zinc endpoint experimental_model: Conditional intestinal knockout with tissue elemental analysis limitations: This measured redistribution supports but does not directly quantify the proposed blood-to-enterocyte-to-lumen excretion route. exposure: Induced enterocyte deletion on zinc-adequate chow. cross_nutrient: false [zinc-trans-24303081] The zinc transporter Zip5 (Slc39a5) regulates intestinal zinc excretion and protects the pancreas against zinc toxicity. (2013). https://pubmed.ncbi.nlm.nih.gov/24303081/ DOI: 10.1371/journal.pone.0082149

availability_state

machinery_impairment Imported condition classification; unverified.

cross_nutrient

false

experimental_model

Acinar-cell-specific knockout and 67Zn tracer kinetics

exposure

Tracer zinc uptake and retention compared between acinar knockouts and controls.

limitations

The negative acute-uptake result is retained; retention differences do not identify every influx or efflux pathway.

nutrient_topic

Zinc research collection; topical membership is not evidence of a direct dietary effect. · Zinc

organism

Mus musculus

plain_language

Pancreatic ZIP5 helped retain zinc after uptake, rather than being required for the initial uptake measured here.

primary_references

[zinc-trans-24303081] The zinc transporter Zip5 (Slc39a5) regulates intestinal zinc excretion and protects the pancreas against zinc toxicity. (2013). https://pubmed.ncbi.nlm.nih.gov/24303081/ DOI: 10.1371/journal.pone.0082149

tissue_or_cell_type

Pancreatic acinar cells

trigger_kind

machinery_impairment Imported condition classification; unverified.

Zinc: transport, enzyme loading, deficiency and nutrient interactions (2026-09-17) · lines 401–412

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Acinar-cell-specific knockout and 67Zn tracer kinetics · source_derived_draft · unverified_draft

### zinc-trans-pancreas-zip5-retention Pancreatic acinar-cell Zip5 deletion impaired retention of administered 67Zn despite no detected impairment of rapid pancreatic 67Zn accumulation. Condition category: machinery_impairment nutrient_topic: Zinc research collection; topical membership is not evidence of a direct dietary effect. plain_language: Pancreatic ZIP5 helped retain zinc after uptake, rather than being required for the initial uptake measured here. organism: Mus musculus tissue_or_cell_type: Pancreatic acinar cells experimental_model: Acinar-cell-specific knockout and 67Zn tracer kinetics limitations: The negative acute-uptake result is retained; retention differences do not identify every influx or efflux pathway. exposure: Tracer zinc uptake and retention compared between acinar knockouts and controls. cross_nutrient: false [zinc-trans-24303081] The zinc transporter Zip5 (Slc39a5) regulates intestinal zinc excretion and protects the pancreas against zinc toxicity. (2013). https://pubmed.ncbi.nlm.nih.gov/24303081/ DOI: 10.1371/journal.pone.0082149

availability_state

machinery_impairment Imported condition classification; unverified.

cross_nutrient

true

experimental_model

Polarized proximal-tubule culture with separately accessible apical and basolateral compartments

exposure

ZIP8 siRNA versus controls during apical manganese exposure.

limitations

This is manganese uptake, not direct proof of zinc reabsorption by ZIP8; ZIP14 and DMT1 knockdowns also affected uptake in the paper.

nutrient_topic

Zinc research collection; topical membership is not evidence of a direct dietary effect. · Zinc

organism

Mus musculus

plain_language

A transporter known to handle zinc also helped kidney-derived cells take up manganese from their lumen-facing side.

primary_references

[zinc-trans-22534978] Roles of ZIP8, ZIP14, and DMT1 in transport of cadmium and manganese in mouse kidney proximal tubule cells. (2012). https://pubmed.ncbi.nlm.nih.gov/22534978/ DOI: 10.1039/c2mt20024d

tissue_or_cell_type

Mouse proximal-tubule epithelial cells

trigger_kind

machinery_impairment Imported condition classification; unverified.

Zinc: transport, enzyme loading, deficiency and nutrient interactions (2026-09-17) · lines 531–542

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Polarized proximal-tubule culture with separately accessible apical and basolateral compartments · source_derived_draft · unverified_draft

### zinc-trans-renal-zip8-manganese ZIP8-specific siRNA reduced manganese uptake from the apical side of polarized mouse proximal-tubule cells. Condition category: machinery_impairment nutrient_topic: Zinc research collection; topical membership is not evidence of a direct dietary effect. plain_language: A transporter known to handle zinc also helped kidney-derived cells take up manganese from their lumen-facing side. organism: Mus musculus tissue_or_cell_type: Mouse proximal-tubule epithelial cells experimental_model: Polarized proximal-tubule culture with separately accessible apical and basolateral compartments limitations: This is manganese uptake, not direct proof of zinc reabsorption by ZIP8; ZIP14 and DMT1 knockdowns also affected uptake in the paper. exposure: ZIP8 siRNA versus controls during apical manganese exposure. cross_nutrient: true [zinc-trans-22534978] Roles of ZIP8, ZIP14, and DMT1 in transport of cadmium and manganese in mouse kidney proximal tubule cells. (2012). https://pubmed.ncbi.nlm.nih.gov/22534978/ DOI: 10.1039/c2mt20024d

cross_nutrient

true

experimental_model

Radiolabeled Cu(I) and Cu(II) uptake in Xenopus oocytes

exposure

Cu(I) and Cu(II) tested separately against controls.

limitations

A bounded negative result does not mean zinc and copper have no interaction through other proteins or intestinal mechanisms.

nutrient_topic

Zinc research collection; topical membership is not evidence of a direct dietary effect. · Zinc

organism

Mouse protein in Xenopus laevis oocytes

plain_language

This ZIP14 experiment found no copper transport despite detecting other metal substrates.

primary_references

[zinc-trans-21653899] Zip14 is a complex broad-scope metal-ion transporter whose functional properties support roles in the cellular uptake of zinc and nontransferrin-bound iron. (2011). https://pubmed.ncbi.nlm.nih.gov/21653899/ DOI: 10.1152/ajpcell.00479.2010

tissue_or_cell_type

Oocyte plasma membrane

Zinc: transport, enzyme loading, deficiency and nutrient interactions (2026-09-17) · lines 518–529

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Radiolabeled Cu(I) and Cu(II) uptake in Xenopus oocytes · source_derived_draft · unverified_draft

### zinc-trans-zip14-copper-negative Mouse ZIP14 did not increase uptake of radiolabeled copper supplied as Cu(I) or Cu(II) in the tested oocyte conditions. Condition category: normal nutrient_topic: Zinc research collection; topical membership is not evidence of a direct dietary effect. plain_language: This ZIP14 experiment found no copper transport despite detecting other metal substrates. organism: Mouse protein in Xenopus laevis oocytes tissue_or_cell_type: Oocyte plasma membrane experimental_model: Radiolabeled Cu(I) and Cu(II) uptake in Xenopus oocytes limitations: A bounded negative result does not mean zinc and copper have no interaction through other proteins or intestinal mechanisms. exposure: Cu(I) and Cu(II) tested separately against controls. cross_nutrient: true [zinc-trans-21653899] Zip14 is a complex broad-scope metal-ion transporter whose functional properties support roles in the cellular uptake of zinc and nontransferrin-bound iron. (2011). https://pubmed.ncbi.nlm.nih.gov/21653899/ DOI: 10.1152/ajpcell.00479.2010

cross_nutrient

true

experimental_model

RNA-injected Xenopus oocytes with radiolabeled metal uptake

exposure

54Mn transport compared with uninjected controls.

limitations

Transport capacity is not proof that manganese supplements improve zinc transport or vice versa.

nutrient_topic

Zinc research collection; topical membership is not evidence of a direct dietary effect. · Zinc

organism

Mouse protein in Xenopus laevis oocytes

plain_language

ZIP14 could carry manganese as well as zinc in this experiment.

primary_references

[zinc-trans-21653899] Zip14 is a complex broad-scope metal-ion transporter whose functional properties support roles in the cellular uptake of zinc and nontransferrin-bound iron. (2011). https://pubmed.ncbi.nlm.nih.gov/21653899/ DOI: 10.1152/ajpcell.00479.2010

tissue_or_cell_type

Oocyte plasma membrane

Zinc: transport, enzyme loading, deficiency and nutrient interactions (2026-09-17) · lines 492–503

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · RNA-injected Xenopus oocytes with radiolabeled metal uptake · source_derived_draft · unverified_draft

### zinc-trans-zip14-manganese-influx Mouse ZIP14 directly mediated 54Mn(II) uptake in RNA-injected Xenopus oocytes. Condition category: normal nutrient_topic: Zinc research collection; topical membership is not evidence of a direct dietary effect. plain_language: ZIP14 could carry manganese as well as zinc in this experiment. organism: Mouse protein in Xenopus laevis oocytes tissue_or_cell_type: Oocyte plasma membrane experimental_model: RNA-injected Xenopus oocytes with radiolabeled metal uptake limitations: Transport capacity is not proof that manganese supplements improve zinc transport or vice versa. exposure: 54Mn transport compared with uninjected controls. cross_nutrient: true [zinc-trans-21653899] Zip14 is a complex broad-scope metal-ion transporter whose functional properties support roles in the cellular uptake of zinc and nontransferrin-bound iron. (2011). https://pubmed.ncbi.nlm.nih.gov/21653899/ DOI: 10.1152/ajpcell.00479.2010

cross_nutrient

false

experimental_model

RNA-injected Xenopus oocytes and 65Zn uptake

exposure

Zinc concentration-response curve under the study transport conditions.

limitations

The apparent affinity belongs to this assay, not a serum zinc cutoff; protein is the mouse ortholog.

nutrient_topic

Zinc research collection; topical membership is not evidence of a direct dietary effect. · Zinc

organism

Mouse protein in Xenopus laevis oocytes

plain_language

Mouse ZIP14 directly carried zinc in the oocyte assay.

primary_references

[zinc-trans-21653899] Zip14 is a complex broad-scope metal-ion transporter whose functional properties support roles in the cellular uptake of zinc and nontransferrin-bound iron. (2011). https://pubmed.ncbi.nlm.nih.gov/21653899/ DOI: 10.1152/ajpcell.00479.2010

tissue_or_cell_type

Oocyte plasma membrane

Zinc: transport, enzyme loading, deficiency and nutrient interactions (2026-09-17) · lines 479–490

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · RNA-injected Xenopus oocytes and 65Zn uptake · source_derived_draft · unverified_draft

### zinc-trans-zip14-zinc-influx Mouse ZIP14 expression in Xenopus oocytes supported saturable zinc uptake with an apparent half-maximal zinc concentration near 2 micromolar. Condition category: normal nutrient_topic: Zinc research collection; topical membership is not evidence of a direct dietary effect. plain_language: Mouse ZIP14 directly carried zinc in the oocyte assay. organism: Mouse protein in Xenopus laevis oocytes tissue_or_cell_type: Oocyte plasma membrane experimental_model: RNA-injected Xenopus oocytes and 65Zn uptake limitations: The apparent affinity belongs to this assay, not a serum zinc cutoff; protein is the mouse ortholog. exposure: Zinc concentration-response curve under the study transport conditions. cross_nutrient: false [zinc-trans-21653899] Zip14 is a complex broad-scope metal-ion transporter whose functional properties support roles in the cellular uptake of zinc and nontransferrin-bound iron. (2011). https://pubmed.ncbi.nlm.nih.gov/21653899/ DOI: 10.1152/ajpcell.00479.2010

cross_nutrient

false

experimental_model

Transfected mammalian cells

exposure

ZIP4 expression versus controls; abstract does not specify zinc concentration.

limitations

Transport in engineered cells establishes capacity, not the fraction of human dietary zinc absorption.

nutrient_topic

Zinc research collection; topical membership is not evidence of a direct dietary effect. · Zinc

organism

Mouse protein in cultured mammalian cells

plain_language

Mouse ZIP4 can bring zinc into cells.

primary_references

[zinc-trans-12801924] The acrodermatitis enteropathica gene ZIP4 encodes a tissue-specific, zinc-regulated zinc transporter in mice. (2003). https://pubmed.ncbi.nlm.nih.gov/12801924/ DOI: 10.1074/jbc.m305000200

tissue_or_cell_type

Cell plasma membrane

Zinc: transport, enzyme loading, deficiency and nutrient interactions (2026-09-17) · lines 219–230

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Transfected mammalian cells · source_derived_draft · unverified_draft

### zinc-trans-zip4-influx Expression of mouse ZIP4 increased zinc influx into transfected cells. Condition category: normal nutrient_topic: Zinc research collection; topical membership is not evidence of a direct dietary effect. plain_language: Mouse ZIP4 can bring zinc into cells. organism: Mouse protein in cultured mammalian cells tissue_or_cell_type: Cell plasma membrane experimental_model: Transfected mammalian cells limitations: Transport in engineered cells establishes capacity, not the fraction of human dietary zinc absorption. exposure: ZIP4 expression versus controls; abstract does not specify zinc concentration. cross_nutrient: false [zinc-trans-12801924] The acrodermatitis enteropathica gene ZIP4 encodes a tissue-specific, zinc-regulated zinc transporter in mice. (2003). https://pubmed.ncbi.nlm.nih.gov/12801924/ DOI: 10.1074/jbc.m305000200

availability_state

machinery_impairment Imported condition classification; unverified.

cross_nutrient

false

experimental_model

Tamoxifen-inducible enterocyte-specific knockout and tissue elemental analysis

exposure

Conditional gene deletion compared with intact controls.

limitations

A genetic transport defect is not interchangeable with low intake. Total tissue zinc does not resolve labile versus protein-bound zinc.

nutrient_topic

Zinc research collection; topical membership is not evidence of a direct dietary effect. · Zinc

organism

Mus musculus

plain_language

Disabling intestinal ZIP4 depleted zinc beyond the intestine.

primary_references

[zinc-trans-22737083] A mouse model of acrodermatitis enteropathica: loss of intestine zinc transporter ZIP4 (Slc39a4) disrupts the stem cell niche and intestine integrity. (2012). https://pubmed.ncbi.nlm.nih.gov/22737083/ DOI: 10.1371/journal.pgen.1002766

tissue_or_cell_type

Small intestine, liver, pancreas

trigger_kind

machinery_impairment Imported condition classification; unverified.

Zinc: transport, enzyme loading, deficiency and nutrient interactions (2026-09-17) · lines 271–282

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Tamoxifen-inducible enterocyte-specific knockout and tissue elemental analysis · source_derived_draft · unverified_draft

### zinc-trans-zip4-knockout-tissue-zinc Enterocyte-specific Slc39a4 deletion rapidly lowered total zinc in mouse small intestine, liver and pancreas. Condition category: machinery_impairment nutrient_topic: Zinc research collection; topical membership is not evidence of a direct dietary effect. plain_language: Disabling intestinal ZIP4 depleted zinc beyond the intestine. organism: Mus musculus tissue_or_cell_type: Small intestine, liver, pancreas experimental_model: Tamoxifen-inducible enterocyte-specific knockout and tissue elemental analysis limitations: A genetic transport defect is not interchangeable with low intake. Total tissue zinc does not resolve labile versus protein-bound zinc. exposure: Conditional gene deletion compared with intact controls. cross_nutrient: false [zinc-trans-22737083] A mouse model of acrodermatitis enteropathica: loss of intestine zinc transporter ZIP4 (Slc39a4) disrupts the stem cell niche and intestine integrity. (2012). https://pubmed.ncbi.nlm.nih.gov/22737083/ DOI: 10.1371/journal.pgen.1002766

cross_nutrient

false

experimental_model

Polarized Madin-Darby canine kidney cells expressing mouse ZIP5

exposure

Polarized-cell localization assay.

limitations

Localization supports a directional hypothesis but does not itself measure net intestinal zinc excretion or demonstrate human renal zinc reabsorption.

nutrient_topic

Zinc research collection; topical membership is not evidence of a direct dietary effect. · Zinc

organism

Mouse protein in Canis lupus familiaris cells

plain_language

In polarized kidney-derived cells, ZIP5 sat on the side facing the tissue rather than the lumen.

primary_references

[zinc-trans-15322118] The mammalian Zip5 protein is a zinc transporter that localizes to the basolateral surface of polarized cells. (2004). https://pubmed.ncbi.nlm.nih.gov/15322118/ DOI: 10.1074/jbc.m408361200

tissue_or_cell_type

MDCK epithelial basolateral membrane

Zinc: transport, enzyme loading, deficiency and nutrient interactions (2026-09-17) · lines 375–386

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Polarized Madin-Darby canine kidney cells expressing mouse ZIP5 · source_derived_draft · unverified_draft

### zinc-trans-zip5-basolateral Mouse ZIP5 localized to the basolateral membrane when expressed in polarized MDCK cells. Condition category: normal nutrient_topic: Zinc research collection; topical membership is not evidence of a direct dietary effect. plain_language: In polarized kidney-derived cells, ZIP5 sat on the side facing the tissue rather than the lumen. organism: Mouse protein in Canis lupus familiaris cells tissue_or_cell_type: MDCK epithelial basolateral membrane experimental_model: Polarized Madin-Darby canine kidney cells expressing mouse ZIP5 limitations: Localization supports a directional hypothesis but does not itself measure net intestinal zinc excretion or demonstrate human renal zinc reabsorption. exposure: Polarized-cell localization assay. cross_nutrient: false [zinc-trans-15322118] The mammalian Zip5 protein is a zinc transporter that localizes to the basolateral surface of polarized cells. (2004). https://pubmed.ncbi.nlm.nih.gov/15322118/ DOI: 10.1074/jbc.m408361200

cross_nutrient

false

experimental_model

Heterologous mouse ZIP5 expression

exposure

Expression and substrate tests; abstract does not specify concentrations.

limitations

Selectivity is bounded by the tested panel and assay; this cannot exclude every other substrate in other systems.

nutrient_topic

Zinc research collection; topical membership is not evidence of a direct dietary effect. · Zinc

organism

Mouse protein in cultured cells

plain_language

Mouse ZIP5 can move zinc into cells.

primary_references

[zinc-trans-15322118] The mammalian Zip5 protein is a zinc transporter that localizes to the basolateral surface of polarized cells. (2004). https://pubmed.ncbi.nlm.nih.gov/15322118/ DOI: 10.1074/jbc.m408361200

tissue_or_cell_type

Cultured-cell plasma membrane

Zinc: transport, enzyme loading, deficiency and nutrient interactions (2026-09-17) · lines 362–373

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Heterologous mouse ZIP5 expression · source_derived_draft · unverified_draft

### zinc-trans-zip5-influx Mouse ZIP5 expression increased cellular Zn(II) uptake and showed selectivity for zinc among the potential substrates tested. Condition category: normal nutrient_topic: Zinc research collection; topical membership is not evidence of a direct dietary effect. plain_language: Mouse ZIP5 can move zinc into cells. organism: Mouse protein in cultured cells tissue_or_cell_type: Cultured-cell plasma membrane experimental_model: Heterologous mouse ZIP5 expression limitations: Selectivity is bounded by the tested panel and assay; this cannot exclude every other substrate in other systems. exposure: Expression and substrate tests; abstract does not specify concentrations. cross_nutrient: false [zinc-trans-15322118] The mammalian Zip5 protein is a zinc transporter that localizes to the basolateral surface of polarized cells. (2004). https://pubmed.ncbi.nlm.nih.gov/15322118/ DOI: 10.1074/jbc.m408361200

cross_nutrient

true

experimental_model

Rat ZIP8-expressing HEK293T radiotracer assay

exposure

2 micromolar labeled zinc and tenfold unlabeled iron excess; uptake medium included ascorbate.

limitations

Transport competition in cells is not a universal dietary zinc/iron ratio or a prediction for mixed meals.

nutrient_topic

Zinc research collection; topical membership is not evidence of a direct dietary effect. · Zinc

organism

Rat protein in human cells

plain_language

Iron reduced zinc entry through this transporter system under the tested culture conditions.

primary_references

[zinc-trans-22898811] ZIP8 is an iron and zinc transporter whose cell-surface expression is up-regulated by cellular iron loading. (2012). https://pubmed.ncbi.nlm.nih.gov/22898811/ DOI: 10.1074/jbc.m112.367284

tissue_or_cell_type

HEK293T cells

Zinc: transport, enzyme loading, deficiency and nutrient interactions (2026-09-17) · lines 440–451

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Rat ZIP8-expressing HEK293T radiotracer assay · source_derived_draft · unverified_draft

### zinc-trans-zip8-iron-inhibits-zinc A tenfold molar excess of iron inhibited radiolabeled zinc uptake in HEK293T cells expressing rat ZIP8. Condition category: normal nutrient_topic: Zinc research collection; topical membership is not evidence of a direct dietary effect. plain_language: Iron reduced zinc entry through this transporter system under the tested culture conditions. organism: Rat protein in human cells tissue_or_cell_type: HEK293T cells experimental_model: Rat ZIP8-expressing HEK293T radiotracer assay limitations: Transport competition in cells is not a universal dietary zinc/iron ratio or a prediction for mixed meals. exposure: 2 micromolar labeled zinc and tenfold unlabeled iron excess; uptake medium included ascorbate. cross_nutrient: true [zinc-trans-22898811] ZIP8 is an iron and zinc transporter whose cell-surface expression is up-regulated by cellular iron loading. (2012). https://pubmed.ncbi.nlm.nih.gov/22898811/ DOI: 10.1074/jbc.m112.367284

availability_state

machinery_impairment Imported condition classification; unverified.

cross_nutrient

true

experimental_model

ZIP8 suppression in BeWo trophoblast-derived cells

exposure

Endogenous ZIP8 knockdown compared with controls.

limitations

This is iron uptake in a placental cell line, not direct transplacental zinc flux or an in vivo fetal iron requirement for dietary zinc.

nutrient_topic

Zinc research collection; topical membership is not evidence of a direct dietary effect. · Zinc

organism

Homo sapiens

plain_language

ZIP8 contributed to iron entry in a human placental cell model.

primary_references

[zinc-trans-22898811] ZIP8 is an iron and zinc transporter whose cell-surface expression is up-regulated by cellular iron loading. (2012). https://pubmed.ncbi.nlm.nih.gov/22898811/ DOI: 10.1074/jbc.m112.367284

tissue_or_cell_type

BeWo placental cell line

trigger_kind

machinery_impairment Imported condition classification; unverified.

Zinc: transport, enzyme loading, deficiency and nutrient interactions (2026-09-17) · lines 466–477

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · ZIP8 suppression in BeWo trophoblast-derived cells · source_derived_draft · unverified_draft

### zinc-trans-zip8-placental-iron Suppressing endogenous human ZIP8 in BeWo placental cells reduced iron uptake by approximately 40%. Condition category: machinery_impairment nutrient_topic: Zinc research collection; topical membership is not evidence of a direct dietary effect. plain_language: ZIP8 contributed to iron entry in a human placental cell model. organism: Homo sapiens tissue_or_cell_type: BeWo placental cell line experimental_model: ZIP8 suppression in BeWo trophoblast-derived cells limitations: This is iron uptake in a placental cell line, not direct transplacental zinc flux or an in vivo fetal iron requirement for dietary zinc. exposure: Endogenous ZIP8 knockdown compared with controls. cross_nutrient: true [zinc-trans-22898811] ZIP8 is an iron and zinc transporter whose cell-surface expression is up-regulated by cellular iron loading. (2012). https://pubmed.ncbi.nlm.nih.gov/22898811/ DOI: 10.1074/jbc.m112.367284

cross_nutrient

false

experimental_model

Rat ZIP8 transfection and 65Zn uptake

exposure

2 micromolar radiolabeled zinc for 1 hour, 48 hours after transfection.

limitations

Overexpression effect; it does not quantify native human tissue flux.

nutrient_topic

Zinc research collection; topical membership is not evidence of a direct dietary effect. · Zinc

organism

Rat protein in human HEK293T cells

plain_language

Rat ZIP8 increased zinc entry when expressed in human-derived cells.

primary_references

[zinc-trans-22898811] ZIP8 is an iron and zinc transporter whose cell-surface expression is up-regulated by cellular iron loading. (2012). https://pubmed.ncbi.nlm.nih.gov/22898811/ DOI: 10.1074/jbc.m112.367284

tissue_or_cell_type

Cultured-cell plasma membrane

Zinc: transport, enzyme loading, deficiency and nutrient interactions (2026-09-17) · lines 427–438

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Rat ZIP8 transfection and 65Zn uptake · source_derived_draft · unverified_draft

### zinc-trans-zip8-zinc-influx Rat ZIP8 expression in HEK293T cells increased radiolabeled zinc uptake by about 40% compared with empty-vector controls. Condition category: normal nutrient_topic: Zinc research collection; topical membership is not evidence of a direct dietary effect. plain_language: Rat ZIP8 increased zinc entry when expressed in human-derived cells. organism: Rat protein in human HEK293T cells tissue_or_cell_type: Cultured-cell plasma membrane experimental_model: Rat ZIP8 transfection and 65Zn uptake limitations: Overexpression effect; it does not quantify native human tissue flux. exposure: 2 micromolar radiolabeled zinc for 1 hour, 48 hours after transfection. cross_nutrient: false [zinc-trans-22898811] ZIP8 is an iron and zinc transporter whose cell-surface expression is up-regulated by cellular iron loading. (2012). https://pubmed.ncbi.nlm.nih.gov/22898811/ DOI: 10.1074/jbc.m112.367284

cross_nutrient

true

experimental_model

Purified full-length human ZnT1 in proteoliposomes; supporting HEK293T transport assays

exposure

Proteoliposomes with or without internal calcium, external zinc titration; zinc transport Km 0.38 ± 0.14 micromolar in this assay.

limitations

In vitro transport direction depends on liposome gradients. This does not establish dietary calcium dependence or a fixed physiological Zn/Ca ratio. Calcium versus proton coupling remains incompletely resolved.

nutrient_topic

Zinc research collection; topical membership is not evidence of a direct dietary effect. · Zinc

organism

Homo sapiens protein

plain_language

A calcium gradient helped purified human ZnT1 move zinc; some movement remained without it.

primary_references

[zinc-trans-38669333] Structural insights into the calcium-coupled zinc export of human ZnT1. (2024). https://pubmed.ncbi.nlm.nih.gov/38669333/ DOI: 10.1126/sciadv.adk5128

tissue_or_cell_type

Reconstituted membrane; cultured-cell plasma membrane

Zinc: transport, enzyme loading, deficiency and nutrient interactions (2026-09-17) · lines 284–295

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purified full-length human ZnT1 in proteoliposomes; supporting HEK293T transport assays · source_derived_draft · unverified_draft

### zinc-trans-znt1-calcium-gradient In reconstituted human ZnT1 proteoliposomes, a transmembrane calcium gradient accelerated zinc transport and zinc addition drove calcium countertransport. Zinc transport persisted at a lower rate without the calcium gradient. Condition category: normal nutrient_topic: Zinc research collection; topical membership is not evidence of a direct dietary effect. plain_language: A calcium gradient helped purified human ZnT1 move zinc; some movement remained without it. organism: Homo sapiens protein tissue_or_cell_type: Reconstituted membrane; cultured-cell plasma membrane experimental_model: Purified full-length human ZnT1 in proteoliposomes; supporting HEK293T transport assays limitations: In vitro transport direction depends on liposome gradients. This does not establish dietary calcium dependence or a fixed physiological Zn/Ca ratio. Calcium versus proton coupling remains incompletely resolved. exposure: Proteoliposomes with or without internal calcium, external zinc titration; zinc transport Km 0.38 ± 0.14 micromolar in this assay. cross_nutrient: true [zinc-trans-38669333] Structural insights into the calcium-coupled zinc export of human ZnT1. (2024). https://pubmed.ncbi.nlm.nih.gov/38669333/ DOI: 10.1126/sciadv.adk5128

cross_nutrient

false

experimental_model

Wild-type human ZnT1 cryo-EM, biochemical assays and molecular dynamics

exposure

Cryo-EM preparations with 1 mM zinc at pH 6.0 or pH 7.5.

limitations

Conformational snapshots and simulations do not directly quantify coupled proton flux or establish that calcium cannot couple transport. This record preserves observations and labels the interpretation.

nutrient_topic

Zinc research collection; topical membership is not evidence of a direct dietary effect. · Zinc

organism

Homo sapiens protein

plain_language

Acidity changed the shapes captured for human ZnT1, informing one proposed export mechanism.

primary_references

[zinc-trans-39390258] Structural insights into human zinc transporter ZnT1 mediated Zn2+ efflux. (2024). https://pubmed.ncbi.nlm.nih.gov/39390258/ DOI: 10.1038/s44319-024-00287-3

tissue_or_cell_type

Detergent-solubilized purified membrane protein

Zinc: transport, enzyme loading, deficiency and nutrient interactions (2026-09-17) · lines 297–308

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Wild-type human ZnT1 cryo-EM, biochemical assays and molecular dynamics · source_derived_draft · unverified_draft

### zinc-trans-znt1-low-ph-conformations Human ZnT1 purified with zinc at pH 6.0 yielded inward-facing, outward-facing and mixed dimers, whereas the pH 7.5 zinc-bound structure was outward-facing; the authors interpreted structures and simulations as supporting proton-dependent zinc release. Condition category: normal nutrient_topic: Zinc research collection; topical membership is not evidence of a direct dietary effect. plain_language: Acidity changed the shapes captured for human ZnT1, informing one proposed export mechanism. organism: Homo sapiens protein tissue_or_cell_type: Detergent-solubilized purified membrane protein experimental_model: Wild-type human ZnT1 cryo-EM, biochemical assays and molecular dynamics limitations: Conformational snapshots and simulations do not directly quantify coupled proton flux or establish that calcium cannot couple transport. This record preserves observations and labels the interpretation. exposure: Cryo-EM preparations with 1 mM zinc at pH 6.0 or pH 7.5. cross_nutrient: false [zinc-trans-39390258] Structural insights into human zinc transporter ZnT1 mediated Zn2+ efflux. (2024). https://pubmed.ncbi.nlm.nih.gov/39390258/ DOI: 10.1038/s44319-024-00287-3

availability_state

machinery_impairment Imported condition classification; unverified.

cross_nutrient

false

experimental_model

Wild-type/mutant coexpression in HEK293 cells

exposure

H54R plus wild type compared with wild type alone.

limitations

Negative result in an overexpression assay; it does not establish complete compensation in lactating women or the penetrance of the variant.

nutrient_topic

Zinc research collection; topical membership is not evidence of a direct dietary effect. · Zinc

organism

Homo sapiens

plain_language

In this assay, the H54R variant did not block the working ZnT2 protein.

primary_references

[zinc-trans-17065149] Identification of a mutation in SLC30A2 (ZnT-2) in women with low milk zinc concentration that results in transient neonatal zinc deficiency. (2006). https://pubmed.ncbi.nlm.nih.gov/17065149/ DOI: 10.1074/jbc.m605821200

tissue_or_cell_type

HEK293 cells

trigger_kind

machinery_impairment Imported condition classification; unverified.

Zinc: transport, enzyme loading, deficiency and nutrient interactions (2026-09-17) · lines 323–334

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Wild-type/mutant coexpression in HEK293 cells · source_derived_draft · unverified_draft

### zinc-trans-znt2-h54r-coexpression Coexpressing human ZnT2 H54R with wild-type ZnT2 did not abolish the increased zinc secretion produced by wild-type ZnT2 overexpression alone. Condition category: machinery_impairment nutrient_topic: Zinc research collection; topical membership is not evidence of a direct dietary effect. plain_language: In this assay, the H54R variant did not block the working ZnT2 protein. organism: Homo sapiens tissue_or_cell_type: HEK293 cells experimental_model: Wild-type/mutant coexpression in HEK293 cells limitations: Negative result in an overexpression assay; it does not establish complete compensation in lactating women or the penetrance of the variant. exposure: H54R plus wild type compared with wild type alone. cross_nutrient: false [zinc-trans-17065149] Identification of a mutation in SLC30A2 (ZnT-2) in women with low milk zinc concentration that results in transient neonatal zinc deficiency. (2006). https://pubmed.ncbi.nlm.nih.gov/17065149/ DOI: 10.1074/jbc.m605821200

availability_state

machinery_impairment Imported condition classification; unverified.

cross_nutrient

false

experimental_model

H54R expression and localization assays in HEK293 cells

exposure

H54R compared with wild-type ZnT2.

limitations

Cultured kidney-derived cells do not reproduce all lactating mammary processes; a specific variant cannot represent all maternal low-zinc milk.

nutrient_topic

Zinc research collection; topical membership is not evidence of a direct dietary effect. · Zinc

organism

Homo sapiens

plain_language

A milk-zinc-associated ZnT2 variant was misplaced inside cells and exported less zinc.

primary_references

[zinc-trans-17065149] Identification of a mutation in SLC30A2 (ZnT-2) in women with low milk zinc concentration that results in transient neonatal zinc deficiency. (2006). https://pubmed.ncbi.nlm.nih.gov/17065149/ DOI: 10.1074/jbc.m605821200

tissue_or_cell_type

HEK293 cells; variant identified in mothers with low milk zinc

trigger_kind

machinery_impairment Imported condition classification; unverified.

Zinc: transport, enzyme loading, deficiency and nutrient interactions (2026-09-17) · lines 310–321

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · H54R expression and localization assays in HEK293 cells · source_derived_draft · unverified_draft

### zinc-trans-znt2-h54r-export Human ZnT2 H54R expressed in HEK293 cells accumulated in perinuclear aggresomal structures and showed reduced zinc secretion. Condition category: machinery_impairment nutrient_topic: Zinc research collection; topical membership is not evidence of a direct dietary effect. plain_language: A milk-zinc-associated ZnT2 variant was misplaced inside cells and exported less zinc. organism: Homo sapiens tissue_or_cell_type: HEK293 cells; variant identified in mothers with low milk zinc experimental_model: H54R expression and localization assays in HEK293 cells limitations: Cultured kidney-derived cells do not reproduce all lactating mammary processes; a specific variant cannot represent all maternal low-zinc milk. exposure: H54R compared with wild-type ZnT2. cross_nutrient: false [zinc-trans-17065149] Identification of a mutation in SLC30A2 (ZnT-2) in women with low milk zinc concentration that results in transient neonatal zinc deficiency. (2006). https://pubmed.ncbi.nlm.nih.gov/17065149/ DOI: 10.1074/jbc.m605821200

availability_state

machinery_impairment Imported condition classification; unverified.

cross_nutrient

false

experimental_model

Human ZnT2 variants in zinc-sensitive DT40 cells; sequence reference NP_001004434

exposure

S296L variant compared with wild type.

limitations

Intrinsic activity and protein abundance must be separated; the variant is not described as completely transport-inactive.

nutrient_topic

Zinc research collection; topical membership is not evidence of a direct dietary effect. · Zinc

organism

Human protein in Gallus gallus cells

plain_language

Another ZnT2 variant could work when present, but was unstable.

primary_references

[zinc-trans-23741301] Compound heterozygous mutations in SLC30A2/ZnT2 results in low milk zinc concentrations: a novel mechanism for zinc deficiency in a breast-fed infant. (2013). https://pubmed.ncbi.nlm.nih.gov/23741301/ DOI: 10.1371/journal.pone.0064045

tissue_or_cell_type

Engineered DT40 cells

trigger_kind

machinery_impairment Imported condition classification; unverified.

Zinc: transport, enzyme loading, deficiency and nutrient interactions (2026-09-17) · lines 349–360

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human ZnT2 variants in zinc-sensitive DT40 cells; sequence reference NP_001004434 · source_derived_draft · unverified_draft

### zinc-trans-znt2-s296l-stability Human ZnT2 S296L retained zinc transport and dimer-forming capacity in the DT40 characterization but had markedly reduced protein stability. Condition category: machinery_impairment nutrient_topic: Zinc research collection; topical membership is not evidence of a direct dietary effect. plain_language: Another ZnT2 variant could work when present, but was unstable. organism: Human protein in Gallus gallus cells tissue_or_cell_type: Engineered DT40 cells experimental_model: Human ZnT2 variants in zinc-sensitive DT40 cells; sequence reference NP_001004434 limitations: Intrinsic activity and protein abundance must be separated; the variant is not described as completely transport-inactive. exposure: S296L variant compared with wild type. cross_nutrient: false [zinc-trans-23741301] Compound heterozygous mutations in SLC30A2/ZnT2 results in low milk zinc concentrations: a novel mechanism for zinc deficiency in a breast-fed infant. (2013). https://pubmed.ncbi.nlm.nih.gov/23741301/ DOI: 10.1371/journal.pone.0064045

availability_state

machinery_impairment Imported condition classification; unverified.

cross_nutrient

false

experimental_model

Human ZnT2 constructs in zinc-sensitive chicken DT40 cells; sequence reference NP_001004434

exposure

W152R compared with wild type; functional complementation and zinc-handling assays.

limitations

Model tests intrinsic variant function; DT40 survival/compartment readouts are not direct measurement of zinc secretion into human milk.

nutrient_topic

Zinc research collection; topical membership is not evidence of a direct dietary effect. · Zinc

organism

Human protein in Gallus gallus cells

plain_language

One maternal ZnT2 variant could no longer move zinc in the test cells.

primary_references

[zinc-trans-23741301] Compound heterozygous mutations in SLC30A2/ZnT2 results in low milk zinc concentrations: a novel mechanism for zinc deficiency in a breast-fed infant. (2013). https://pubmed.ncbi.nlm.nih.gov/23741301/ DOI: 10.1371/journal.pone.0064045

tissue_or_cell_type

Engineered DT40-cell zinc compartments

trigger_kind

machinery_impairment Imported condition classification; unverified.

Zinc: transport, enzyme loading, deficiency and nutrient interactions (2026-09-17) · lines 336–347

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human ZnT2 constructs in zinc-sensitive chicken DT40 cells; sequence reference NP_001004434 · source_derived_draft · unverified_draft

### zinc-trans-znt2-w152r-transport Human ZnT2 W152R lost zinc transport activity in zinc-sensitive DT40 cells. Condition category: machinery_impairment nutrient_topic: Zinc research collection; topical membership is not evidence of a direct dietary effect. plain_language: One maternal ZnT2 variant could no longer move zinc in the test cells. organism: Human protein in Gallus gallus cells tissue_or_cell_type: Engineered DT40-cell zinc compartments experimental_model: Human ZnT2 constructs in zinc-sensitive chicken DT40 cells; sequence reference NP_001004434 limitations: Model tests intrinsic variant function; DT40 survival/compartment readouts are not direct measurement of zinc secretion into human milk. exposure: W152R compared with wild type; functional complementation and zinc-handling assays. cross_nutrient: false [zinc-trans-23741301] Compound heterozygous mutations in SLC30A2/ZnT2 results in low milk zinc concentrations: a novel mechanism for zinc deficiency in a breast-fed infant. (2013). https://pubmed.ncbi.nlm.nih.gov/23741301/ DOI: 10.1371/journal.pone.0064045

cross_nutrient

Copper (affected_nutrient); Iron (coadministered_nutrient); Zinc(II) ion (administered_element)

evidence_location

Indexed primary abstract.

evidence_span

{"source_cache": "artifacts/zinc-clinical-sources/yadrick1989.abstract.txt", "locator": "Primary indexed abstract; complete local file", "file_sha256": "e2d70d43dded75edb026cac237f238d9e59399db6094098796e169f20e819443", "utf8_bytes": 969}

experimental_model

Ten-week zinc or zinc-plus-iron intervention in adult women

exposure

50 mg elemental zinc/day as gluconate, with or without 50 mg iron/day as ferrous sulfate monohydrate.

limitations

Reported comparisons are within-group pretreatment versus 10 weeks, not placebo-adjusted effects. ESOD is a functional biomarker, not a diagnosis of symptomatic copper deficiency.

nutrient_topic

Zinc research collection; topical membership is not evidence of a direct dietary effect. · Zinc

organism

Homo sapiens

plain_language

Adding iron did not prevent the fall in this copper/zinc enzyme marker.

primary_references

[zn-clin-yadrick1989] Iron, copper, and zinc status: response to supplementation with zinc or zinc and iron in adult females. (1989). https://pubmed.ncbi.nlm.nih.gov/2912000/ DOI: 10.1093/ajcn/49.1.145

tissue_or_cell_type

Blood and erythrocytes

Zinc: transport, enzyme loading, deficiency and nutrient interactions (2026-09-17) · lines 1181–1194

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Ten-week zinc or zinc-plus-iron intervention in adult women · source_derived_draft · unverified_draft

### zn-clin-esod-zinc After ten weeks, erythrocyte Cu/Zn-superoxide dismutase activity was lower than pretreatment in both the zinc-only and zinc-plus-iron groups (P<0.05). Condition category: normal nutrient_topic: Zinc research collection; topical membership is not evidence of a direct dietary effect. plain_language: Adding iron did not prevent the fall in this copper/zinc enzyme marker. organism: Homo sapiens tissue_or_cell_type: Blood and erythrocytes experimental_model: Ten-week zinc or zinc-plus-iron intervention in adult women limitations: Reported comparisons are within-group pretreatment versus 10 weeks, not placebo-adjusted effects. ESOD is a functional biomarker, not a diagnosis of symptomatic copper deficiency. exposure: 50 mg elemental zinc/day as gluconate, with or without 50 mg iron/day as ferrous sulfate monohydrate. cross_nutrient: Copper (affected_nutrient); Iron (coadministered_nutrient); Zinc(II) ion (administered_element) evidence_location: Indexed primary abstract. evidence_span: {"source_cache": "artifacts/zinc-clinical-sources/yadrick1989.abstract.txt", "locator": "Primary indexed abstract; complete local file", "file_sha256": "e2d70d43dded75edb026cac237f238d9e59399db6094098796e169f20e819443", "utf8_bytes": 969} [zn-clin-yadrick1989] Iron, copper, and zinc status: response to supplementation with zinc or zinc and iron in adult females. (1989). https://pubmed.ncbi.nlm.nih.gov/2912000/ DOI: 10.1093/ajcn/49.1.145

cross_nutrient

Ferrous iron (competing_ion); Zinc(II) ion (absorbed_ion)

evidence_location

Indexed primary abstract.

evidence_span

{"source_cache": "artifacts/zinc-clinical-sources/sandstrom1985.abstract.txt", "locator": "Primary indexed abstract; complete local file", "file_sha256": "aa462f6a961ec4190690f8def1be1f5e54491574698b131992161a989103ca76", "utf8_bytes": 1044}

experimental_model

Human 65Zn tracer study with whole-body counting after two weeks

exposure

Ferrous iron with ascorbic acid; Fe:Zn molar ratios 1:1, 2.5:1 and 25:1, in fasting water or a meal; histidine and iron-preloading comparisons.

limitations

Meal matrix, iron ratio and ligand differed. Absolute administered amounts and sample sizes were not verified in the indexed abstract; no universal spacing rule follows.

nutrient_topic

Zinc research collection; topical membership is not evidence of a direct dietary effect. · Zinc

organism

Homo sapiens

plain_language

A ligand changed the interaction between iron and zinc in this experiment.

primary_references

[zn-clin-sandstrom1985] Oral iron, dietary ligands and zinc absorption. (1985). https://pubmed.ncbi.nlm.nih.gov/3973750/ DOI: 10.1093/jn/115.3.411

tissue_or_cell_type

Intestinal absorption

Zinc: transport, enzyme loading, deficiency and nutrient interactions (2026-09-17) · lines 1256–1269

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human 65Zn tracer study with whole-body counting after two weeks · source_derived_draft · unverified_draft

### zn-clin-histidine-iron Adding histidine to the high-iron water solution attenuated inhibition, with zinc absorption of 47% compared with 34% at the high iron ratio without that ligand. Condition category: normal nutrient_topic: Zinc research collection; topical membership is not evidence of a direct dietary effect. plain_language: A ligand changed the interaction between iron and zinc in this experiment. organism: Homo sapiens tissue_or_cell_type: Intestinal absorption experimental_model: Human 65Zn tracer study with whole-body counting after two weeks limitations: Meal matrix, iron ratio and ligand differed. Absolute administered amounts and sample sizes were not verified in the indexed abstract; no universal spacing rule follows. exposure: Ferrous iron with ascorbic acid; Fe:Zn molar ratios 1:1, 2.5:1 and 25:1, in fasting water or a meal; histidine and iron-preloading comparisons. cross_nutrient: Ferrous iron (competing_ion); Zinc(II) ion (absorbed_ion) evidence_location: Indexed primary abstract. evidence_span: {"source_cache": "artifacts/zinc-clinical-sources/sandstrom1985.abstract.txt", "locator": "Primary indexed abstract; complete local file", "file_sha256": "aa462f6a961ec4190690f8def1be1f5e54491574698b131992161a989103ca76", "utf8_bytes": 1044} [zn-clin-sandstrom1985] Oral iron, dietary ligands and zinc absorption. (1985). https://pubmed.ncbi.nlm.nih.gov/3973750/ DOI: 10.1093/jn/115.3.411

cross_nutrient

Zinc(II) ion (absorbed_nutrient_ion); Iron (coadministered_nutrient); L-Ascorbate (coadministered_ligand)

evidence_location

Indexed primary abstract.

evidence_span

{"source_cache": "artifacts/zinc-clinical-sources/sandstrom1985.abstract.txt", "locator": "Primary indexed abstract; complete local file", "file_sha256": "aa462f6a961ec4190690f8def1be1f5e54491574698b131992161a989103ca76", "utf8_bytes": 1044}

experimental_model

Human 65Zn tracer study with whole-body counting after two weeks

exposure

Ferrous iron with ascorbic acid; Fe:Zn molar ratios 1:1, 2.5:1 and 25:1, in fasting water or a meal; histidine and iron-preloading comparisons.

limitations

Meal matrix, iron ratio and ligand differed. Absolute administered amounts and sample sizes were not verified in the indexed abstract; no universal spacing rule follows.

nutrient_topic

Zinc research collection; topical membership is not evidence of a direct dietary effect. · Zinc

organism

Homo sapiens

plain_language

The high iron-to-zinc ratio reduced zinc uptake in the fasting solution.

primary_references

[zn-clin-sandstrom1985] Oral iron, dietary ligands and zinc absorption. (1985). https://pubmed.ncbi.nlm.nih.gov/3973750/ DOI: 10.1093/jn/115.3.411

tissue_or_cell_type

Intestinal absorption

Zinc: transport, enzyme loading, deficiency and nutrient interactions (2026-09-17) · lines 1226–1239

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human 65Zn tracer study with whole-body counting after two weeks · source_derived_draft · unverified_draft

### zn-clin-iron-fasting Fasting-water zinc absorption was 59%, 58% and 34% at ferrous Fe:Zn molar ratios of 1:1, 2.5:1 and 25:1 respectively; inhibition was significant at the highest ratio. Condition category: normal nutrient_topic: Zinc research collection; topical membership is not evidence of a direct dietary effect. plain_language: The high iron-to-zinc ratio reduced zinc uptake in the fasting solution. organism: Homo sapiens tissue_or_cell_type: Intestinal absorption experimental_model: Human 65Zn tracer study with whole-body counting after two weeks limitations: Meal matrix, iron ratio and ligand differed. Absolute administered amounts and sample sizes were not verified in the indexed abstract; no universal spacing rule follows. exposure: Ferrous iron with ascorbic acid; Fe:Zn molar ratios 1:1, 2.5:1 and 25:1, in fasting water or a meal; histidine and iron-preloading comparisons. cross_nutrient: Zinc(II) ion (absorbed_nutrient_ion); Iron (coadministered_nutrient); L-Ascorbate (coadministered_ligand) evidence_location: Indexed primary abstract. evidence_span: {"source_cache": "artifacts/zinc-clinical-sources/sandstrom1985.abstract.txt", "locator": "Primary indexed abstract; complete local file", "file_sha256": "aa462f6a961ec4190690f8def1be1f5e54491574698b131992161a989103ca76", "utf8_bytes": 1044} [zn-clin-sandstrom1985] Oral iron, dietary ligands and zinc absorption. (1985). https://pubmed.ncbi.nlm.nih.gov/3973750/ DOI: 10.1093/jn/115.3.411

cross_nutrient

Zinc(II) ion (absorbed_nutrient_ion); Iron (dietary_context)

evidence_location

Indexed primary abstract.

evidence_span

{"source_cache": "artifacts/zinc-clinical-sources/sandstrom1985.abstract.txt", "locator": "Primary indexed abstract; complete local file", "file_sha256": "aa462f6a961ec4190690f8def1be1f5e54491574698b131992161a989103ca76", "utf8_bytes": 1044}

experimental_model

Human 65Zn tracer study with whole-body counting after two weeks

exposure

Ferrous iron with ascorbic acid; Fe:Zn molar ratios 1:1, 2.5:1 and 25:1, in fasting water or a meal; histidine and iron-preloading comparisons.

limitations

Meal matrix, iron ratio and ligand differed. Absolute administered amounts and sample sizes were not verified in the indexed abstract; no universal spacing rule follows.

nutrient_topic

Zinc research collection; topical membership is not evidence of a direct dietary effect. · Zinc

organism

Homo sapiens

plain_language

The fasting-solution result did not carry over to the tested meal.

primary_references

[zn-clin-sandstrom1985] Oral iron, dietary ligands and zinc absorption. (1985). https://pubmed.ncbi.nlm.nih.gov/3973750/ DOI: 10.1093/jn/115.3.411

tissue_or_cell_type

Intestinal absorption

Zinc: transport, enzyme loading, deficiency and nutrient interactions (2026-09-17) · lines 1241–1254

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human 65Zn tracer study with whole-body counting after two weeks · source_derived_draft · unverified_draft

### zn-clin-iron-meal When the corresponding iron-to-zinc ratios were administered with a meal, zinc absorption was 25%, 23% and 22%, without the inhibitory iron effect detected in fasting water. Two weeks of iron preloading also did not alter zinc absorption from water. Condition category: normal nutrient_topic: Zinc research collection; topical membership is not evidence of a direct dietary effect. plain_language: The fasting-solution result did not carry over to the tested meal. organism: Homo sapiens tissue_or_cell_type: Intestinal absorption experimental_model: Human 65Zn tracer study with whole-body counting after two weeks limitations: Meal matrix, iron ratio and ligand differed. Absolute administered amounts and sample sizes were not verified in the indexed abstract; no universal spacing rule follows. exposure: Ferrous iron with ascorbic acid; Fe:Zn molar ratios 1:1, 2.5:1 and 25:1, in fasting water or a meal; histidine and iron-preloading comparisons. cross_nutrient: Zinc(II) ion (absorbed_nutrient_ion); Iron (dietary_context) evidence_location: Indexed primary abstract. evidence_span: {"source_cache": "artifacts/zinc-clinical-sources/sandstrom1985.abstract.txt", "locator": "Primary indexed abstract; complete local file", "file_sha256": "aa462f6a961ec4190690f8def1be1f5e54491574698b131992161a989103ca76", "utf8_bytes": 1044} [zn-clin-sandstrom1985] Oral iron, dietary ligands and zinc absorption. (1985). https://pubmed.ncbi.nlm.nih.gov/3973750/ DOI: 10.1093/jn/115.3.411

cross_nutrient

ZIP7 phosphorylation (regulatory_event); Zinc(II) ion (transported_ion)

evidence_span

{"source_cache": "artifacts/zinc-signaling-sources/22317921-abstract.txt", "locator": "Primary indexed abstract", "file_sha256": "a8e31db38c22019d7ebef8ff165e2b3dc0b3a338e18514f0bf0c48cc5215944d"}

experimental_model

Human breast-cell model with ZIP7/CK2 perturbations

exposure

Signaling stimuli and ZIP7/CK2 phosphorylation comparisons.

limitations

Cellular signaling study; it does not establish dietary zinc supplementation as an anticancer intervention. Intracellular release is different from net dietary uptake.

nutrient_topic

Zinc research collection; topical membership is not evidence of a direct dietary effect. · Zinc

organism

Homo sapiens

plain_language

A kinase can open the route from stored zinc to a cytoplasmic signal.

primary_references

[zn-sig-22317921] Protein kinase CK2 triggers cytosolic zinc signaling pathways by phosphorylation of zinc channel ZIP7. (2012). https://pubmed.ncbi.nlm.nih.gov/22317921/ DOI: 10.1126/scisignal.2002585

tissue_or_cell_type

Endoplasmic reticulum and cytoplasm

Zinc: transport, enzyme loading, deficiency and nutrient interactions (2026-09-17) · lines 985–997

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human breast-cell model with ZIP7/CK2 perturbations · source_derived_draft · unverified_draft

### zn-sig-ck2-zip7 The study identified CK2-dependent phosphorylation of ZIP7 as a regulatory step preceding cytosolic zinc release from intracellular stores. Condition category: normal nutrient_topic: Zinc research collection; topical membership is not evidence of a direct dietary effect. plain_language: A kinase can open the route from stored zinc to a cytoplasmic signal. organism: Homo sapiens tissue_or_cell_type: Endoplasmic reticulum and cytoplasm experimental_model: Human breast-cell model with ZIP7/CK2 perturbations limitations: Cellular signaling study; it does not establish dietary zinc supplementation as an anticancer intervention. Intracellular release is different from net dietary uptake. exposure: Signaling stimuli and ZIP7/CK2 phosphorylation comparisons. cross_nutrient: ZIP7 phosphorylation (regulatory_event); Zinc(II) ion (transported_ion) evidence_span: {"source_cache": "artifacts/zinc-signaling-sources/22317921-abstract.txt", "locator": "Primary indexed abstract", "file_sha256": "a8e31db38c22019d7ebef8ff165e2b3dc0b3a338e18514f0bf0c48cc5215944d"} [zn-sig-22317921] Protein kinase CK2 triggers cytosolic zinc signaling pathways by phosphorylation of zinc channel ZIP7. (2012). https://pubmed.ncbi.nlm.nih.gov/22317921/ DOI: 10.1126/scisignal.2002585

cross_nutrient

Zinc(II) ion (availability_modifier)

evidence_span

{"source_cache": "artifacts/zinc-signaling-sources/16892068-abstract.txt", "locator": "Primary indexed abstract", "file_sha256": "922aedddf1d5d49fc62e39285307917b93201e23b5b7ea57a60136edd6762a17"}

experimental_model

Dendritic-cell signaling study

exposure

LPS stimulation, zinc supplementation and Zip6 overexpression; exact doses and duration are not verified from the abstract.

limitations

Cell-specific maturation markers are not a general measure of whole-person immune strength. Abstract supports endpoints without unverified protocol details.

nutrient_topic

Zinc research collection; topical membership is not evidence of a direct dietary effect. · Zinc

organism

Mus musculus

plain_language

A lower zinc pool accompanied one dendritic-cell maturation response, illustrating cell-specific regulation.

primary_references

[zn-sig-16892068] Toll-like receptor-mediated regulation of zinc homeostasis influences dendritic cell function. (2006). https://pubmed.ncbi.nlm.nih.gov/16892068/ DOI: 10.1038/ni1373

tissue_or_cell_type

Dendritic cells

Zinc: transport, enzyme loading, deficiency and nutrient interactions (2026-09-17) · lines 1069–1081

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Dendritic-cell signaling study · source_derived_draft · unverified_draft

### zn-sig-dendritic-maturation Zinc supplementation or increased Zip6 expression inhibited LPS-associated upregulation of MHC-II and costimulatory molecules in the dendritic-cell study. Condition category: normal nutrient_topic: Zinc research collection; topical membership is not evidence of a direct dietary effect. plain_language: A lower zinc pool accompanied one dendritic-cell maturation response, illustrating cell-specific regulation. organism: Mus musculus tissue_or_cell_type: Dendritic cells experimental_model: Dendritic-cell signaling study limitations: Cell-specific maturation markers are not a general measure of whole-person immune strength. Abstract supports endpoints without unverified protocol details. exposure: LPS stimulation, zinc supplementation and Zip6 overexpression; exact doses and duration are not verified from the abstract. cross_nutrient: Zinc(II) ion (availability_modifier) evidence_span: {"source_cache": "artifacts/zinc-signaling-sources/16892068-abstract.txt", "locator": "Primary indexed abstract", "file_sha256": "922aedddf1d5d49fc62e39285307917b93201e23b5b7ea57a60136edd6762a17"} [zn-sig-16892068] Toll-like receptor-mediated regulation of zinc homeostasis influences dendritic cell function. (2006). https://pubmed.ncbi.nlm.nih.gov/16892068/ DOI: 10.1038/ni1373

cross_nutrient

Human metal-regulatory transcription factor 1 / MTF1 (human_protein); Mouse metal-regulatory transcription factor 1 / Mtf1 (mouse_protein); Zinc(II) ion (activating_ion)

evidence_span

{"source_cache": "artifacts/zinc-signaling-sources/9507026-abstract.txt", "locator": "Primary indexed abstract", "file_sha256": "ecd19e16b15909d46328c2c5dcd9f9536422db7bb12b9dfd9d91763fafe164bd"}

experimental_model

Human and mouse cell extracts and recombinant MTF1

exposure

Zinc versus other tested transition metals; DNA-binding assays. Glutathione was 1 mM in the recombinant-protein cadmium challenge; this is an in-vitro assay concentration.

limitations

In-vitro metal specificity does not mean all cellular metal responses are mediated by direct MTF1 binding.

nutrient_topic

Zinc research collection; topical membership is not evidence of a direct dietary effect. · Zinc

organism

Homo sapiens; Mus musculus

plain_language

Glutathione helped preserve the zinc-dependent sensor under this chemical stress.

primary_references

[zn-sig-9507026] The DNA binding activity of metal response element-binding transcription factor-1 is activated in vivo and in vitro by zinc, but not by other transition metals. (1998). https://pubmed.ncbi.nlm.nih.gov/9507026/ DOI: 10.1074/jbc.273.12.7127

tissue_or_cell_type

Cell extracts and recombinant protein

Zinc: transport, enzyme loading, deficiency and nutrient interactions (2026-09-17) · lines 887–899

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human and mouse cell extracts and recombinant MTF1 · source_derived_draft · unverified_draft

### zn-sig-gsh-mtf1-protection Glutathione protected recombinant MTF1 from cadmium-mediated inactivation, allowing zinc-dependent DNA-binding activity in the assay. Condition category: normal nutrient_topic: Zinc research collection; topical membership is not evidence of a direct dietary effect. plain_language: Glutathione helped preserve the zinc-dependent sensor under this chemical stress. organism: Homo sapiens; Mus musculus tissue_or_cell_type: Cell extracts and recombinant protein experimental_model: Human and mouse cell extracts and recombinant MTF1 limitations: In-vitro metal specificity does not mean all cellular metal responses are mediated by direct MTF1 binding. exposure: Zinc versus other tested transition metals; DNA-binding assays. Glutathione was 1 mM in the recombinant-protein cadmium challenge; this is an in-vitro assay concentration. cross_nutrient: Human metal-regulatory transcription factor 1 / MTF1 (human_protein); Mouse metal-regulatory transcription factor 1 / Mtf1 (mouse_protein); Zinc(II) ion (activating_ion) evidence_span: {"source_cache": "artifacts/zinc-signaling-sources/9507026-abstract.txt", "locator": "Primary indexed abstract", "file_sha256": "ecd19e16b15909d46328c2c5dcd9f9536422db7bb12b9dfd9d91763fafe164bd"} [zn-sig-9507026] The DNA binding activity of metal response element-binding transcription factor-1 is activated in vivo and in vitro by zinc, but not by other transition metals. (1998). https://pubmed.ncbi.nlm.nih.gov/9507026/ DOI: 10.1074/jbc.273.12.7127

availability_state

machinery_impairment Imported condition classification; unverified.

cross_nutrient

Mouse metal-regulatory transcription factor 1 / Mtf1 (affected_machinery); Mouse metallothionein 1 / Mt1 (regulated_protein); Mouse metallothionein 2 / Mt2 (regulated_protein); Zinc(II) ion (signal)

evidence_span

{"source_cache": "artifacts/zinc-signaling-sources/8026472-abstract.txt", "locator": "Primary indexed abstract", "file_sha256": "6647e4132df7d568ef07c1a33501887c1682b18442af37dbac9f390cd212fea5"}

experimental_model

Mouse embryonic stem cells lacking Mtf1

exposure

Mtf1-null versus control and restored-expression comparisons.

limitations

Genetic transcription-factor loss is not nutritional zinc deficiency.

nutrient_topic

Zinc research collection; topical membership is not evidence of a direct dietary effect. · Zinc

organism

Mus musculus

plain_language

Without the transcription factor, the cell could not activate these zinc-binding proteins.

primary_references

[zn-sig-8026472] The transcription factor MTF-1 is essential for basal and heavy metal-induced metallothionein gene expression. (1994). https://pubmed.ncbi.nlm.nih.gov/8026472/ DOI: 10.1002/j.1460-2075.1994.tb06581.x

tissue_or_cell_type

Embryonic stem cells

trigger_kind

machinery_impairment Imported condition classification; unverified.

Zinc: transport, enzyme loading, deficiency and nutrient interactions (2026-09-17) · lines 859–871

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Mouse embryonic stem cells lacking Mtf1 · source_derived_draft · unverified_draft

### zn-sig-mtf1-mt1 Mtf1-null mouse embryonic stem cells lacked detectable basal and zinc-induced Mt1 and Mt2 transcription. Condition category: machinery_impairment nutrient_topic: Zinc research collection; topical membership is not evidence of a direct dietary effect. plain_language: Without the transcription factor, the cell could not activate these zinc-binding proteins. organism: Mus musculus tissue_or_cell_type: Embryonic stem cells experimental_model: Mouse embryonic stem cells lacking Mtf1 limitations: Genetic transcription-factor loss is not nutritional zinc deficiency. exposure: Mtf1-null versus control and restored-expression comparisons. cross_nutrient: Mouse metal-regulatory transcription factor 1 / Mtf1 (affected_machinery); Mouse metallothionein 1 / Mt1 (regulated_protein); Mouse metallothionein 2 / Mt2 (regulated_protein); Zinc(II) ion (signal) evidence_span: {"source_cache": "artifacts/zinc-signaling-sources/8026472-abstract.txt", "locator": "Primary indexed abstract", "file_sha256": "6647e4132df7d568ef07c1a33501887c1682b18442af37dbac9f390cd212fea5"} [zn-sig-8026472] The transcription factor MTF-1 is essential for basal and heavy metal-induced metallothionein gene expression. (1994). https://pubmed.ncbi.nlm.nih.gov/8026472/ DOI: 10.1002/j.1460-2075.1994.tb06581.x

cross_nutrient

Zinc(II) ion (transported_ion)

evidence_span

{"source_cache": "artifacts/zinc-signaling-sources/21422171-abstract.txt", "locator": "Primary indexed abstract", "file_sha256": "e3b0e519eb5c44185655c0195cb81c713f2b005d70a982466e3e041e997fae59"}

experimental_model

Primary human T-cell receptor signaling study

exposure

Receptor activation, extracellular zinc availability and ZIP6 suppression comparisons.

limitations

Culture zinc availability and local signals cannot be mapped directly to oral doses or plasma thresholds. Calcium fluorescence tracks the signal rather than proving one specific calcium channel mechanism.

nutrient_topic

Zinc research collection; topical membership is not evidence of a direct dietary effect. · Zinc

organism

Homo sapiens

plain_language

ZIP6 helped generate a rapid local zinc signal after receptor activation.

primary_references

[zn-sig-21422171] Regulation of T cell receptor signaling by activation-induced zinc influx. (2011). https://pubmed.ncbi.nlm.nih.gov/21422171/ DOI: 10.1084/jem.20100031

tissue_or_cell_type

CD4 T cells at the receptor-contact region

Zinc: transport, enzyme loading, deficiency and nutrient interactions (2026-09-17) · lines 1013–1025

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Primary human T-cell receptor signaling study · source_derived_draft · unverified_draft

### zn-sig-zip6-influx T-cell receptor activation raised cytoplasmic zinc within one minute, especially near the receptor-contact region; the rise depended on extracellular zinc and was attenuated by ZIP6 suppression. Condition category: normal nutrient_topic: Zinc research collection; topical membership is not evidence of a direct dietary effect. plain_language: ZIP6 helped generate a rapid local zinc signal after receptor activation. organism: Homo sapiens tissue_or_cell_type: CD4 T cells at the receptor-contact region experimental_model: Primary human T-cell receptor signaling study limitations: Culture zinc availability and local signals cannot be mapped directly to oral doses or plasma thresholds. Calcium fluorescence tracks the signal rather than proving one specific calcium channel mechanism. exposure: Receptor activation, extracellular zinc availability and ZIP6 suppression comparisons. cross_nutrient: Zinc(II) ion (transported_ion) evidence_span: {"source_cache": "artifacts/zinc-signaling-sources/21422171-abstract.txt", "locator": "Primary indexed abstract", "file_sha256": "e3b0e519eb5c44185655c0195cb81c713f2b005d70a982466e3e041e997fae59"} [zn-sig-21422171] Regulation of T cell receptor signaling by activation-induced zinc influx. (2011). https://pubmed.ncbi.nlm.nih.gov/21422171/ DOI: 10.1084/jem.20100031

dose

Single 50 mg tartrazine beverage challenge

duration

120 min monitoring

evidence_access

Primary full-text methods/results and metadata.

evidence_scope

literature_reviewed; source-specific experimental curation

experimental_model

Selected children with parent-reported food-color reactions; tartrazine group n=23, matched tartrazine control subgroup n=5

limitations

No placebo challenge group in this 1997 experiment; selected population and small control subgroup. The source reports significant changes, but provides no zinc balance or intracellular threshold. Association does not prove chelation, ADHD causation, or benefit from zinc supplementation.

nutrient_topic

Tartrazine food-colorant chapter; nutrient, drug and peptide interactions retain their models and limits. · Tartrazine

organism

Selected children with parent-reported food-color reactions; tartrazine group n=23, matched tartrazine control subgroup n=5

plain_language

The small matched control subgroup showed no significant zinc change after tartrazine.

primary_references

Assessment of Chemical Factors in Relation to Child Hyperactivity (1997). https://doi.org/10.1080/13590849762466 DOI: 10.1080/13590849762466

route

Oral beverage

tissue

Serum and urine zinc

Tartrazine: mechanisms, molecular forms and cross-actor connections (2026-09-20) · lines 303–312

Original AI-assisted curation of eighteen primary studies. Study-specific citations, negative findings and limitations retained. Not publisher full text. · supports · Selected children with parent-reported food-color reactions; tartrazine group n=23, matched tartrazine control subgroup n=5 · source_derived_draft · unverified_draft

## tartrazine-zinc-control-null The small matched control subgroup showed no significant zinc change after tartrazine. Model/species: Selected children with parent-reported food-color reactions; tartrazine group n=23, matched tartrazine control subgroup n=5 Tissue: Serum and urine zinc Exposure: Single 50 mg tartrazine beverage challenge Route: Oral beverage Duration: 120 min monitoring Limits: No placebo challenge group in this 1997 experiment; selected population and small control subgroup. The source reports significant changes, but provides no zinc balance or intracellular threshold. Association does not prove chelation, ADHD causation, or benefit from zinc supplementation. Primary reference: Assessment of Chemical Factors in Relation to Child Hyperactivity (1997). https://doi.org/10.1080/13590849762466 DOI: 10.1080/13590849762466 Access: Primary full-text methods/results and metadata.

dose

Single 50 mg tartrazine beverage challenge

duration

120 min monitoring

evidence_access

Primary full-text methods/results and metadata.

evidence_scope

literature_reviewed; source-specific experimental curation

experimental_model

Selected children with parent-reported food-color reactions; tartrazine group n=23, matched tartrazine control subgroup n=5

limitations

No placebo challenge group in this 1997 experiment; selected population and small control subgroup. The source reports significant changes, but provides no zinc balance or intracellular threshold. Association does not prove chelation, ADHD causation, or benefit from zinc supplementation.

nutrient_topic

Tartrazine food-colorant chapter; nutrient, drug and peptide interactions retain their models and limits. · Tartrazine

organism

Selected children with parent-reported food-color reactions; tartrazine group n=23, matched tartrazine control subgroup n=5

plain_language

The selected food-color-reactive children had lower serum zinc after the tartrazine challenge.

primary_references

Assessment of Chemical Factors in Relation to Child Hyperactivity (1997). https://doi.org/10.1080/13590849762466 DOI: 10.1080/13590849762466

route

Oral beverage

tissue

Serum and urine zinc

Tartrazine: mechanisms, molecular forms and cross-actor connections (2026-09-20) · lines 281–290

Original AI-assisted curation of eighteen primary studies. Study-specific citations, negative findings and limitations retained. Not publisher full text. · supports · Selected children with parent-reported food-color reactions; tartrazine group n=23, matched tartrazine control subgroup n=5 · source_derived_draft · unverified_draft

## tartrazine-zinc-serum The selected food-color-reactive children had lower serum zinc after the tartrazine challenge. Model/species: Selected children with parent-reported food-color reactions; tartrazine group n=23, matched tartrazine control subgroup n=5 Tissue: Serum and urine zinc Exposure: Single 50 mg tartrazine beverage challenge Route: Oral beverage Duration: 120 min monitoring Limits: No placebo challenge group in this 1997 experiment; selected population and small control subgroup. The source reports significant changes, but provides no zinc balance or intracellular threshold. Association does not prove chelation, ADHD causation, or benefit from zinc supplementation. Primary reference: Assessment of Chemical Factors in Relation to Child Hyperactivity (1997). https://doi.org/10.1080/13590849762466 DOI: 10.1080/13590849762466 Access: Primary full-text methods/results and metadata.

dose

Single 50 mg tartrazine beverage challenge

duration

120 min monitoring

evidence_access

Primary full-text methods/results and metadata.

evidence_scope

literature_reviewed; source-specific experimental curation

experimental_model

Selected children with parent-reported food-color reactions; tartrazine group n=23, matched tartrazine control subgroup n=5

limitations

No placebo challenge group in this 1997 experiment; selected population and small control subgroup. The source reports significant changes, but provides no zinc balance or intracellular threshold. Association does not prove chelation, ADHD causation, or benefit from zinc supplementation.

nutrient_topic

Tartrazine food-colorant chapter; nutrient, drug and peptide interactions retain their models and limits. · Tartrazine

organism

Selected children with parent-reported food-color reactions; tartrazine group n=23, matched tartrazine control subgroup n=5

plain_language

The selected food-color-reactive children had higher urinary zinc output after the tartrazine challenge.

primary_references

Assessment of Chemical Factors in Relation to Child Hyperactivity (1997). https://doi.org/10.1080/13590849762466 DOI: 10.1080/13590849762466

route

Oral beverage

tissue

Serum and urine zinc

Tartrazine: mechanisms, molecular forms and cross-actor connections (2026-09-20) · lines 292–301

Original AI-assisted curation of eighteen primary studies. Study-specific citations, negative findings and limitations retained. Not publisher full text. · supports · Selected children with parent-reported food-color reactions; tartrazine group n=23, matched tartrazine control subgroup n=5 · source_derived_draft · unverified_draft

## tartrazine-zinc-urine The selected food-color-reactive children had higher urinary zinc output after the tartrazine challenge. Model/species: Selected children with parent-reported food-color reactions; tartrazine group n=23, matched tartrazine control subgroup n=5 Tissue: Serum and urine zinc Exposure: Single 50 mg tartrazine beverage challenge Route: Oral beverage Duration: 120 min monitoring Limits: No placebo challenge group in this 1997 experiment; selected population and small control subgroup. The source reports significant changes, but provides no zinc balance or intracellular threshold. Association does not prove chelation, ADHD causation, or benefit from zinc supplementation. Primary reference: Assessment of Chemical Factors in Relation to Child Hyperactivity (1997). https://doi.org/10.1080/13590849762466 DOI: 10.1080/13590849762466 Access: Primary full-text methods/results and metadata.

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary abstract

experimental_model

Mouse knockout, zinc measurements and transient ischemia.

limitations

The experiment did not test dietary zinc deficiency or toxicity thresholds.

nutrient_topic

L-Cysteine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Cysteine

plain_language

Impaired cysteine supply affected metal handling as well as antioxidant capacity.

primary_references

EAAC1 gene deletion alters zinc homeostasis and exacerbates neuronal injury after transient cerebral ischemia. · 2010 · https://pubmed.ncbi.nlm.nih.gov/21084597/ · DOI 10.1523/JNEUROSCI.2084-10.2010

trigger_kind

machinery_impairment Imported condition classification; unverified.

L-Cysteine: sulfur allocation, redox supply and cross-nutrient mechanisms (2026-09-19) · lines 116–122

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Mouse knockout, zinc measurements and transient ischemia. · source_derived_draft · unverified_draft

## l-cysteine-neuronal-zinc-link Impaired cysteine supply affected metal handling as well as antioxidant capacity. EAAC1-null mice had increased vesicular/cytosolic hippocampal zinc and greater zinc redistribution and neuronal injury after transient cerebral ischemia. Model: Mouse knockout, zinc measurements and transient ischemia. Limitations: The experiment did not test dietary zinc deficiency or toxicity thresholds. Evidence access: Primary abstract EAAC1 gene deletion alters zinc homeostasis and exacerbates neuronal injury after transient cerebral ischemia. · 2010 · https://pubmed.ncbi.nlm.nih.gov/21084597/ · DOI 10.1523/JNEUROSCI.2084-10.2010

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary abstract

experimental_model

Mouse EAAC1-null ischemia model.

limitations

NAC and chelators are separate interventions; the study does not show that extra dietary cysteine and zinc are synergistic.

nutrient_topic

L-Cysteine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Cysteine

plain_language

Restoring precursor supply and binding excess labile zinc were distinct rescue routes.

primary_references

EAAC1 gene deletion alters zinc homeostasis and exacerbates neuronal injury after transient cerebral ischemia. · 2010 · https://pubmed.ncbi.nlm.nih.gov/21084597/ · DOI 10.1523/JNEUROSCI.2084-10.2010

trigger_kind

machinery_impairment Imported condition classification; unverified.

L-Cysteine: sulfur allocation, redox supply and cross-nutrient mechanisms (2026-09-19) · lines 124–130

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Mouse EAAC1-null ischemia model. · source_derived_draft · unverified_draft

## l-cysteine-neuronal-zinc-rescue Restoring precursor supply and binding excess labile zinc were distinct rescue routes. NAC restored neuronal glutathione and normalized basal zinc levels in EAAC1-null mice; NAC or zinc chelation reduced ischemia-associated zinc movement, superoxide and neuronal death. Model: Mouse EAAC1-null ischemia model. Limitations: NAC and chelators are separate interventions; the study does not show that extra dietary cysteine and zinc are synergistic. Evidence access: Primary abstract EAAC1 gene deletion alters zinc homeostasis and exacerbates neuronal injury after transient cerebral ischemia. · 2010 · https://pubmed.ncbi.nlm.nih.gov/21084597/ · DOI 10.1523/JNEUROSCI.2084-10.2010

evidence_access

Primary full text, intervention methods; tocotrienol isomer not specified

experimental_model

Adults aged 65–82; combined supplement and treadmill training.

limitations

The design cannot isolate astaxanthin, tocotrienol or zinc effects or demonstrate synergy among them.

nutrient_topic

Astaxanthin collection; molecular form, preparation, species, exposure and manipulation remain explicit. · Astaxanthin

plain_language

The intervention tested three ingredients with exercise.

primary_references

Astaxanthin supplementation enhances metabolic adaptation with aerobic training in the elderly. · 2021 · https://pubmed.ncbi.nlm.nih.gov/34110707/ · DOI 10.14814/phy2.14887

Astaxanthin: transport, membrane chemistry, signaling and nutrient interactions (2026-09-19) · lines 478–484

AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Adults aged 65–82; combined supplement and treadmill training. · source_derived_draft · unverified_draft

## astaxanthin-combination-training The intervention tested three ingredients with exercise. The older-adult training study used 12 mg astaxanthin, 10 mg tocotrienol and 6 mg zinc per day alongside 12 weeks of exercise; metabolic adaptations differed by sex. Model: Adults aged 65–82; combined supplement and treadmill training. Limitations: The design cannot isolate astaxanthin, tocotrienol or zinc effects or demonstrate synergy among them. Evidence access: Primary full text, intervention methods; tocotrienol isomer not specified Astaxanthin supplementation enhances metabolic adaptation with aerobic training in the elderly. · 2021 · https://pubmed.ncbi.nlm.nih.gov/34110707/ · DOI 10.14814/phy2.14887

evidence_access

Primary abstract

experimental_model

Eight-person four-arm crossover trial.

limitations

Small study; does not establish prevention of heat stroke.

nutrient_topic

Carnosine collection; isomer, preparation, species, exposure and manipulation remain explicit. · L-Carnosine / beta-alanyl-L-histidine

plain_language

A separate challenge model showed a barrier-marker effect.

primary_references

Zinc carnosine works with bovine colostrum in truncating heavy exercise-induced increase in gut permeability in healthy volunteers. · 2016 · https://pubmed.ncbi.nlm.nih.gov/27357095/ · DOI 10.3945/ajcn.116.134403

Carnosine: synthesis, transport, carbonyl chemistry and nutrient interactions (2026-09-19) · lines 380–386

AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Eight-person four-arm crossover trial. · source_derived_draft · unverified_draft

## carnosine-zinc-exercise A separate challenge model showed a barrier-marker effect. Zinc-carnosine reduced the exercise-associated permeability rise after fourteen days; combined colostrum treatment also showed an earlier response. Model: Eight-person four-arm crossover trial. Limitations: Small study; does not establish prevention of heat stroke. Evidence access: Primary abstract Zinc carnosine works with bovine colostrum in truncating heavy exercise-induced increase in gut permeability in healthy volunteers. · 2016 · https://pubmed.ncbi.nlm.nih.gov/27357095/ · DOI 10.3945/ajcn.116.134403

evidence_access

Primary abstract

experimental_model

Ten healthy volunteers; five-day crossover; lactulose:rhamnose measurement.

limitations

Small trial and surrogate endpoint; not free-carnosine efficacy.

nutrient_topic

Carnosine collection; isomer, preparation, species, exposure and manipulation remain explicit. · L-Carnosine / beta-alanyl-L-histidine

plain_language

The complex changed a human intestinal-barrier marker.

primary_references

Zinc carnosine, a health food supplement that stabilises small bowel integrity and stimulates gut repair processes. · 2007 · https://pubmed.ncbi.nlm.nih.gov/16777920/ · DOI 10.1136/gut.2006.099929

Carnosine: synthesis, transport, carbonyl chemistry and nutrient interactions (2026-09-19) · lines 372–378

AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Ten healthy volunteers; five-day crossover; lactulose:rhamnose measurement. · source_derived_draft · unverified_draft

## carnosine-zinc-indomethacin The complex changed a human intestinal-barrier marker. Zinc-carnosine coadministration prevented the significant permeability rise seen during the placebo/indomethacin arm. Model: Ten healthy volunteers; five-day crossover; lactulose:rhamnose measurement. Limitations: Small trial and surrogate endpoint; not free-carnosine efficacy. Evidence access: Primary abstract Zinc carnosine, a health food supplement that stabilises small bowel integrity and stimulates gut repair processes. · 2007 · https://pubmed.ncbi.nlm.nih.gov/16777920/ · DOI 10.1136/gut.2006.099929

evidence_access

Primary abstract

experimental_model

Human Caco-2/HT29 cell models with a 2-degree temperature increase.

limitations

Cell experiments do not prove this mediated the volunteer outcome.

nutrient_topic

Carnosine collection; isomer, preparation, species, exposure and manipulation remain explicit. · L-Carnosine / beta-alanyl-L-histidine

plain_language

Tight-junction proteins offered a possible explanation.

primary_references

Zinc carnosine works with bovine colostrum in truncating heavy exercise-induced increase in gut permeability in healthy volunteers. · 2016 · https://pubmed.ncbi.nlm.nih.gov/27357095/ · DOI 10.3945/ajcn.116.134403

Carnosine: synthesis, transport, carbonyl chemistry and nutrient interactions (2026-09-19) · lines 388–394

AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Human Caco-2/HT29 cell models with a 2-degree temperature increase. · source_derived_draft · unverified_draft

## carnosine-zinc-occludin Tight-junction proteins offered a possible explanation. In heated intestinal-cell models, zinc-carnosine increased total occludin and reduced measured occludin phosphorylation changes. Model: Human Caco-2/HT29 cell models with a 2-degree temperature increase. Limitations: Cell experiments do not prove this mediated the volunteer outcome. Evidence access: Primary abstract Zinc carnosine works with bovine colostrum in truncating heavy exercise-induced increase in gut permeability in healthy volunteers. · 2016 · https://pubmed.ncbi.nlm.nih.gov/27357095/ · DOI 10.3945/ajcn.116.134403

evidence_access

Primary abstract

experimental_model

Human HT29 culture.

limitations

Cell proliferation is not universally beneficial and is not proof of whole-gut healing.

nutrient_topic

Carnosine collection; isomer, preparation, species, exposure and manipulation remain explicit. · L-Carnosine / beta-alanyl-L-histidine

plain_language

Cell growth was measured separately from migration.

primary_references

Zinc carnosine, a health food supplement that stabilises small bowel integrity and stimulates gut repair processes. · 2007 · https://pubmed.ncbi.nlm.nih.gov/16777920/ · DOI 10.1136/gut.2006.099929

Carnosine: synthesis, transport, carbonyl chemistry and nutrient interactions (2026-09-19) · lines 364–370

AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Human HT29 culture. · source_derived_draft · unverified_draft

## carnosine-zinc-proliferation Cell growth was measured separately from migration. Zinc-carnosine increased HT29 proliferation in thymidine-incorporation assays. Model: Human HT29 culture. Limitations: Cell proliferation is not universally beneficial and is not proof of whole-gut healing. Evidence access: Primary abstract Zinc carnosine, a health food supplement that stabilises small bowel integrity and stimulates gut repair processes. · 2007 · https://pubmed.ncbi.nlm.nih.gov/16777920/ · DOI 10.1136/gut.2006.099929

evidence_access

Primary abstract

experimental_model

Human colon-derived HT29 cells; maximal reported response near 100 micromolar.

limitations

Complex-specific experiment; not automatically attributable to free carnosine.

nutrient_topic

Carnosine collection; isomer, preparation, species, exposure and manipulation remain explicit. · L-Carnosine / beta-alanyl-L-histidine

plain_language

The zinc complex supported repair behavior in culture.

primary_references

Zinc carnosine, a health food supplement that stabilises small bowel integrity and stimulates gut repair processes. · 2007 · https://pubmed.ncbi.nlm.nih.gov/16777920/ · DOI 10.1136/gut.2006.099929

Carnosine: synthesis, transport, carbonyl chemistry and nutrient interactions (2026-09-19) · lines 356–362

AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Human colon-derived HT29 cells; maximal reported response near 100 micromolar. · source_derived_draft · unverified_draft

## carnosine-zinc-repair The zinc complex supported repair behavior in culture. Zinc-carnosine treatment stimulated epithelial migration in wounded HT29 monolayers. Model: Human colon-derived HT29 cells; maximal reported response near 100 micromolar. Limitations: Complex-specific experiment; not automatically attributable to free carnosine. Evidence access: Primary abstract Zinc carnosine, a health food supplement that stabilises small bowel integrity and stimulates gut repair processes. · 2007 · https://pubmed.ncbi.nlm.nih.gov/16777920/ · DOI 10.1136/gut.2006.099929

cross_nutrient

Zinc and cobalt substitutions were less effective than Mn; in-vitro substitution does not establish nutritional equivalence.

experimental_model

Metal-substitution crystallography and kinetics of purified human ARG1

exposure

Non-native metal reconstitution or added zinc

limitations

Primary experimental scope only; no human dietary threshold, clinical treatment rule, or universal metal substitution is established.

nutrient_topic

Manganese research collection; topical membership is not evidence of a direct dietary effect. · Manganese

organism

Homo sapiens protein

plain_language

Manganese gave the most efficient ARG1 catalysis in this comparison.

primary_references

[mn-enz-23061982] Structure and function of non-native metal clusters in human arginase I. (2012). https://pubmed.ncbi.nlm.nih.gov/23061982/ DOI: 10.1021/bi301145n

tissue_or_cell_type

Purified enzyme

Manganese: enzyme cofactors, glycosylation, transport and nutrient interactions (2026-09-17) · lines 546–557

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Metal-substitution crystallography and kinetics of purified human ARG1 · source_derived_draft · unverified_draft

### mn-enz-arg1-manganese-optimum For reconstituted human ARG1, turnover and catalytic efficiency ranked Mn(II) > Ni(II) ≈ Co(II) ≫ Zn(II). Condition category: normal nutrient_topic: Manganese research collection; topical membership is not evidence of a direct dietary effect. plain_language: Manganese gave the most efficient ARG1 catalysis in this comparison. organism: Homo sapiens protein tissue_or_cell_type: Purified enzyme experimental_model: Metal-substitution crystallography and kinetics of purified human ARG1 limitations: Primary experimental scope only; no human dietary threshold, clinical treatment rule, or universal metal substitution is established. exposure: Non-native metal reconstitution or added zinc cross_nutrient: Zinc and cobalt substitutions were less effective than Mn; in-vitro substitution does not establish nutritional equivalence. [mn-enz-23061982] Structure and function of non-native metal clusters in human arginase I. (2012). https://pubmed.ncbi.nlm.nih.gov/23061982/ DOI: 10.1021/bi301145n

cross_nutrient

Copper and zinc cofactor identity in SOD1 is distinguished from Mn-dependent SOD2.

experimental_model

NMR of copper-depleted human SOD1 C6A/C111S preparation

exposure

Copper-depleted zinc-containing disulfide-reduced preparation

limitations

The study structurally examined the C6A/C111S copper-depleted, zinc-containing preparation. This identity statement does not assert Mn can replace either SOD1 metal.

nutrient_topic

Manganese research collection; topical membership is not evidence of a direct dietary effect. · Manganese

organism

Homo sapiens protein

plain_language

SOD1 and SOD2 use different metals.

primary_references

[mn-enz-16291742] Human SOD1 before harboring the catalytic metal: solution structure of copper-depleted, disulfide-reduced form. (2006). https://pubmed.ncbi.nlm.nih.gov/16291742/ DOI: 10.1074/jbc.m506497200

tissue_or_cell_type

Purified SOD1

Manganese: enzyme cofactors, glycosylation, transport and nutrient interactions (2026-09-17) · lines 458–469

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · NMR of copper-depleted human SOD1 C6A/C111S preparation · source_derived_draft · unverified_draft

### mn-enz-sod1-distinct-metals Human SOD1 maturation involves copper and zinc insertion and a Cys57–Cys146 disulfide; this is a different metalloprotein system from manganese SOD2. Condition category: normal nutrient_topic: Manganese research collection; topical membership is not evidence of a direct dietary effect. plain_language: SOD1 and SOD2 use different metals. organism: Homo sapiens protein tissue_or_cell_type: Purified SOD1 experimental_model: NMR of copper-depleted human SOD1 C6A/C111S preparation limitations: The study structurally examined the C6A/C111S copper-depleted, zinc-containing preparation. This identity statement does not assert Mn can replace either SOD1 metal. exposure: Copper-depleted zinc-containing disulfide-reduced preparation cross_nutrient: Copper and zinc cofactor identity in SOD1 is distinguished from Mn-dependent SOD2. [mn-enz-16291742] Human SOD1 before harboring the catalytic metal: solution structure of copper-depleted, disulfide-reduced form. (2006). https://pubmed.ncbi.nlm.nih.gov/16291742/ DOI: 10.1074/jbc.m506497200

cross_nutrient

true

experimental_model

Purified full-length human SLC30A10 reconstituted into liposomes; Figure 1f and Supplementary Figure 3e-g

exposure

Separate MnCl2, ZnCl2, CaCl2 and MgCl2 proteoliposome transport tests.

limitations

The negative results are assay-bounded; they do not rule out calcium coupling under other gradients, establish exchange stoichiometry, or define a nutritional threshold.

nutrient_topic

Manganese research collection; topical membership is not evidence of a direct dietary effect. · Manganese

organism

Human protein

plain_language

The purified transporter carried manganese without measurable transport of the three comparison metals in this assay.

primary_references

[mn-trans-41022720] Molecular mechanisms of SLC30A10-mediated manganese transport. (2025). https://pubmed.ncbi.nlm.nih.gov/41022720/ DOI: 10.1038/s41467-025-63616-7

tissue_or_cell_type

Proteoliposomes

Manganese: enzyme cofactors, glycosylation, transport and nutrient interactions (2026-09-17) · lines 396–407

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purified full-length human SLC30A10 reconstituted into liposomes; Figure 1f and Supplementary Figure 3e-g · source_derived_draft · unverified_draft

### mn-trans-slc30a10-metal-selectivity Reconstituted human SLC30A10 transported Mn(II), while the same study detected no significant Zn(II), Ca(II) or Mg(II) transport under its tested conditions. Condition category: normal nutrient_topic: Manganese research collection; topical membership is not evidence of a direct dietary effect. plain_language: The purified transporter carried manganese without measurable transport of the three comparison metals in this assay. organism: Human protein tissue_or_cell_type: Proteoliposomes experimental_model: Purified full-length human SLC30A10 reconstituted into liposomes; Figure 1f and Supplementary Figure 3e-g limitations: The negative results are assay-bounded; they do not rule out calcium coupling under other gradients, establish exchange stoichiometry, or define a nutritional threshold. exposure: Separate MnCl2, ZnCl2, CaCl2 and MgCl2 proteoliposome transport tests. cross_nutrient: true [mn-trans-41022720] Molecular mechanisms of SLC30A10-mediated manganese transport. (2025). https://pubmed.ncbi.nlm.nih.gov/41022720/ DOI: 10.1038/s41467-025-63616-7

availability_state

nutrient_deficiency Imported condition classification; unverified.

cross_nutrient

Zinc -> hepatic retinoid metabolism.

experimental_model

Pair-feeding controls; three weeks.

limitations

Does not show that every retinol dehydrogenase is a zinc enzyme.

nutrient_topic

Vitamin A research collection; topical membership is not evidence of a direct dietary effect. · Vitamin A

organism

Rattus norvegicus

plain_language

Zinc depletion changed retinoid handling in the liver.

primary_references

[va-kim1988] Effect of zinc deficiency on hepatic enzymes regulating vitamin A status (1988). https://pubmed.ncbi.nlm.nih.gov/3404291/ DOI: 10.1093/jn/118.8.995

tissue_or_cell_type

Liver

trigger_kind

nutrient_deficiency Imported condition classification; unverified.

Vitamin A: forms, mechanisms, deficiency and excess (2026-09-17) · lines 1519–1529

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Pair-feeding controls; three weeks. · source_derived_draft · unverified_draft

### va-zinc-deficiency-adh-decrease Zinc-deficient rats had lower hepatic retinol-oxidizing ADH activity and greater hepatic vitamin A content. Condition category: nutrient_deficiency nutrient_topic: Vitamin A research collection; topical membership is not evidence of a direct dietary effect. plain_language: Zinc depletion changed retinoid handling in the liver. organism: Rattus norvegicus tissue_or_cell_type: Liver experimental_model: Pair-feeding controls; three weeks. limitations: Does not show that every retinol dehydrogenase is a zinc enzyme. cross_nutrient: Zinc -> hepatic retinoid metabolism. [va-kim1988] Effect of zinc deficiency on hepatic enzymes regulating vitamin A status (1988). https://pubmed.ncbi.nlm.nih.gov/3404291/ DOI: 10.1093/jn/118.8.995

cross_nutrient

Zinc -> vitamin A biomarkers.

experimental_model

Six-month preschool trial.

limitations

No direct proof of restored liver release or increased RBP synthesis.

nutrient_topic

Vitamin A research collection; topical membership is not evidence of a direct dietary effect. · Vitamin A

organism

Homo sapiens

plain_language

Zinc status can influence vitamin A transport-related blood measurements.

primary_references

[va-munoz2000] Iron and zinc supplementation improves indicators of vitamin A status of Mexican preschoolers (2000). https://pubmed.ncbi.nlm.nih.gov/10702174/ DOI: 10.1093/ajcn/71.3.789

tissue_or_cell_type

Plasma

Vitamin A: forms, mechanisms, deficiency and excess (2026-09-17) · lines 1483–1493

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Six-month preschool trial. · source_derived_draft · unverified_draft

### va-zinc-improves-retinol-marker Zinc increased plasma retinol and transthyretin versus placebo; the RBP increase was not significant. Condition category: normal nutrient_topic: Vitamin A research collection; topical membership is not evidence of a direct dietary effect. plain_language: Zinc status can influence vitamin A transport-related blood measurements. organism: Homo sapiens tissue_or_cell_type: Plasma experimental_model: Six-month preschool trial. limitations: No direct proof of restored liver release or increased RBP synthesis. cross_nutrient: Zinc -> vitamin A biomarkers. [va-munoz2000] Iron and zinc supplementation improves indicators of vitamin A status of Mexican preschoolers (2000). https://pubmed.ncbi.nlm.nih.gov/10702174/ DOI: 10.1093/ajcn/71.3.789

availability_state

nutrient_deficiency Imported condition classification; unverified.

cross_nutrient

Zinc/vitamin A -> dark-adaptation response.

experimental_model

Three-week zinc randomization, existing vitamin A allocation.

limitations

Not a universal zinc requirement; relative estimate had a wide confidence interval.

nutrient_topic

Vitamin A research collection; topical membership is not evidence of a direct dietary effect. · Vitamin A

organism

Homo sapiens

plain_language

An additional shortage may limit the response, but this result was subgroup-specific.

primary_references

[va-christian2001] Zinc supplementation might potentiate the effect of vitamin A in restoring night vision in pregnant Nepalese women (2001). https://pubmed.ncbi.nlm.nih.gov/11382658/ DOI: 10.1093/ajcn/73.6.1045

tissue_or_cell_type

Human visual function

trigger_kind

nutrient_deficiency Imported condition classification; unverified.

Vitamin A: forms, mechanisms, deficiency and excess (2026-09-17) · lines 1507–1517

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Three-week zinc randomization, existing vitamin A allocation. · source_derived_draft · unverified_draft

### va-zinc-night-vision-subgroup In women with low initial zinc, vitamin A plus zinc improved night-vision recovery versus double placebo; zinc alone did not. Condition category: nutrient_deficiency nutrient_topic: Vitamin A research collection; topical membership is not evidence of a direct dietary effect. plain_language: An additional shortage may limit the response, but this result was subgroup-specific. organism: Homo sapiens tissue_or_cell_type: Human visual function experimental_model: Three-week zinc randomization, existing vitamin A allocation. limitations: Not a universal zinc requirement; relative estimate had a wide confidence interval. cross_nutrient: Zinc/vitamin A -> dark-adaptation response. [va-christian2001] Zinc supplementation might potentiate the effect of vitamin A in restoring night vision in pregnant Nepalese women (2001). https://pubmed.ncbi.nlm.nih.gov/11382658/ DOI: 10.1093/ajcn/73.6.1045