Copper(I) ion

evidence_access

Primary abstract

experimental_model

Spectroscopy and competition against histidine/phenanthroline.

limitations

This is not demonstrated copper depletion in humans.

nutrient_topic

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

plain_language

Copper oxidation state matters for binding.

primary_references

Ergothioneine prevents copper-induced oxidative damage to DNA and protein by forming a redox-inactive ergothioneine-copper complex. · 2011 · https://pubmed.ncbi.nlm.nih.gov/21047085/ · DOI 10.1021/tx100214t

Ergothioneine: transport, redox chemistry and cross-nutrient mechanisms (2026-09-19) · lines 120–126

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Spectroscopy and competition against histidine/phenanthroline. · source_derived_draft · unverified_draft

## ergothioneine-copper-binding Copper oxidation state matters for binding. Ergothioneine bound copper(I), rather than copper(II), and formed a redox-inactive complex in the tested chemical systems. Model: Spectroscopy and competition against histidine/phenanthroline. Limitations: This is not demonstrated copper depletion in humans. Evidence access: Primary abstract Ergothioneine prevents copper-induced oxidative damage to DNA and protein by forming a redox-inactive ergothioneine-copper complex. · 2011 · https://pubmed.ncbi.nlm.nih.gov/21047085/ · DOI 10.1021/tx100214t

evidence_span

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experimental_model

Biochemistry, solution NMR and small-angle X-ray scattering

exposure

Apo versus copper-loaded ATOX1

limitations

Domain motion and ATP hydrolysis were studied directly; these assays do not establish a whole-body copper requirement.

nutrient_topic

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

organism

Human proteins

plain_language

The courier also helps switch on the copper pump.

primary_references

[copper-p28900031] The metal chaperone Atox1 regulates the activity of the human copper transporter ATP7B by modulating domain dynamics. (2017). https://pubmed.ncbi.nlm.nih.gov/28900031/ DOI: 10.1074/jbc.m117.811752

tissue_or_cell_type

Purified ATOX1 and ATP7B domains

Copper: transport, cuproenzymes, deficiency, excess and nutrient interactions (2026-09-17) · lines 390–401

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Biochemistry, solution NMR and small-angle X-ray scattering · source_derived_draft · unverified_draft

### copper-atox1-atp7b-activation Copper-loaded ATOX1 activated ATP7B ATP hydrolysis while changing interactions among its first three metal-binding domains. Condition category: normal nutrient_topic: Copper research collection; topical membership is not evidence of a direct dietary effect. plain_language: The courier also helps switch on the copper pump. organism: Human proteins tissue_or_cell_type: Purified ATOX1 and ATP7B domains experimental_model: Biochemistry, solution NMR and small-angle X-ray scattering limitations: Domain motion and ATP hydrolysis were studied directly; these assays do not establish a whole-body copper requirement. exposure: Apo versus copper-loaded ATOX1 evidence_span: {"source_cache": "artifacts/copper-research/28900031.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "64fceb98b5bf2ca406f26799cea5832b0306883118b9ad2416ba87db47b18ce8", "start_char": 0, "end_char": 1471, "text_sha256": "64fceb98b5bf2ca406f26799cea5832b0306883118b9ad2416ba87db47b18ce8"} [copper-p28900031] The metal chaperone Atox1 regulates the activity of the human copper transporter ATP7B by modulating domain dynamics. (2017). https://pubmed.ncbi.nlm.nih.gov/28900031/ DOI: 10.1074/jbc.m117.811752

evidence_span

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experimental_model

Mouse Steap expression constructs and metal-reduction assays

exposure

Transient expression of Steap2, Steap3 or Steap4

limitations

Protein species verified in primary Methods (PMC1785011). Overexpression does not establish the dominant intestinal reductase in humans; relative activity can reflect localization and abundance.

nutrient_topic

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

organism

Mouse proteins expressed in human HEK293T cells

plain_language

This enzyme prepares copper in a chemical form compatible with uptake.

primary_references

[copper-p16609065] The Steap proteins are metalloreductases. (2006). https://pubmed.ncbi.nlm.nih.gov/16609065/ DOI: 10.1182/blood-2006-02-003681

tissue_or_cell_type

Cell surface and endosomal compartments

Copper: transport, cuproenzymes, deficiency, excess and nutrient interactions (2026-09-17) · lines 273–284

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Mouse Steap expression constructs and metal-reduction assays · source_derived_draft · unverified_draft

### copper-steap2-reduces-copper Expressed mouse Steap2 reduced Cu(II) to Cu(I) and increased cellular copper uptake in the tested human cell system. Condition category: normal nutrient_topic: Copper research collection; topical membership is not evidence of a direct dietary effect. plain_language: This enzyme prepares copper in a chemical form compatible with uptake. organism: Mouse proteins expressed in human HEK293T cells tissue_or_cell_type: Cell surface and endosomal compartments experimental_model: Mouse Steap expression constructs and metal-reduction assays limitations: Protein species verified in primary Methods (PMC1785011). Overexpression does not establish the dominant intestinal reductase in humans; relative activity can reflect localization and abundance. exposure: Transient expression of Steap2, Steap3 or Steap4 evidence_span: {"source_cache": "artifacts/copper-research/16609065.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "d0f42a3f30c22ba4235d82f21ba165c78b6c519a6218f487411fb2247ecc0d9f", "start_char": 0, "end_char": 827, "text_sha256": "d0f42a3f30c22ba4235d82f21ba165c78b6c519a6218f487411fb2247ecc0d9f"} [copper-p16609065] The Steap proteins are metalloreductases. (2006). https://pubmed.ncbi.nlm.nih.gov/16609065/ DOI: 10.1182/blood-2006-02-003681

evidence_span

{"source_cache": "artifacts/copper-research/16609065.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "d0f42a3f30c22ba4235d82f21ba165c78b6c519a6218f487411fb2247ecc0d9f", "start_char": 0, "end_char": 827, "text_sha256": "d0f42a3f30c22ba4235d82f21ba165c78b6c519a6218f487411fb2247ecc0d9f"}

experimental_model

Mouse Steap expression constructs and metal-reduction assays

exposure

Transient expression of Steap2, Steap3 or Steap4

limitations

Protein species verified in primary Methods (PMC1785011). Overexpression does not establish the dominant intestinal reductase in humans; relative activity can reflect localization and abundance.

nutrient_topic

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

organism

Mouse proteins expressed in human HEK293T cells

plain_language

This enzyme prepares copper in a chemical form compatible with uptake.

primary_references

[copper-p16609065] The Steap proteins are metalloreductases. (2006). https://pubmed.ncbi.nlm.nih.gov/16609065/ DOI: 10.1182/blood-2006-02-003681

tissue_or_cell_type

Cell surface and endosomal compartments

Copper: transport, cuproenzymes, deficiency, excess and nutrient interactions (2026-09-17) · lines 286–297

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Mouse Steap expression constructs and metal-reduction assays · source_derived_draft · unverified_draft

### copper-steap3-reduces-copper Expressed mouse Steap3 reduced Cu(II) to Cu(I) and increased cellular copper uptake in the tested human cell system. Condition category: normal nutrient_topic: Copper research collection; topical membership is not evidence of a direct dietary effect. plain_language: This enzyme prepares copper in a chemical form compatible with uptake. organism: Mouse proteins expressed in human HEK293T cells tissue_or_cell_type: Cell surface and endosomal compartments experimental_model: Mouse Steap expression constructs and metal-reduction assays limitations: Protein species verified in primary Methods (PMC1785011). Overexpression does not establish the dominant intestinal reductase in humans; relative activity can reflect localization and abundance. exposure: Transient expression of Steap2, Steap3 or Steap4 evidence_span: {"source_cache": "artifacts/copper-research/16609065.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "d0f42a3f30c22ba4235d82f21ba165c78b6c519a6218f487411fb2247ecc0d9f", "start_char": 0, "end_char": 827, "text_sha256": "d0f42a3f30c22ba4235d82f21ba165c78b6c519a6218f487411fb2247ecc0d9f"} [copper-p16609065] The Steap proteins are metalloreductases. (2006). https://pubmed.ncbi.nlm.nih.gov/16609065/ DOI: 10.1182/blood-2006-02-003681

evidence_span

{"source_cache": "artifacts/copper-research/16609065.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "d0f42a3f30c22ba4235d82f21ba165c78b6c519a6218f487411fb2247ecc0d9f", "start_char": 0, "end_char": 827, "text_sha256": "d0f42a3f30c22ba4235d82f21ba165c78b6c519a6218f487411fb2247ecc0d9f"}

experimental_model

Mouse Steap expression constructs and metal-reduction assays

exposure

Transient expression of Steap2, Steap3 or Steap4

limitations

Protein species verified in primary Methods (PMC1785011). Overexpression does not establish the dominant intestinal reductase in humans; relative activity can reflect localization and abundance.

nutrient_topic

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

organism

Mouse proteins expressed in human HEK293T cells

plain_language

This enzyme prepares copper in a chemical form compatible with uptake.

primary_references

[copper-p16609065] The Steap proteins are metalloreductases. (2006). https://pubmed.ncbi.nlm.nih.gov/16609065/ DOI: 10.1182/blood-2006-02-003681

tissue_or_cell_type

Cell surface and endosomal compartments

Copper: transport, cuproenzymes, deficiency, excess and nutrient interactions (2026-09-17) · lines 299–310

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Mouse Steap expression constructs and metal-reduction assays · source_derived_draft · unverified_draft

### copper-steap4-reduces-copper Expressed mouse Steap4 reduced Cu(II) to Cu(I) and increased cellular copper uptake in the tested human cell system. Condition category: normal nutrient_topic: Copper research collection; topical membership is not evidence of a direct dietary effect. plain_language: This enzyme prepares copper in a chemical form compatible with uptake. organism: Mouse proteins expressed in human HEK293T cells tissue_or_cell_type: Cell surface and endosomal compartments experimental_model: Mouse Steap expression constructs and metal-reduction assays limitations: Protein species verified in primary Methods (PMC1785011). Overexpression does not establish the dominant intestinal reductase in humans; relative activity can reflect localization and abundance. exposure: Transient expression of Steap2, Steap3 or Steap4 evidence_span: {"source_cache": "artifacts/copper-research/16609065.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "d0f42a3f30c22ba4235d82f21ba165c78b6c519a6218f487411fb2247ecc0d9f", "start_char": 0, "end_char": 827, "text_sha256": "d0f42a3f30c22ba4235d82f21ba165c78b6c519a6218f487411fb2247ecc0d9f"} [copper-p16609065] The Steap proteins are metalloreductases. (2006). https://pubmed.ncbi.nlm.nih.gov/16609065/ DOI: 10.1182/blood-2006-02-003681

evidence_access

Primary abstract

experimental_model

Cell-free copper/ascorbate and copper/peroxide systems.

limitations

Exposure and free-metal speciation limit extrapolation.

nutrient_topic

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

plain_language

Binding the catalyst can protect several targets.

primary_references

Ergothioneine prevents copper-induced oxidative damage to DNA and protein by forming a redox-inactive ergothioneine-copper complex. · 2011 · https://pubmed.ncbi.nlm.nih.gov/21047085/ · DOI 10.1021/tx100214t

Ergothioneine: transport, redox chemistry and cross-nutrient mechanisms (2026-09-19) · lines 128–134

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Cell-free copper/ascorbate and copper/peroxide systems. · source_derived_draft · unverified_draft

## ergothioneine-copper-oxidation Binding the catalyst can protect several targets. Ergothioneine at 0.1-1 mM protected DNA and albumin against 0.1 mM copper with ascorbate or peroxide. Model: Cell-free copper/ascorbate and copper/peroxide systems. Limitations: Exposure and free-metal speciation limit extrapolation. Evidence access: Primary abstract Ergothioneine prevents copper-induced oxidative damage to DNA and protein by forming a redox-inactive ergothioneine-copper complex. · 2011 · https://pubmed.ncbi.nlm.nih.gov/21047085/ · DOI 10.1021/tx100214t

evidence_span

{"source_cache": "artifacts/ala-research/9680174.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "ac15770e92102947345520296b7795e8ff2dca2c345ac76c14b929fbd19739f1", "start_char": 0, "end_char": 2034, "text_sha256": "ac15770e92102947345520296b7795e8ff2dca2c345ac76c14b929fbd19739f1"}

experimental_model

Cell-free human LDL oxidation and electron-spin-resonance assays

exposure

Copper 5 micromolar; DHLA 0–20 micromolar; oxygen and pH varied

limitations

Metal binding, reduction and radical production depend on ratio, oxygen and pH; not evidence for human metal-detoxification efficacy.

nutrient_topic

Alpha-lipoic acid research collection; topical membership is not evidence of a direct dietary effect. · Lipoic acid

organism

Human LDL; cell-free chemistry

plain_language

Whether copper was bound or chemically reduced depended on the relative amounts.

primary_references

[ala-p9680174] Thiol chelation of Cu2+ by dihydrolipoic acid prevents human low density lipoprotein peroxidation. (1998). https://pubmed.ncbi.nlm.nih.gov/9680174/ DOI: 10.1016/s0891-5849(98)00048-3

tissue_or_cell_type

LDL and copper/DHLA solutions

Alpha-lipoic acid: cofactor assembly, redox signaling and nutrient interactions (2026-09-17) · lines 1053–1064

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Cell-free human LDL oxidation and electron-spin-resonance assays · source_derived_draft · unverified_draft

### ala-dhla-copper-ratio DHLA favored copper reduction when copper was in excess and chelation when DHLA was in excess. Condition category: normal nutrient_topic: Alpha-lipoic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: Whether copper was bound or chemically reduced depended on the relative amounts. organism: Human LDL; cell-free chemistry tissue_or_cell_type: LDL and copper/DHLA solutions experimental_model: Cell-free human LDL oxidation and electron-spin-resonance assays limitations: Metal binding, reduction and radical production depend on ratio, oxygen and pH; not evidence for human metal-detoxification efficacy. exposure: Copper 5 micromolar; DHLA 0–20 micromolar; oxygen and pH varied evidence_span: {"source_cache": "artifacts/ala-research/9680174.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "ac15770e92102947345520296b7795e8ff2dca2c345ac76c14b929fbd19739f1", "start_char": 0, "end_char": 2034, "text_sha256": "ac15770e92102947345520296b7795e8ff2dca2c345ac76c14b929fbd19739f1"} [ala-p9680174] Thiol chelation of Cu2+ by dihydrolipoic acid prevents human low density lipoprotein peroxidation. (1998). https://pubmed.ncbi.nlm.nih.gov/9680174/ DOI: 10.1016/s0891-5849(98)00048-3

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

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

evidence_span

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experimental_model

Computational and binding comparison of metformin and propanediimidamide with copper

exposure

Copper(I) and copper(II) binding energies, pKa and hydrophilicity

limitations

A chemistry study proposing a pro-oxidant role. It is explicitly a hypothesis about mitochondrial activity, not a cellular measurement.

nutrient_topic

Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. · Metformin

organism

Chemical and computational

plain_language

The drug grabs copper tightly enough that it could pull it off proteins and oxidise it.

primary_references

[metformin-p24433134] Biomolecular mode of action of metformin in relation to its copper binding properties. (2014). https://pubmed.ncbi.nlm.nih.gov/24433134/ DOI: 10.1021/bi401444n

tissue_or_cell_type

Molecular interaction

Metformin: transport, molecular targets, gut mechanisms and nutrient interactions (2026-09-19) · lines 1373–1384

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Computational and binding comparison of metformin and propanediimidamide with copper · source_derived_draft · unverified_draft

### metformin-copper-binding-chemistry Metformin can occur as an anion in aqueous medium at moderate pH and forms much stronger complexes with Cu(II) ions than the comparator propanediimidamide, suggesting that biguanides may induce oxidation of Cu(I) ions extracted from proteins. Condition category: normal nutrient_topic: Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. plain_language: The drug grabs copper tightly enough that it could pull it off proteins and oxidise it. organism: Chemical and computational tissue_or_cell_type: Molecular interaction experimental_model: Computational and binding comparison of metformin and propanediimidamide with copper limitations: A chemistry study proposing a pro-oxidant role. It is explicitly a hypothesis about mitochondrial activity, not a cellular measurement. exposure: Copper(I) and copper(II) binding energies, pKa and hydrophilicity evidence_span: {"source_cache": "artifacts/metformin-research/24433134.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "a6dda36e30a49ba48e8200b6de36f39a8ab80a1bcbda819c03d3442bb8705963", "start_char": 0, "end_char": 1430, "text_sha256": "a6dda36e30a49ba48e8200b6de36f39a8ab80a1bcbda819c03d3442bb8705963"} [metformin-p24433134] Biomolecular mode of action of metformin in relation to its copper binding properties. (2014). https://pubmed.ncbi.nlm.nih.gov/24433134/ DOI: 10.1021/bi401444n

cross_nutrient

Vitamin C chemistry in collagen, modified-lysine/carnitine metabolism or copper-dependent peptide/catecholamine processing.

experimental_model

Bovine dopamine beta-hydroxylase X-ray absorption and EXAFS

exposure

Ascorbate reduction of purified Cu(II)-DBH to Cu(I)-DBH.

limitations

Purified bovine enzyme, not a dietary copper-status measurement. Scott 1988 and Blumberg 1989 disagree on the detailed coordination change and heavy-atom ligation; this record retains only the shared Cu(II)-to-Cu(I) redox conclusion.

nutrient_topic

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

organism

Bos taurus

plain_language

Vitamin C supplies reducing power to copper held inside this neurotransmitter enzyme.

primary_references

[scott1988] The copper sites of dopamine beta-hydroxylase: an X-ray absorption spectroscopic study. (1988). https://pubmed.ncbi.nlm.nih.gov/3179263/ DOI: 10.1021/bi00415a005 [blumberg1989] X-ray absorption spectroscopic study of the active copper sites in dopamine beta-hydroxylase. (1989). https://pubmed.ncbi.nlm.nih.gov/2703478/ DOI: 10.1016/s0021-9258(18)83307-5

tissue_or_cell_type

Adrenal-medullary enzyme preparation

Vitamin C: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 793–805

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Bovine dopamine beta-hydroxylase X-ray absorption and EXAFS · source_derived_draft · unverified_draft

### vc-enzyme-dbh-copper-reduction Ascorbate reduced enzyme-bound copper in purified bovine dopamine beta-hydroxylase from Cu(II) to Cu(I), as examined by X-ray absorption spectroscopy. Condition category: normal nutrient_topic: Vitamin C research collection; topical membership is not evidence of a direct dietary effect. plain_language: Vitamin C supplies reducing power to copper held inside this neurotransmitter enzyme. organism: Bos taurus tissue_or_cell_type: Adrenal-medullary enzyme preparation experimental_model: Bovine dopamine beta-hydroxylase X-ray absorption and EXAFS limitations: Purified bovine enzyme, not a dietary copper-status measurement. Scott 1988 and Blumberg 1989 disagree on the detailed coordination change and heavy-atom ligation; this record retains only the shared Cu(II)-to-Cu(I) redox conclusion. cross_nutrient: Vitamin C chemistry in collagen, modified-lysine/carnitine metabolism or copper-dependent peptide/catecholamine processing. exposure: Ascorbate reduction of purified Cu(II)-DBH to Cu(I)-DBH. [scott1988] The copper sites of dopamine beta-hydroxylase: an X-ray absorption spectroscopic study. (1988). https://pubmed.ncbi.nlm.nih.gov/3179263/ DOI: 10.1021/bi00415a005 [blumberg1989] X-ray absorption spectroscopic study of the active copper sites in dopamine beta-hydroxylase. (1989). https://pubmed.ncbi.nlm.nih.gov/2703478/ DOI: 10.1016/s0021-9258(18)83307-5