Nutrient chapter

L-Proline

Study-scoped entity; inspect species, exposure and experimental limitations on each claim.

66 recorded mechanisms · 11 availability situations · 9 preserved sources. Draft and verified records are labeled separately.

Read recorded mechanisms Open recursive mind map

The mechanisms

What the sources say this nutrient does, one relationship at a time. Plain wording comes first; the technical statement follows.

Recombinant human PYCR1 reduced P5C to proline with NADH or NADPH; in the tested conditions its specific activity was higher with NADH.
Human pyrroline-5-carboxylate reductase 1 / PYCR1 → L-Proline source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary full text
experimental_model
Purified human enzyme; comparison with 0.1 mM P5C and 0.1 mM reduced cofactor, 37 degrees C.
limitations
Cofactor preference depends on assay conditions and does not make the alternative cofactor unusable.
nutrient_topic
L-Proline collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Proline
plain_language
One mitochondrial enzyme finishes the synthesis of proline.
primary_references
Functional specialization in proline biosynthesis of melanoma. · 2012 · https://pubmed.ncbi.nlm.nih.gov/23024808/ · DOI 10.1371/journal.pone.0045190
L-Proline: synthesis, collagen processing, redox metabolism and cross-nutrient mechanisms (2026-09-19) · lines 14–20
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Purified human enzyme; comparison with 0.1 mM P5C and 0.1 mM reduced cofactor, 37 degrees C. · source_derived_draft · unverified_draft
## l-proline-pycr1-reduction One mitochondrial enzyme finishes the synthesis of proline. Recombinant human PYCR1 reduced P5C to proline with NADH or NADPH; in the tested conditions its specific activity was higher with NADH. Model: Purified human enzyme; comparison with 0.1 mM P5C and 0.1 mM reduced cofactor, 37 degrees C. Limitations: Cofactor preference depends on assay conditions and does not make the alternative cofactor unusable. Evidence access: Primary full text Functional specialization in proline biosynthesis of melanoma. · 2012 · https://pubmed.ncbi.nlm.nih.gov/23024808/ · DOI 10.1371/journal.pone.0045190
Complete structured claim and evidence
Recombinant human PYCR2 reduced P5C to proline and favored NADH over NADPH under the reported comparison conditions.
Human pyrroline-5-carboxylate reductase 2 / PYCR2 → L-Proline source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary full text
experimental_model
Purified human PYCR2 and human melanoma-cell localization experiments.
limitations
PYCR2 has its own identity and disease associations; it is not interchangeable with PYCR1.
nutrient_topic
L-Proline collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Proline
plain_language
A second mitochondrial enzyme performs the final reduction.
primary_references
Functional specialization in proline biosynthesis of melanoma. · 2012 · https://pubmed.ncbi.nlm.nih.gov/23024808/ · DOI 10.1371/journal.pone.0045190
L-Proline: synthesis, collagen processing, redox metabolism and cross-nutrient mechanisms (2026-09-19) · lines 22–28
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Purified human PYCR2 and human melanoma-cell localization experiments. · source_derived_draft · unverified_draft
## l-proline-pycr2-reduction A second mitochondrial enzyme performs the final reduction. Recombinant human PYCR2 reduced P5C to proline and favored NADH over NADPH under the reported comparison conditions. Model: Purified human PYCR2 and human melanoma-cell localization experiments. Limitations: PYCR2 has its own identity and disease associations; it is not interchangeable with PYCR1. Evidence access: Primary full text Functional specialization in proline biosynthesis of melanoma. · 2012 · https://pubmed.ncbi.nlm.nih.gov/23024808/ · DOI 10.1371/journal.pone.0045190
Complete structured claim and evidence
Human PYCRL/PYCR3 localized predominantly to the cytosol in the tested melanoma cells and was more efficient with NADPH in the biochemical comparison.
Human pyrroline-5-carboxylate reductase 3 / PYCR3 / PYCRL → L-Proline source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary full text
experimental_model
Lu1205 cell fractionation and recombinant human PYCRL kinetics.
limitations
The melanoma routing pattern is not asserted to apply identically in every human tissue.
nutrient_topic
L-Proline collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Proline
plain_language
The cytosolic version has different preferences from the mitochondrial enzymes.
primary_references
Functional specialization in proline biosynthesis of melanoma. · 2012 · https://pubmed.ncbi.nlm.nih.gov/23024808/ · DOI 10.1371/journal.pone.0045190
L-Proline: synthesis, collagen processing, redox metabolism and cross-nutrient mechanisms (2026-09-19) · lines 30–36
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Lu1205 cell fractionation and recombinant human PYCRL kinetics. · source_derived_draft · unverified_draft
## l-proline-pycr3-reduction The cytosolic version has different preferences from the mitochondrial enzymes. Human PYCRL/PYCR3 localized predominantly to the cytosol in the tested melanoma cells and was more efficient with NADPH in the biochemical comparison. Model: Lu1205 cell fractionation and recombinant human PYCRL kinetics. Limitations: The melanoma routing pattern is not asserted to apply identically in every human tissue. Evidence access: Primary full text Functional specialization in proline biosynthesis of melanoma. · 2012 · https://pubmed.ncbi.nlm.nih.gov/23024808/ · DOI 10.1371/journal.pone.0045190
Complete structured claim and evidence
Isotope tracing with gene silencing linked glutamine/glutamate-derived proline mainly to PYCR1/PYCR2 and ornithine-derived proline mainly to PYCRL in human melanoma cells.
L-Ornithine → L-Proline source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary full text
experimental_model
Lu1205 cells; 1 mM labeled precursors for eight hours; ornithine labeling required omission of extracellular proline.
limitations
The ornithine experiment used conditions the authors regarded as likely nonphysiological; no universal exclusive routing rule is inferred.
nutrient_topic
L-Proline collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Proline
plain_language
Two precursor routes can feed the same product through differently placed enzymes.
primary_references
Functional specialization in proline biosynthesis of melanoma. · 2012 · https://pubmed.ncbi.nlm.nih.gov/23024808/ · DOI 10.1371/journal.pone.0045190
L-Proline: synthesis, collagen processing, redox metabolism and cross-nutrient mechanisms (2026-09-19) · lines 38–44
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Lu1205 cells; 1 mM labeled precursors for eight hours; ornithine labeling required omission of extracellular proline. · source_derived_draft · unverified_draft
## l-proline-precursor-routing Two precursor routes can feed the same product through differently placed enzymes. Isotope tracing with gene silencing linked glutamine/glutamate-derived proline mainly to PYCR1/PYCR2 and ornithine-derived proline mainly to PYCRL in human melanoma cells. Model: Lu1205 cells; 1 mM labeled precursors for eight hours; ornithine labeling required omission of extracellular proline. Limitations: The ornithine experiment used conditions the authors regarded as likely nonphysiological; no universal exclusive routing rule is inferred. Evidence access: Primary full text Functional specialization in proline biosynthesis of melanoma. · 2012 · https://pubmed.ncbi.nlm.nih.gov/23024808/ · DOI 10.1371/journal.pone.0045190
Complete structured claim and evidence
Proline inhibited recombinant PYCR2 more strongly than PYCR1 or PYCRL; approximate apparent inhibition constants were 0.1, 0.6 and 8 mM, respectively.
L-Proline → Human pyrroline-5-carboxylate reductase 2 / PYCR2 source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary full text
experimental_model
Purified human enzymes; product-inhibition assays, with PYCR2 losing about 90% activity at 0.3 mM proline.
limitations
These assay concentrations are not blood targets or supplement recommendations.
nutrient_topic
L-Proline collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Proline
plain_language
Accumulating product can slow further production, with unequal sensitivity among enzymes.
primary_references
Functional specialization in proline biosynthesis of melanoma. · 2012 · https://pubmed.ncbi.nlm.nih.gov/23024808/ · DOI 10.1371/journal.pone.0045190
L-Proline: synthesis, collagen processing, redox metabolism and cross-nutrient mechanisms (2026-09-19) · lines 46–52
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Purified human enzymes; product-inhibition assays, with PYCR2 losing about 90% activity at 0.3 mM proline. · source_derived_draft · unverified_draft
## l-proline-product-feedback Accumulating product can slow further production, with unequal sensitivity among enzymes. Proline inhibited recombinant PYCR2 more strongly than PYCR1 or PYCRL; approximate apparent inhibition constants were 0.1, 0.6 and 8 mM, respectively. Model: Purified human enzymes; product-inhibition assays, with PYCR2 losing about 90% activity at 0.3 mM proline. Limitations: These assay concentrations are not blood targets or supplement recommendations. Evidence access: Primary full text Functional specialization in proline biosynthesis of melanoma. · 2012 · https://pubmed.ncbi.nlm.nih.gov/23024808/ · DOI 10.1371/journal.pone.0045190
Complete structured claim and evidence
CRISPR deletion of NADK2 in human DLD1 cells reduced mitochondrial NADP(H) by more than 80% while whole-cell NADP(H) was not similarly depleted.
NADK2 → Mitochondrial NADP(H) content source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
evidence_access
Primary full text
experimental_model
Human DLD1 cells; immunopurified mitochondrial fractions and enzyme-cycling assays.
limitations
A compartment-specific genetic manipulation is not equivalent to dietary niacin deficiency.
nutrient_topic
L-Proline collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Proline
plain_language
The cofactor pool inside mitochondria can fail even when a whole-cell measurement looks adequate.
primary_references
Mitochondrial NADP(H) generation is essential for proline biosynthesis. · 2021 · https://pubmed.ncbi.nlm.nih.gov/33888598/ · DOI 10.1126/science.abd5491
trigger_kind
machinery_impairment Imported condition classification; unverified.
L-Proline: synthesis, collagen processing, redox metabolism and cross-nutrient mechanisms (2026-09-19) · lines 54–60
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human DLD1 cells; immunopurified mitochondrial fractions and enzyme-cycling assays. · source_derived_draft · unverified_draft
## l-proline-nadk2-pool The cofactor pool inside mitochondria can fail even when a whole-cell measurement looks adequate. CRISPR deletion of NADK2 in human DLD1 cells reduced mitochondrial NADP(H) by more than 80% while whole-cell NADP(H) was not similarly depleted. Model: Human DLD1 cells; immunopurified mitochondrial fractions and enzyme-cycling assays. Limitations: A compartment-specific genetic manipulation is not equivalent to dietary niacin deficiency. Evidence access: Primary full text Mitochondrial NADP(H) generation is essential for proline biosynthesis. · 2021 · https://pubmed.ncbi.nlm.nih.gov/33888598/ · DOI 10.1126/science.abd5491
Complete structured claim and evidence
NADK2 deletion reduced glutamine-derived proline synthesis; mitochondrial NADP(H) was needed for the P5CS step reducing glutamate toward P5C.
NADK2 → L-Proline source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
evidence_access
Primary full text
experimental_model
Human cell deletion, isotope tracing and rescue experiments.
limitations
The limiting step was cofactor-dependent synthesis, not a demonstrated lack of glutamine in the diet.
nutrient_topic
L-Proline collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Proline
plain_language
Proline production needs reducing power in the right compartment.
primary_references
Mitochondrial NADP(H) generation is essential for proline biosynthesis. · 2021 · https://pubmed.ncbi.nlm.nih.gov/33888598/ · DOI 10.1126/science.abd5491
trigger_kind
machinery_impairment Imported condition classification; unverified.
L-Proline: synthesis, collagen processing, redox metabolism and cross-nutrient mechanisms (2026-09-19) · lines 62–68
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human cell deletion, isotope tracing and rescue experiments. · source_derived_draft · unverified_draft
## l-proline-nadk2-proline Proline production needs reducing power in the right compartment. NADK2 deletion reduced glutamine-derived proline synthesis; mitochondrial NADP(H) was needed for the P5CS step reducing glutamate toward P5C. Model: Human cell deletion, isotope tracing and rescue experiments. Limitations: The limiting step was cofactor-dependent synthesis, not a demonstrated lack of glutamine in the diet. Evidence access: Primary full text Mitochondrial NADP(H) generation is essential for proline biosynthesis. · 2021 · https://pubmed.ncbi.nlm.nih.gov/33888598/ · DOI 10.1126/science.abd5491
Complete structured claim and evidence
Adding proline restored growth of NADK2-deleted human cells in minimal medium, whereas the defect was largely absent in nutrient-rich medium.
L-Proline → Human NADK2-null cell proliferation in minimal medium source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
evidence_access
Primary full text
experimental_model
Human NADK2-knockout cell cultures; DMEM compared with DMEM/F12 and individual amino-acid add-back.
limitations
Cell-culture rescue does not establish a treatment for inherited NADK2 disease.
nutrient_topic
L-Proline collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Proline
plain_language
An external supply can bypass a synthesis bottleneck in these cells.
primary_references
Mitochondrial NADP(H) generation is essential for proline biosynthesis. · 2021 · https://pubmed.ncbi.nlm.nih.gov/33888598/ · DOI 10.1126/science.abd5491
trigger_kind
machinery_impairment Imported condition classification; unverified.
L-Proline: synthesis, collagen processing, redox metabolism and cross-nutrient mechanisms (2026-09-19) · lines 70–76
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human NADK2-knockout cell cultures; DMEM compared with DMEM/F12 and individual amino-acid add-back. · source_derived_draft · unverified_draft
## l-proline-nadk2-rescue An external supply can bypass a synthesis bottleneck in these cells. Adding proline restored growth of NADK2-deleted human cells in minimal medium, whereas the defect was largely absent in nutrient-rich medium. Model: Human NADK2-knockout cell cultures; DMEM compared with DMEM/F12 and individual amino-acid add-back. Limitations: Cell-culture rescue does not establish a treatment for inherited NADK2 disease. Evidence access: Primary full text Mitochondrial NADP(H) generation is essential for proline biosynthesis. · 2021 · https://pubmed.ncbi.nlm.nih.gov/33888598/ · DOI 10.1126/science.abd5491
Complete structured claim and evidence
A separate study found NADK2 loss depleted mitochondrial NADPH, limited P5C generation and made tested mammalian cells dependent on exogenous proline for growth.
NADK2 → P5C production during NADK2-dependent proline synthesis source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
evidence_access
Primary abstract
experimental_model
Mammalian NADK2-deletion cell models; primary abstract.
limitations
Detailed model and exposure differences remain distinct; the two publications are not duplicate evidence records from one experiment.
nutrient_topic
L-Proline collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Proline
plain_language
A second research group found the same synthesis vulnerability.
primary_references
Mitochondrial NADP+ is essential for proline biosynthesis during cell growth. · 2021 · https://pubmed.ncbi.nlm.nih.gov/33833463/ · DOI 10.1038/s42255-021-00374-y
trigger_kind
machinery_impairment Imported condition classification; unverified.
L-Proline: synthesis, collagen processing, redox metabolism and cross-nutrient mechanisms (2026-09-19) · lines 78–84
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Mammalian NADK2-deletion cell models; primary abstract. · source_derived_draft · unverified_draft
## l-proline-nadk2-independent-study A second research group found the same synthesis vulnerability. A separate study found NADK2 loss depleted mitochondrial NADPH, limited P5C generation and made tested mammalian cells dependent on exogenous proline for growth. Model: Mammalian NADK2-deletion cell models; primary abstract. Limitations: Detailed model and exposure differences remain distinct; the two publications are not duplicate evidence records from one experiment. Evidence access: Primary abstract Mitochondrial NADP+ is essential for proline biosynthesis during cell growth. · 2021 · https://pubmed.ncbi.nlm.nih.gov/33833463/ · DOI 10.1038/s42255-021-00374-y
Complete structured claim and evidence
Under the tested culture conditions, NADK2 deletion did not increase measured mitochondrial oxidative stress or disrupt mitochondrial folate pathway activity despite reduced proline synthesis.
NADK2 → Oxidative-stress readouts in NADK2-deleted human cells source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
evidence_access
Primary full text
experimental_model
Human cell models; ROS probes, targeted redox sensors and serine isotope tracing.
limitations
The authors do not exclude effects during other physiological stresses; this is not a universal claim that mitochondrial NADPH is irrelevant to antioxidant defense.
nutrient_topic
L-Proline collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Proline
plain_language
Losing this cofactor pool did not shut down every pathway that might be connected to it.
primary_references
Mitochondrial NADP(H) generation is essential for proline biosynthesis. · 2021 · https://pubmed.ncbi.nlm.nih.gov/33888598/ · DOI 10.1126/science.abd5491
trigger_kind
machinery_impairment Imported condition classification; unverified.
L-Proline: synthesis, collagen processing, redox metabolism and cross-nutrient mechanisms (2026-09-19) · lines 86–92
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human cell models; ROS probes, targeted redox sensors and serine isotope tracing. · source_derived_draft · unverified_draft
## l-proline-nadk2-redox-boundary Losing this cofactor pool did not shut down every pathway that might be connected to it. Under the tested culture conditions, NADK2 deletion did not increase measured mitochondrial oxidative stress or disrupt mitochondrial folate pathway activity despite reduced proline synthesis. Model: Human cell models; ROS probes, targeted redox sensors and serine isotope tracing. Limitations: The authors do not exclude effects during other physiological stresses; this is not a universal claim that mitochondrial NADPH is irrelevant to antioxidant defense. Evidence access: Primary full text Mitochondrial NADP(H) generation is essential for proline biosynthesis. · 2021 · https://pubmed.ncbi.nlm.nih.gov/33888598/ · DOI 10.1126/science.abd5491
Complete structured claim and evidence
Mitochondrial PRODH catalyzes the FAD-dependent oxidation of proline to P5C, linking proline breakdown to mitochondrial electron transfer.
Human proline dehydrogenase / PRODH → Delta-1-pyrroline-5-carboxylate / P5C source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary full text; background reaction distinguished from new experiments
experimental_model
Established reaction described in a primary mitochondrial proline-oxidation study.
limitations
The reaction description is biochemical background, distinct from the paper-specific ROS-site experiments.
nutrient_topic
L-Proline collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Proline
plain_language
Breaking proline down starts with a flavin-dependent mitochondrial enzyme.
primary_references
Sources of superoxide/H2O2 during mitochondrial proline oxidation. · 2014 · https://pubmed.ncbi.nlm.nih.gov/25184115/ · DOI 10.1016/j.redox.2014.07.003
L-Proline: synthesis, collagen processing, redox metabolism and cross-nutrient mechanisms (2026-09-19) · lines 94–100
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Established reaction described in a primary mitochondrial proline-oxidation study. · source_derived_draft · unverified_draft
## l-proline-prodh-oxidation Breaking proline down starts with a flavin-dependent mitochondrial enzyme. Mitochondrial PRODH catalyzes the FAD-dependent oxidation of proline to P5C, linking proline breakdown to mitochondrial electron transfer. Model: Established reaction described in a primary mitochondrial proline-oxidation study. Limitations: The reaction description is biochemical background, distinct from the paper-specific ROS-site experiments. Evidence access: Primary full text; background reaction distinguished from new experiments Sources of superoxide/H2O2 during mitochondrial proline oxidation. · 2014 · https://pubmed.ncbi.nlm.nih.gov/25184115/ · DOI 10.1016/j.redox.2014.07.003
Complete structured claim and evidence
ALDH4A1 catalyzes NAD+-dependent oxidation of glutamate semialdehyde to glutamate, completing the second enzymatic stage of proline catabolism.
Human glutamate-5-semialdehyde dehydrogenase / ALDH4A1 → L-Glutamate source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
Human enzyme structures and kinetics; mouse enzyme complexes supplied high-resolution ligand views.
limitations
P5C and glutamate semialdehyde interconvert; the aldehyde is the oxidation substrate. Mouse ligand structures are not relabeled as human complexes.
nutrient_topic
L-Proline collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Proline
plain_language
A second enzyme turns the breakdown intermediate into glutamate.
primary_references
The three-dimensional structural basis of type II hyperprolinemia. · 2012 · https://pubmed.ncbi.nlm.nih.gov/22516612/ · DOI 10.1016/j.jmb.2012.04.010
L-Proline: synthesis, collagen processing, redox metabolism and cross-nutrient mechanisms (2026-09-19) · lines 102–108
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human enzyme structures and kinetics; mouse enzyme complexes supplied high-resolution ligand views. · source_derived_draft · unverified_draft
## l-proline-aldh4-oxidation A second enzyme turns the breakdown intermediate into glutamate. ALDH4A1 catalyzes NAD+-dependent oxidation of glutamate semialdehyde to glutamate, completing the second enzymatic stage of proline catabolism. Model: Human enzyme structures and kinetics; mouse enzyme complexes supplied high-resolution ligand views. Limitations: P5C and glutamate semialdehyde interconvert; the aldehyde is the oxidation substrate. Mouse ligand structures are not relabeled as human complexes. Evidence access: Primary abstract The three-dimensional structural basis of type II hyperprolinemia. · 2012 · https://pubmed.ncbi.nlm.nih.gov/22516612/ · DOI 10.1016/j.jmb.2012.04.010
Complete structured claim and evidence
The human ALDH4A1 S352L disease-associated variant abolished catalytic activity and NAD+ binding, with a major rearrangement of the catalytic loop.
Human glutamate-5-semialdehyde dehydrogenase / ALDH4A1 → Human ALDH4A1 S352L catalytic function source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
evidence_access
Primary abstract
experimental_model
Recombinant human mutant/wild-type structures and kinetic analysis.
limitations
This tests one inherited variant and does not establish a nutrient-addition rescue.
nutrient_topic
L-Proline collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Proline
plain_language
A structural defect can block proline breakdown even when substrate is plentiful.
primary_references
The three-dimensional structural basis of type II hyperprolinemia. · 2012 · https://pubmed.ncbi.nlm.nih.gov/22516612/ · DOI 10.1016/j.jmb.2012.04.010
trigger_kind
machinery_impairment Imported condition classification; unverified.
L-Proline: synthesis, collagen processing, redox metabolism and cross-nutrient mechanisms (2026-09-19) · lines 110–116
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Recombinant human mutant/wild-type structures and kinetic analysis. · source_derived_draft · unverified_draft
## l-proline-aldh4-failure A structural defect can block proline breakdown even when substrate is plentiful. The human ALDH4A1 S352L disease-associated variant abolished catalytic activity and NAD+ binding, with a major rearrangement of the catalytic loop. Model: Recombinant human mutant/wild-type structures and kinetic analysis. Limitations: This tests one inherited variant and does not establish a nutrient-addition rescue. Evidence access: Primary abstract The three-dimensional structural basis of type II hyperprolinemia. · 2012 · https://pubmed.ncbi.nlm.nih.gov/22516612/ · DOI 10.1016/j.jmb.2012.04.010
Complete structured claim and evidence
P5C reacted with pyridoxal phosphate at pH 7.4 and 310 K to form three characterized adducts through condensation involving the PLP aldehyde group.
Delta-1-pyrroline-5-carboxylate / P5C → PLP source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
Cell-free NMR, chromatography and mass-spectrometry experiments motivated by hyperprolinemia type II.
limitations
This demonstrates chemistry under the tested conditions, not B6 depletion from an ordinary proline-containing meal.
nutrient_topic
L-Proline collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Proline
plain_language
An accumulating proline intermediate can chemically trap active vitamin B6.
primary_references
Pyridoxal phosphate de-activation by pyrroline-5-carboxylic acid. Increased risk of vitamin B6 deficiency and seizures in hyperprolinemia type II. · 2001 · https://pubmed.ncbi.nlm.nih.gov/11134058/ · DOI 10.1074/jbc.M010860200
L-Proline: synthesis, collagen processing, redox metabolism and cross-nutrient mechanisms (2026-09-19) · lines 118–124
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Cell-free NMR, chromatography and mass-spectrometry experiments motivated by hyperprolinemia type II. · source_derived_draft · unverified_draft
## l-proline-p5c-b6-trapping An accumulating proline intermediate can chemically trap active vitamin B6. P5C reacted with pyridoxal phosphate at pH 7.4 and 310 K to form three characterized adducts through condensation involving the PLP aldehyde group. Model: Cell-free NMR, chromatography and mass-spectrometry experiments motivated by hyperprolinemia type II. Limitations: This demonstrates chemistry under the tested conditions, not B6 depletion from an ordinary proline-containing meal. Evidence access: Primary abstract Pyridoxal phosphate de-activation by pyrroline-5-carboxylic acid. Increased risk of vitamin B6 deficiency and seizures in hyperprolinemia type II. · 2001 · https://pubmed.ncbi.nlm.nih.gov/11134058/ · DOI 10.1074/jbc.M010860200
Complete structured claim and evidence
The study was prompted by B6 deficiency and seizures in a child with hyperprolinemia type II; the adduct experiments support P5C-mediated cofactor inactivation as a contributing mechanism.
Delta-1-pyrroline-5-carboxylate / P5C → Secondary vitamin B6 deficiency associated with hyperprolinemia type II source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
evidence_access
Primary abstract
experimental_model
Human index-case context combined with in-vitro chemical mechanism.
limitations
Contribution to seizures is an interpretation; the paper does not establish controlled efficacy or a universal treatment dose.
nutrient_topic
L-Proline collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Proline
plain_language
A breakdown disorder can create a secondary cofactor problem.
primary_references
Pyridoxal phosphate de-activation by pyrroline-5-carboxylic acid. Increased risk of vitamin B6 deficiency and seizures in hyperprolinemia type II. · 2001 · https://pubmed.ncbi.nlm.nih.gov/11134058/ · DOI 10.1074/jbc.M010860200
trigger_kind
machinery_impairment Imported condition classification; unverified.
L-Proline: synthesis, collagen processing, redox metabolism and cross-nutrient mechanisms (2026-09-19) · lines 126–132
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human index-case context combined with in-vitro chemical mechanism. · source_derived_draft · unverified_draft
## l-proline-p5c-clinical-link A breakdown disorder can create a secondary cofactor problem. The study was prompted by B6 deficiency and seizures in a child with hyperprolinemia type II; the adduct experiments support P5C-mediated cofactor inactivation as a contributing mechanism. Model: Human index-case context combined with in-vitro chemical mechanism. Limitations: Contribution to seizures is an interpretation; the paper does not establish controlled efficacy or a universal treatment dose. Evidence access: Primary abstract Pyridoxal phosphate de-activation by pyrroline-5-carboxylic acid. Increased risk of vitamin B6 deficiency and seizures in hyperprolinemia type II. · 2001 · https://pubmed.ncbi.nlm.nih.gov/11134058/ · DOI 10.1074/jbc.M010860200
Complete structured claim and evidence
Isolated mitochondria from human ZR75-30 breast cancer cells consumed oxygen with proline as the sole added substrate.
L-Proline → Proline-supported respiration in human ZR75-30 mitochondria source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary full text
experimental_model
Isolated human cancer-cell mitochondria.
limitations
Fuel use in this model does not quantify whole-body energy contribution or show a supplement benefit.
nutrient_topic
L-Proline collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Proline
plain_language
In this model, proline can help fuel mitochondrial respiration.
primary_references
Sources of superoxide/H2O2 during mitochondrial proline oxidation. · 2014 · https://pubmed.ncbi.nlm.nih.gov/25184115/ · DOI 10.1016/j.redox.2014.07.003
L-Proline: synthesis, collagen processing, redox metabolism and cross-nutrient mechanisms (2026-09-19) · lines 134–140
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Isolated human cancer-cell mitochondria. · source_derived_draft · unverified_draft
## l-proline-proline-respiration In this model, proline can help fuel mitochondrial respiration. Isolated mitochondria from human ZR75-30 breast cancer cells consumed oxygen with proline as the sole added substrate. Model: Isolated human cancer-cell mitochondria. Limitations: Fuel use in this model does not quantify whole-body energy contribution or show a supplement benefit. Evidence access: Primary full text Sources of superoxide/H2O2 during mitochondrial proline oxidation. · 2014 · https://pubmed.ncbi.nlm.nih.gov/25184115/ · DOI 10.1016/j.redox.2014.07.003
Complete structured claim and evidence
During proline oxidation in ZR75-30 mitochondria, the main measured ROS sources were complex I and 2-oxoglutarate dehydrogenase, with no significant direct PRODH contribution under the tested substrate/inhibitor conditions.
L-Proline → Sites of ROS formation during proline oxidation in ZR75-30 mitochondria source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary full text
experimental_model
Isolated human mitochondria; inhibitor combinations used to distinguish ROS-generating sites.
limitations
Results in Drosophila instead emphasized complexes I and II; these species-specific observations do not identify a universal source.
nutrient_topic
L-Proline collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Proline
plain_language
A pathway can increase ROS without its first enzyme being the direct ROS-producing site.
primary_references
Sources of superoxide/H2O2 during mitochondrial proline oxidation. · 2014 · https://pubmed.ncbi.nlm.nih.gov/25184115/ · DOI 10.1016/j.redox.2014.07.003
L-Proline: synthesis, collagen processing, redox metabolism and cross-nutrient mechanisms (2026-09-19) · lines 142–148
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Isolated human mitochondria; inhibitor combinations used to distinguish ROS-generating sites. · source_derived_draft · unverified_draft
## l-proline-ros-source-boundary A pathway can increase ROS without its first enzyme being the direct ROS-producing site. During proline oxidation in ZR75-30 mitochondria, the main measured ROS sources were complex I and 2-oxoglutarate dehydrogenase, with no significant direct PRODH contribution under the tested substrate/inhibitor conditions. Model: Isolated human mitochondria; inhibitor combinations used to distinguish ROS-generating sites. Limitations: Results in Drosophila instead emphasized complexes I and II; these species-specific observations do not identify a universal source. Evidence access: Primary full text Sources of superoxide/H2O2 during mitochondrial proline oxidation. · 2014 · https://pubmed.ncbi.nlm.nih.gov/25184115/ · DOI 10.1016/j.redox.2014.07.003
Complete structured claim and evidence
Fibroblasts from people with PYCR1-related cutis laxa showed altered mitochondrial morphology and membrane potential and greater apoptosis during oxidative stress.
Human pyrroline-5-carboxylate reductase 1 / PYCR1 → Mitochondrial integrity in PYCR1-deficient human fibroblasts source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
evidence_access
Primary abstract
experimental_model
Human genetic families and patient fibroblasts.
limitations
The clinical disorder is not shown to be an isolated dietary proline deficiency or reliably corrected by proline supplementation. Correction record: Author correction PMID 35064218 / DOI 10.1038/s41588-022-01013-2 adds an omitted funding acknowledgment for Hulya Kayserili (TUBITAK SBAG-108S418). The notice does not report a change to the mechanism results. https://www.nature.com/articles/s41588-022-01013-2
nutrient_topic
L-Proline collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Proline
plain_language
An enzyme defect can affect connective tissue and cellular stress handling together.
primary_references
Mutations in PYCR1 cause cutis laxa with progeroid features. · 2009 · https://pubmed.ncbi.nlm.nih.gov/19648921/ · DOI 10.1038/ng.413
trigger_kind
machinery_impairment Imported condition classification; unverified.
L-Proline: synthesis, collagen processing, redox metabolism and cross-nutrient mechanisms (2026-09-19) · lines 150–156
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human genetic families and patient fibroblasts. · source_derived_draft · unverified_draft
## l-proline-pycr1-genetic An enzyme defect can affect connective tissue and cellular stress handling together. Fibroblasts from people with PYCR1-related cutis laxa showed altered mitochondrial morphology and membrane potential and greater apoptosis during oxidative stress. Model: Human genetic families and patient fibroblasts. Limitations: The clinical disorder is not shown to be an isolated dietary proline deficiency or reliably corrected by proline supplementation. Correction record: Author correction PMID 35064218 / DOI 10.1038/s41588-022-01013-2 adds an omitted funding acknowledgment for Hulya Kayserili (TUBITAK SBAG-108S418). The notice does not report a change to the mechanism results. https://www.nature.com/articles/s41588-022-01013-2 Evidence access: Primary abstract Mutations in PYCR1 cause cutis laxa with progeroid features. · 2009 · https://pubmed.ncbi.nlm.nih.gov/19648921/ · DOI 10.1038/ng.413
Complete structured claim and evidence
PYCR2 variants in two families were associated with microcephaly and hypomyelination; engineered PYCR2 loss in HEK293FT cells lowered mitochondrial membrane potential and increased oxidative-stress-induced apoptosis.
Human pyrroline-5-carboxylate reductase 2 / PYCR2 → Mitochondrial stress response in PYCR2-deficient human cells source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
evidence_access
Primary abstract
experimental_model
Human families, variant-expression studies and CRISPR-modified human cells.
limitations
This does not prove that low circulating proline is the disease mechanism or that extra substrate rescues it.
nutrient_topic
L-Proline collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Proline
plain_language
A related enzyme has a distinct neurological disease pattern.
primary_references
Mutations in PYCR2, Encoding Pyrroline-5-Carboxylate Reductase 2, Cause Microcephaly and Hypomyelination. · 2015 · https://pubmed.ncbi.nlm.nih.gov/25865492/ · DOI 10.1016/j.ajhg.2015.03.003
trigger_kind
machinery_impairment Imported condition classification; unverified.
L-Proline: synthesis, collagen processing, redox metabolism and cross-nutrient mechanisms (2026-09-19) · lines 158–164
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human families, variant-expression studies and CRISPR-modified human cells. · source_derived_draft · unverified_draft
## l-proline-pycr2-genetic A related enzyme has a distinct neurological disease pattern. PYCR2 variants in two families were associated with microcephaly and hypomyelination; engineered PYCR2 loss in HEK293FT cells lowered mitochondrial membrane potential and increased oxidative-stress-induced apoptosis. Model: Human families, variant-expression studies and CRISPR-modified human cells. Limitations: This does not prove that low circulating proline is the disease mechanism or that extra substrate rescues it. Evidence access: Primary abstract Mutations in PYCR2, Encoding Pyrroline-5-Carboxylate Reductase 2, Cause Microcephaly and Hypomyelination. · 2015 · https://pubmed.ncbi.nlm.nih.gov/25865492/ · DOI 10.1016/j.ajhg.2015.03.003
Complete structured claim and evidence
Human SIT1/SLC6A20 functioned as a sodium-dependent proline transporter when expressed for functional testing.
Human imino-acid transporter / SLC6A20 → L-Proline source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
Human SIT1 heterologous expression in the mammalian transporter identification study.
limitations
Rat concentration-response and ion-substitution details are recorded separately rather than assumed identical in humans.
nutrient_topic
L-Proline collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Proline
plain_language
Cell entry depends on transport machinery and ion gradients.
primary_references
Identification of mammalian proline transporter SIT1 (SLC6A20) with characteristics of classical system imino. · 2005 · https://pubmed.ncbi.nlm.nih.gov/15632147/ · DOI 10.1074/jbc.M413027200
transport_effect
raises Functioned as a sodium-dependent proline transporter, which is inward.
transport_pool
the expressing cell Functioned as a sodium-dependent proline transporter, which is inward.
L-Proline: synthesis, collagen processing, redox metabolism and cross-nutrient mechanisms (2026-09-19) · lines 166–172
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human SIT1 heterologous expression in the mammalian transporter identification study. · source_derived_draft · unverified_draft
## l-proline-sit1-uptake Cell entry depends on transport machinery and ion gradients. Human SIT1/SLC6A20 functioned as a sodium-dependent proline transporter when expressed for functional testing. Model: Human SIT1 heterologous expression in the mammalian transporter identification study. Limitations: Rat concentration-response and ion-substitution details are recorded separately rather than assumed identical in humans. Evidence access: Primary abstract Identification of mammalian proline transporter SIT1 (SLC6A20) with characteristics of classical system imino. · 2005 · https://pubmed.ncbi.nlm.nih.gov/15632147/ · DOI 10.1074/jbc.M413027200
Complete structured claim and evidence
Rat SIT1 expressed in Xenopus oocytes transported proline with apparent K0.5 about 0.2 mM; transport depended on sodium, was stimulated by chloride and depended on voltage.
Rat sodium/imino-acid transporter 1 / Slc6a20 → L-Proline source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
Rat protein in Xenopus oocytes; alanine and lysine did not inhibit the reported proline transport.
limitations
This is not a human dietary sodium or chloride threshold.
nutrient_topic
L-Proline collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Proline
plain_language
The driving ions and membrane voltage affect how this transporter works.
primary_references
Identification of mammalian proline transporter SIT1 (SLC6A20) with characteristics of classical system imino. · 2005 · https://pubmed.ncbi.nlm.nih.gov/15632147/ · DOI 10.1074/jbc.M413027200
transport_effect
raises Sodium-dependent, chloride-stimulated, voltage-dependent proline transport, which is inward.
transport_pool
the expressing cell Sodium-dependent, chloride-stimulated, voltage-dependent proline transport, which is inward.
L-Proline: synthesis, collagen processing, redox metabolism and cross-nutrient mechanisms (2026-09-19) · lines 174–180
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Rat protein in Xenopus oocytes; alanine and lysine did not inhibit the reported proline transport. · source_derived_draft · unverified_draft
## l-proline-rat-sit1-ion-coupling The driving ions and membrane voltage affect how this transporter works. Rat SIT1 expressed in Xenopus oocytes transported proline with apparent K0.5 about 0.2 mM; transport depended on sodium, was stimulated by chloride and depended on voltage. Model: Rat protein in Xenopus oocytes; alanine and lysine did not inhibit the reported proline transport. Limitations: This is not a human dietary sodium or chloride threshold. Evidence access: Primary abstract Identification of mammalian proline transporter SIT1 (SLC6A20) with characteristics of classical system imino. · 2005 · https://pubmed.ncbi.nlm.nih.gov/15632147/ · DOI 10.1074/jbc.M413027200
Complete structured claim and evidence
Cryo-EM resolved human SIT1 in complex with ACE2, with pipecolate-bound and substrate-free conformations identifying the cytoplasmic gate and substrate-release changes.
Human imino-acid transporter / SLC6A20 → Human angiotensin-converting enzyme 2 / ACE2 source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary full text
experimental_model
Purified human ACE2-SIT1 complex; pipecolate is a proline-related ligand, not proline itself.
limitations
ACE2 partnership does not establish that proline intake changes susceptibility to viral infection.
nutrient_topic
L-Proline collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Proline
plain_language
A transporter can use a partner protein and still have its own distinct transport mechanism.
primary_references
Structure and function of the SIT1 proline transporter in complex with the COVID-19 receptor ACE2. · 2024 · https://pubmed.ncbi.nlm.nih.gov/38951531/ · DOI 10.1038/s41467-024-48921-x
L-Proline: synthesis, collagen processing, redox metabolism and cross-nutrient mechanisms (2026-09-19) · lines 182–188
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Purified human ACE2-SIT1 complex; pipecolate is a proline-related ligand, not proline itself. · source_derived_draft · unverified_draft
## l-proline-sit1-ace2 A transporter can use a partner protein and still have its own distinct transport mechanism. Cryo-EM resolved human SIT1 in complex with ACE2, with pipecolate-bound and substrate-free conformations identifying the cytoplasmic gate and substrate-release changes. Model: Purified human ACE2-SIT1 complex; pipecolate is a proline-related ligand, not proline itself. Limitations: ACE2 partnership does not establish that proline intake changes susceptibility to viral infection. Evidence access: Primary full text Structure and function of the SIT1 proline transporter in complex with the COVID-19 receptor ACE2. · 2024 · https://pubmed.ncbi.nlm.nih.gov/38951531/ · DOI 10.1038/s41467-024-48921-x
Complete structured claim and evidence
Human SIT1 produced glycine-evoked current about 18% of the proline response in the reported substrate comparison; sarcosine current was about 83%.
Human imino-acid transporter / SLC6A20 → Glycine source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary full text
experimental_model
Human SIT1 in Xenopus oocytes; 1 mM substrates at pH 7.4 and -60 mV.
limitations
Failure of glycine to stabilize purified SIT1 thermally did not rule out its transport; binding-proxy and transport assays measure different things.
nutrient_topic
L-Proline collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Proline
plain_language
This transporter has overlapping amino-acid routes with unequal efficiency.
primary_references
Structure and function of the SIT1 proline transporter in complex with the COVID-19 receptor ACE2. · 2024 · https://pubmed.ncbi.nlm.nih.gov/38951531/ · DOI 10.1038/s41467-024-48921-x
L-Proline: synthesis, collagen processing, redox metabolism and cross-nutrient mechanisms (2026-09-19) · lines 190–196
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human SIT1 in Xenopus oocytes; 1 mM substrates at pH 7.4 and -60 mV. · source_derived_draft · unverified_draft
## l-proline-sit1-glycine This transporter has overlapping amino-acid routes with unequal efficiency. Human SIT1 produced glycine-evoked current about 18% of the proline response in the reported substrate comparison; sarcosine current was about 83%. Model: Human SIT1 in Xenopus oocytes; 1 mM substrates at pH 7.4 and -60 mV. Limitations: Failure of glycine to stabilize purified SIT1 thermally did not rule out its transport; binding-proxy and transport assays measure different things. Evidence access: Primary full text Structure and function of the SIT1 proline transporter in complex with the COVID-19 receptor ACE2. · 2024 · https://pubmed.ncbi.nlm.nih.gov/38951531/ · DOI 10.1038/s41467-024-48921-x
Complete structured claim and evidence
SIT1 T199M reduced maximal proline-induced transport current about threefold, supporting a defect in gate dynamics implicated in iminoglycinuria.
Human imino-acid transporter / SLC6A20 → Human SIT1 T199M proline transport capacity source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
evidence_access
Primary full text
experimental_model
Human SIT1 variant expressed in Xenopus oocytes with structural interpretation.
limitations
The proposed packing mechanism is an interpretation informed by structure, while reduced current was measured.
nutrient_topic
L-Proline collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Proline
plain_language
A transporter can reach the assay system yet move substrate less efficiently.
primary_references
Structure and function of the SIT1 proline transporter in complex with the COVID-19 receptor ACE2. · 2024 · https://pubmed.ncbi.nlm.nih.gov/38951531/ · DOI 10.1038/s41467-024-48921-x
trigger_kind
machinery_impairment Imported condition classification; unverified.
L-Proline: synthesis, collagen processing, redox metabolism and cross-nutrient mechanisms (2026-09-19) · lines 198–204
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human SIT1 variant expressed in Xenopus oocytes with structural interpretation. · source_derived_draft · unverified_draft
## l-proline-sit1-variant A transporter can reach the assay system yet move substrate less efficiently. SIT1 T199M reduced maximal proline-induced transport current about threefold, supporting a defect in gate dynamics implicated in iminoglycinuria. Model: Human SIT1 variant expressed in Xenopus oocytes with structural interpretation. Limitations: The proposed packing mechanism is an interpretation informed by structure, while reduced current was measured. Evidence access: Primary full text Structure and function of the SIT1 proline transporter in complex with the COVID-19 receptor ACE2. · 2024 · https://pubmed.ncbi.nlm.nih.gov/38951531/ · DOI 10.1038/s41467-024-48921-x
Complete structured claim and evidence
Slc6a20a-knockout mice had higher extracellular brain glycine and increased NMDA-receptor currents.
Mouse sodium/imino-acid transporter / Slc6a20a → Glycine source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
evidence_access
Primary full text
experimental_model
Mouse genetic deletion with extracellular amino-acid measurements and electrophysiology.
limitations
This does not show that oral proline treats NMDAR dysfunction in humans. Correction record: Author correction PMID 39242973 / DOI 10.1038/s44321-024-00125-y corrects the human embryonic stem-cell neuron protocol IRB approval number to KH2017-109 from KA2018-61 and KH2020-55. It does not report a change to experimental results. https://link.springer.com/article/10.1038/s44321-024-00125-y
nutrient_topic
L-Proline collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Proline
plain_language
Changing a proline-sharing transporter can change glycine-dependent brain signaling.
primary_references
SLC6A20 transporter: a novel regulator of brain glycine homeostasis and NMDAR function. · 2021 · https://pubmed.ncbi.nlm.nih.gov/33428810/ · DOI 10.15252/emmm.202012632
trigger_kind
machinery_impairment Imported condition classification; unverified.
L-Proline: synthesis, collagen processing, redox metabolism and cross-nutrient mechanisms (2026-09-19) · lines 206–212
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Mouse genetic deletion with extracellular amino-acid measurements and electrophysiology. · source_derived_draft · unverified_draft
## l-proline-brain-transporter-loss Changing a proline-sharing transporter can change glycine-dependent brain signaling. Slc6a20a-knockout mice had higher extracellular brain glycine and increased NMDA-receptor currents. Model: Mouse genetic deletion with extracellular amino-acid measurements and electrophysiology. Limitations: This does not show that oral proline treats NMDAR dysfunction in humans. Correction record: Author correction PMID 39242973 / DOI 10.1038/s44321-024-00125-y corrects the human embryonic stem-cell neuron protocol IRB approval number to KH2017-109 from KA2018-61 and KH2020-55. It does not report a change to experimental results. https://link.springer.com/article/10.1038/s44321-024-00125-y Evidence access: Primary full text SLC6A20 transporter: a novel regulator of brain glycine homeostasis and NMDAR function. · 2021 · https://pubmed.ncbi.nlm.nih.gov/33428810/ · DOI 10.15252/emmm.202012632
Complete structured claim and evidence
Mice carrying C-terminally truncated PTEN showed increased Slc6a20a expression, lower extracellular brain proline and glycine, and reduced NMDAR currents.
Mouse sodium/imino-acid transporter / Slc6a20a → L-Proline source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
evidence_access
Primary full text
experimental_model
Engineered mouse PTEN model; transcriptional, microdialysis and electrophysiological observations.
limitations
Multiple consequences of PTEN mutation remain possible; the model is not ordinary dietary deficiency. Correction record: Author correction PMID 39242973 / DOI 10.1038/s44321-024-00125-y corrects the human embryonic stem-cell neuron protocol IRB approval number to KH2017-109 from KA2018-61 and KH2020-55. It does not report a change to experimental results. https://link.springer.com/article/10.1038/s44321-024-00125-y
nutrient_topic
L-Proline collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Proline
plain_language
Transporter regulation can alter the extracellular supply of two amino acids together.
primary_references
SLC6A20 transporter: a novel regulator of brain glycine homeostasis and NMDAR function. · 2021 · https://pubmed.ncbi.nlm.nih.gov/33428810/ · DOI 10.15252/emmm.202012632
trigger_kind
machinery_impairment Imported condition classification; unverified.
L-Proline: synthesis, collagen processing, redox metabolism and cross-nutrient mechanisms (2026-09-19) · lines 214–220
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Engineered mouse PTEN model; transcriptional, microdialysis and electrophysiological observations. · source_derived_draft · unverified_draft
## l-proline-brain-transporter-increase Transporter regulation can alter the extracellular supply of two amino acids together. Mice carrying C-terminally truncated PTEN showed increased Slc6a20a expression, lower extracellular brain proline and glycine, and reduced NMDAR currents. Model: Engineered mouse PTEN model; transcriptional, microdialysis and electrophysiological observations. Limitations: Multiple consequences of PTEN mutation remain possible; the model is not ordinary dietary deficiency. Correction record: Author correction PMID 39242973 / DOI 10.1038/s44321-024-00125-y corrects the human embryonic stem-cell neuron protocol IRB approval number to KH2017-109 from KA2018-61 and KH2020-55. It does not report a change to experimental results. https://link.springer.com/article/10.1038/s44321-024-00125-y Evidence access: Primary full text SLC6A20 transporter: a novel regulator of brain glycine homeostasis and NMDAR function. · 2021 · https://pubmed.ncbi.nlm.nih.gov/33428810/ · DOI 10.15252/emmm.202012632
Complete structured claim and evidence
The prolyl-tRNA synthetase domain of human EPRS attaches proline to its cognate tRNA in an ATP-dependent aminoacylation reaction.
Human glutamyl-prolyl-tRNA synthetase / EPRS1 → Human cytosolic tRNA(Pro) source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary full text
experimental_model
Purified human EPRS/ProRS biochemical assays.
limitations
tRNA charging and collagen hydroxylation are separate enzyme steps.
nutrient_topic
L-Proline collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Proline
plain_language
A protein-building block must first be loaded onto the correct tRNA.
primary_references
Halofuginone and other febrifugine derivatives inhibit prolyl-tRNA synthetase. · 2012 · https://pubmed.ncbi.nlm.nih.gov/22327401/ · DOI 10.1038/nchembio.790
L-Proline: synthesis, collagen processing, redox metabolism and cross-nutrient mechanisms (2026-09-19) · lines 222–228
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Purified human EPRS/ProRS biochemical assays. · source_derived_draft · unverified_draft
## l-proline-eprs-charging A protein-building block must first be loaded onto the correct tRNA. The prolyl-tRNA synthetase domain of human EPRS attaches proline to its cognate tRNA in an ATP-dependent aminoacylation reaction. Model: Purified human EPRS/ProRS biochemical assays. Limitations: tRNA charging and collagen hydroxylation are separate enzyme steps. Evidence access: Primary full text Halofuginone and other febrifugine derivatives inhibit prolyl-tRNA synthetase. · 2012 · https://pubmed.ncbi.nlm.nih.gov/22327401/ · DOI 10.1038/nchembio.790
Complete structured claim and evidence
Halofuginone inhibited the prolyl-tRNA synthetase activity of EPRS by competing with proline; added proline or enzyme reversed inhibition in the tested systems.
Halofuginone → Human glutamyl-prolyl-tRNA synthetase / EPRS1 source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
evidence_access
Primary full text
experimental_model
Biochemical charging assays and mammalian-cell experiments.
limitations
This is pharmacological machinery inhibition, not a claim that halofuginone physically removes all cellular proline.
nutrient_topic
L-Proline collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Proline
plain_language
Blocking the loading enzyme can mimic a shortage even while proline is present.
primary_references
Halofuginone and other febrifugine derivatives inhibit prolyl-tRNA synthetase. · 2012 · https://pubmed.ncbi.nlm.nih.gov/22327401/ · DOI 10.1038/nchembio.790
trigger_kind
machinery_impairment Imported condition classification; unverified.
L-Proline: synthesis, collagen processing, redox metabolism and cross-nutrient mechanisms (2026-09-19) · lines 230–236
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Biochemical charging assays and mammalian-cell experiments. · source_derived_draft · unverified_draft
## l-proline-eprs-inhibition Blocking the loading enzyme can mimic a shortage even while proline is present. Halofuginone inhibited the prolyl-tRNA synthetase activity of EPRS by competing with proline; added proline or enzyme reversed inhibition in the tested systems. Model: Biochemical charging assays and mammalian-cell experiments. Limitations: This is pharmacological machinery inhibition, not a claim that halofuginone physically removes all cellular proline. Evidence access: Primary full text Halofuginone and other febrifugine derivatives inhibit prolyl-tRNA synthetase. · 2012 · https://pubmed.ncbi.nlm.nih.gov/22327401/ · DOI 10.1038/nchembio.790
Complete structured claim and evidence
Exogenous proline reversed halofuginone-induced amino-acid response signaling and selected cellular effects in the study, consistent with competition at the prolyl-tRNA synthetase step.
L-Proline → Mouse-cell amino acid response during halofuginone exposure source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
evidence_access
Primary full text
experimental_model
Mouse embryonic fibroblast and immune-cell experiments with halofuginone; model and assay-specific concentrations.
limitations
Not every proline-processing defect is competitively reversible, and this is not a clinical drug-interaction dose recommendation.
nutrient_topic
L-Proline collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Proline
plain_language
Restoring access to a blocked loading step can turn off a shortage-like signal.
primary_references
Halofuginone and other febrifugine derivatives inhibit prolyl-tRNA synthetase. · 2012 · https://pubmed.ncbi.nlm.nih.gov/22327401/ · DOI 10.1038/nchembio.790
trigger_kind
machinery_impairment Imported condition classification; unverified.
L-Proline: synthesis, collagen processing, redox metabolism and cross-nutrient mechanisms (2026-09-19) · lines 238–244
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Mouse embryonic fibroblast and immune-cell experiments with halofuginone; model and assay-specific concentrations. · source_derived_draft · unverified_draft
## l-proline-eprs-stress-rescue Restoring access to a blocked loading step can turn off a shortage-like signal. Exogenous proline reversed halofuginone-induced amino-acid response signaling and selected cellular effects in the study, consistent with competition at the prolyl-tRNA synthetase step. Model: Mouse embryonic fibroblast and immune-cell experiments with halofuginone; model and assay-specific concentrations. Limitations: Not every proline-processing defect is competitively reversible, and this is not a clinical drug-interaction dose recommendation. Evidence access: Primary full text Halofuginone and other febrifugine derivatives inhibit prolyl-tRNA synthetase. · 2012 · https://pubmed.ncbi.nlm.nih.gov/22327401/ · DOI 10.1038/nchembio.790
Complete structured claim and evidence
Carbon-13 glutamine tracing in human mammary cancer-associated fibroblasts demonstrated incorporation of newly synthesized proline into COL1A1 peptides.
L-Glutamine → Human collagen type I alpha 1 / COL1A1 source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary full text
experimental_model
Human fibroblast cultures; 2 mM labeled glutamine for 72 hours in the collagen-peptide experiment.
limitations
Atom tracing does not show that dietary glutamine or proline is the limiting substrate in a person. Correction record: Author correction PMID 35927357 / DOI 10.1038/s42255-022-00632-7 corrects the author surname Riero-Domingo to Riera-Domingo. It does not report a change to the experimental results. https://www.nature.com/articles/s42255-022-00632-7
nutrient_topic
L-Proline collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Proline
plain_language
Collagen-building cells can make their own proline from glutamine.
primary_references
Cancer-associated fibroblasts require proline synthesis by PYCR1 for the deposition of pro-tumorigenic extracellular matrix. · 2022 · https://pubmed.ncbi.nlm.nih.gov/35760868/ · DOI 10.1038/s42255-022-00582-0
L-Proline: synthesis, collagen processing, redox metabolism and cross-nutrient mechanisms (2026-09-19) · lines 246–252
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human fibroblast cultures; 2 mM labeled glutamine for 72 hours in the collagen-peptide experiment. · source_derived_draft · unverified_draft
## l-proline-collagen-carbon Collagen-building cells can make their own proline from glutamine. Carbon-13 glutamine tracing in human mammary cancer-associated fibroblasts demonstrated incorporation of newly synthesized proline into COL1A1 peptides. Model: Human fibroblast cultures; 2 mM labeled glutamine for 72 hours in the collagen-peptide experiment. Limitations: Atom tracing does not show that dietary glutamine or proline is the limiting substrate in a person. Correction record: Author correction PMID 35927357 / DOI 10.1038/s42255-022-00632-7 corrects the author surname Riero-Domingo to Riera-Domingo. It does not report a change to the experimental results. https://www.nature.com/articles/s42255-022-00632-7 Evidence access: Primary full text Cancer-associated fibroblasts require proline synthesis by PYCR1 for the deposition of pro-tumorigenic extracellular matrix. · 2022 · https://pubmed.ncbi.nlm.nih.gov/35760868/ · DOI 10.1038/s42255-022-00582-0
Complete structured claim and evidence
Reducing PYCR1 in human mammary cancer-associated fibroblasts lowered proline supply for collagen production and decreased collagen deposition.
Human pyrroline-5-carboxylate reductase 1 / PYCR1 → Collagen deposition by human cancer-associated fibroblasts source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
evidence_access
Primary full text
experimental_model
Human CAF knockdown and matrix measurements; xenograft experiments separately examined tumor consequences.
limitations
This is a tumor-associated fibroblast model, not a trial of ordinary wound healing. Correction record: Author correction PMID 35927357 / DOI 10.1038/s42255-022-00632-7 corrects the author surname Riero-Domingo to Riera-Domingo. It does not report a change to the experimental results. https://www.nature.com/articles/s42255-022-00632-7
nutrient_topic
L-Proline collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Proline
plain_language
Endogenous synthesis can limit matrix production in activated fibroblasts.
primary_references
Cancer-associated fibroblasts require proline synthesis by PYCR1 for the deposition of pro-tumorigenic extracellular matrix. · 2022 · https://pubmed.ncbi.nlm.nih.gov/35760868/ · DOI 10.1038/s42255-022-00582-0
trigger_kind
machinery_impairment Imported condition classification; unverified.
L-Proline: synthesis, collagen processing, redox metabolism and cross-nutrient mechanisms (2026-09-19) · lines 254–260
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human CAF knockdown and matrix measurements; xenograft experiments separately examined tumor consequences. · source_derived_draft · unverified_draft
## l-proline-collagen-pycr1 Endogenous synthesis can limit matrix production in activated fibroblasts. Reducing PYCR1 in human mammary cancer-associated fibroblasts lowered proline supply for collagen production and decreased collagen deposition. Model: Human CAF knockdown and matrix measurements; xenograft experiments separately examined tumor consequences. Limitations: This is a tumor-associated fibroblast model, not a trial of ordinary wound healing. Correction record: Author correction PMID 35927357 / DOI 10.1038/s42255-022-00632-7 corrects the author surname Riero-Domingo to Riera-Domingo. It does not report a change to the experimental results. https://www.nature.com/articles/s42255-022-00632-7 Evidence access: Primary full text Cancer-associated fibroblasts require proline synthesis by PYCR1 for the deposition of pro-tumorigenic extracellular matrix. · 2022 · https://pubmed.ncbi.nlm.nih.gov/35760868/ · DOI 10.1038/s42255-022-00582-0
Complete structured claim and evidence
Human prolidase hydrolyzes dipeptides with C-terminal proline or hydroxyproline; substrate- and product-bound structures explain its terminal peptide-cleavage reaction.
Human prolidase / PEPD → L-Proline source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
Recombinant human wild-type prolidase, high-resolution substrate/product complexes.
limitations
This does not mean prolidase by itself cleaves an intact collagen triple helix.
nutrient_topic
L-Proline collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Proline
plain_language
Recycling a proline-containing peptide requires a suitable peptidase.
primary_references
Substrate specificity and reaction mechanism of human prolidase. · 2017 · https://pubmed.ncbi.nlm.nih.gov/28677335/ · DOI 10.1111/febs.14158
L-Proline: synthesis, collagen processing, redox metabolism and cross-nutrient mechanisms (2026-09-19) · lines 262–268
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Recombinant human wild-type prolidase, high-resolution substrate/product complexes. · source_derived_draft · unverified_draft
## l-proline-pepd-recycling Recycling a proline-containing peptide requires a suitable peptidase. Human prolidase hydrolyzes dipeptides with C-terminal proline or hydroxyproline; substrate- and product-bound structures explain its terminal peptide-cleavage reaction. Model: Recombinant human wild-type prolidase, high-resolution substrate/product complexes. Limitations: This does not mean prolidase by itself cleaves an intact collagen triple helix. Evidence access: Primary abstract Substrate specificity and reaction mechanism of human prolidase. · 2017 · https://pubmed.ncbi.nlm.nih.gov/28677335/ · DOI 10.1111/febs.14158
Complete structured claim and evidence
Human prolidase structures contain a binuclear manganese active site associated with the hydrolytic reaction; the study proposes hydroxide as the attacking catalytic species.
Mn2+ → Human prolidase / PEPD source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract and linked primary deposited structure 5M4G
experimental_model
Human enzyme crystal structures, including deposited structure 5M4G at 1.48 angstroms.
limitations
Structural metal dependence does not establish that adding manganese improves recycling when manganese is already adequate.
nutrient_topic
L-Proline collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Proline
plain_language
A mineral is part of the machinery that recycles proline from dipeptides.
primary_references
Substrate specificity and reaction mechanism of human prolidase. · 2017 · https://pubmed.ncbi.nlm.nih.gov/28677335/ · DOI 10.1111/febs.14158
L-Proline: synthesis, collagen processing, redox metabolism and cross-nutrient mechanisms (2026-09-19) · lines 270–276
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human enzyme crystal structures, including deposited structure 5M4G at 1.48 angstroms. · source_derived_draft · unverified_draft
## l-proline-pepd-manganese A mineral is part of the machinery that recycles proline from dipeptides. Human prolidase structures contain a binuclear manganese active site associated with the hydrolytic reaction; the study proposes hydroxide as the attacking catalytic species. Model: Human enzyme crystal structures, including deposited structure 5M4G at 1.48 angstroms. Limitations: Structural metal dependence does not establish that adding manganese improves recycling when manganese is already adequate. Evidence access: Primary abstract and linked primary deposited structure 5M4G Substrate specificity and reaction mechanism of human prolidase. · 2017 · https://pubmed.ncbi.nlm.nih.gov/28677335/ · DOI 10.1111/febs.14158
Complete structured claim and evidence
Purified truncated human PRODH2/HYPDH contained one FAD and showed approximately twelvefold higher catalytic efficiency for hydroxyproline than proline.
Human hydroxyproline dehydrogenase / PRODH2 → 4-Hydroxyproline source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
Human recombinant catalytic core, residues 157–515; substrate kinetics.
limitations
PRODH2 is not simply a second interchangeable proline oxidase.
nutrient_topic
L-Proline collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Proline
plain_language
Hydroxyproline uses a related but distinct breakdown enzyme.
primary_references
Proline dehydrogenase 2 (PRODH2) is a hydroxyproline dehydrogenase (HYPDH) and molecular target for treating primary hyperoxaluria. · 2015 · https://pubmed.ncbi.nlm.nih.gov/25697095/ · DOI 10.1042/BJ20141159
L-Proline: synthesis, collagen processing, redox metabolism and cross-nutrient mechanisms (2026-09-19) · lines 278–284
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human recombinant catalytic core, residues 157–515; substrate kinetics. · source_derived_draft · unverified_draft
## l-proline-hypdh-specificity Hydroxyproline uses a related but distinct breakdown enzyme. Purified truncated human PRODH2/HYPDH contained one FAD and showed approximately twelvefold higher catalytic efficiency for hydroxyproline than proline. Model: Human recombinant catalytic core, residues 157–515; substrate kinetics. Limitations: PRODH2 is not simply a second interchangeable proline oxidase. Evidence access: Primary abstract Proline dehydrogenase 2 (PRODH2) is a hydroxyproline dehydrogenase (HYPDH) and molecular target for treating primary hyperoxaluria. · 2015 · https://pubmed.ncbi.nlm.nih.gov/25697095/ · DOI 10.1042/BJ20141159
Complete structured claim and evidence
Quinone acceptors including CoQ1 reacted more efficiently than oxygen during purified human HYPDH turnover, supporting a dehydrogenase mechanism.
Human hydroxyproline dehydrogenase / PRODH2 → Coenzyme Q1, experimental ubiquinone analogue source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
Truncated purified human HYPDH; quinone analogue and oxygen comparisons.
limitations
CoQ10 as the physiological acceptor is inferred, not directly measured in intact human tissues; this does not demonstrate benefit from CoQ10 supplements.
nutrient_topic
L-Proline collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Proline
plain_language
Hydroxyproline breakdown can feed a quinone electron-transfer route.
primary_references
Proline dehydrogenase 2 (PRODH2) is a hydroxyproline dehydrogenase (HYPDH) and molecular target for treating primary hyperoxaluria. · 2015 · https://pubmed.ncbi.nlm.nih.gov/25697095/ · DOI 10.1042/BJ20141159
L-Proline: synthesis, collagen processing, redox metabolism and cross-nutrient mechanisms (2026-09-19) · lines 286–292
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Truncated purified human HYPDH; quinone analogue and oxygen comparisons. · source_derived_draft · unverified_draft
## l-proline-hypdh-electrons Hydroxyproline breakdown can feed a quinone electron-transfer route. Quinone acceptors including CoQ1 reacted more efficiently than oxygen during purified human HYPDH turnover, supporting a dehydrogenase mechanism. Model: Truncated purified human HYPDH; quinone analogue and oxygen comparisons. Limitations: CoQ10 as the physiological acceptor is inferred, not directly measured in intact human tissues; this does not demonstrate benefit from CoQ10 supplements. Evidence access: Primary abstract Proline dehydrogenase 2 (PRODH2) is a hydroxyproline dehydrogenase (HYPDH) and molecular target for treating primary hyperoxaluria. · 2015 · https://pubmed.ncbi.nlm.nih.gov/25697095/ · DOI 10.1042/BJ20141159
Complete structured claim and evidence
Prodh2 deletion reduced urinary oxalate in mouse hyperoxaluria models; combined Grhpr/Prodh2 deletion prevented kidney calcium-oxalate deposition during a 1% hydroxyproline diet.
Mouse hydroxyproline dehydrogenase / Prodh2 → Hydroxyproline-derived urinary oxalate in mouse hyperoxaluria models source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
evidence_access
Primary abstract
experimental_model
Genetic mouse models, including Grhpr knockout and a 1% hydroxyproline diet.
limitations
Hydroxyproline loading is not equivalent to free proline intake; human efficacy of pathway inhibition was not established.
nutrient_topic
L-Proline collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Proline
plain_language
A collagen-derived amino acid can feed an oxalate-producing pathway under specific conditions.
primary_references
The effects of the inactivation of Hydroxyproline dehydrogenase on urinary oxalate and glycolate excretion in mouse models of primary hyperoxaluria. · 2020 · https://pubmed.ncbi.nlm.nih.gov/31821850/ · DOI 10.1016/j.bbadis.2019.165633
trigger_kind
machinery_impairment Imported condition classification; unverified.
L-Proline: synthesis, collagen processing, redox metabolism and cross-nutrient mechanisms (2026-09-19) · lines 294–300
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Genetic mouse models, including Grhpr knockout and a 1% hydroxyproline diet. · source_derived_draft · unverified_draft
## l-proline-hypdh-oxalate A collagen-derived amino acid can feed an oxalate-producing pathway under specific conditions. Prodh2 deletion reduced urinary oxalate in mouse hyperoxaluria models; combined Grhpr/Prodh2 deletion prevented kidney calcium-oxalate deposition during a 1% hydroxyproline diet. Model: Genetic mouse models, including Grhpr knockout and a 1% hydroxyproline diet. Limitations: Hydroxyproline loading is not equivalent to free proline intake; human efficacy of pathway inhibition was not established. Evidence access: Primary abstract The effects of the inactivation of Hydroxyproline dehydrogenase on urinary oxalate and glycolate excretion in mouse models of primary hyperoxaluria. · 2020 · https://pubmed.ncbi.nlm.nih.gov/31821850/ · DOI 10.1016/j.bbadis.2019.165633
Complete structured claim and evidence
Cultured human fetal RPE consumed proline preferentially among the measured nutrients and used its carbon in the TCA cycle and reductive citrate synthesis, with preferential apical citrate export.
L-Proline → Proline-derived carbon metabolism and apical export by human RPE source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
Polarized human fetal RPE culture, carbon-13 tracing and metabolite measurements.
limitations
Culture preferences do not establish a universal human dietary proline requirement or AMD treatment.
nutrient_topic
L-Proline collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Proline
plain_language
The eye support layer can turn proline into fuel intermediates for its neighbors.
primary_references
Human retinal pigment epithelial cells prefer proline as a nutrient and transport metabolic intermediates to the retinal side. · 2017 · https://pubmed.ncbi.nlm.nih.gov/28615447/ · DOI 10.1074/jbc.M117.788422
L-Proline: synthesis, collagen processing, redox metabolism and cross-nutrient mechanisms (2026-09-19) · lines 302–308
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Polarized human fetal RPE culture, carbon-13 tracing and metabolite measurements. · source_derived_draft · unverified_draft
## l-proline-rpe-carbon The eye support layer can turn proline into fuel intermediates for its neighbors. Cultured human fetal RPE consumed proline preferentially among the measured nutrients and used its carbon in the TCA cycle and reductive citrate synthesis, with preferential apical citrate export. Model: Polarized human fetal RPE culture, carbon-13 tracing and metabolite measurements. Limitations: Culture preferences do not establish a universal human dietary proline requirement or AMD treatment. Evidence access: Primary abstract Human retinal pigment epithelial cells prefer proline as a nutrient and transport metabolic intermediates to the retinal side. · 2017 · https://pubmed.ncbi.nlm.nih.gov/28615447/ · DOI 10.1074/jbc.M117.788422
Complete structured claim and evidence
Proline supported de novo serine synthesis and reductive carboxylation in cultured human RPE.
L-Proline → De novo serine synthesis in human RPE source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
Primary human RPE culture and isotope tracing.
limitations
This is not a direct one-step conversion or a clinical serine-repletion trial.
nutrient_topic
L-Proline collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Proline
plain_language
Using one amino acid can support production of another.
primary_references
Proline mediates metabolic communication between retinal pigment epithelial cells and the retina. · 2019 · https://pubmed.ncbi.nlm.nih.gov/31110046/ · DOI 10.1074/jbc.RA119.007983
L-Proline: synthesis, collagen processing, redox metabolism and cross-nutrient mechanisms (2026-09-19) · lines 310–316
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Primary human RPE culture and isotope tracing. · source_derived_draft · unverified_draft
## l-proline-rpe-serine Using one amino acid can support production of another. Proline supported de novo serine synthesis and reductive carboxylation in cultured human RPE. Model: Primary human RPE culture and isotope tracing. Limitations: This is not a direct one-step conversion or a clinical serine-repletion trial. Evidence access: Primary abstract Proline mediates metabolic communication between retinal pigment epithelial cells and the retina. · 2019 · https://pubmed.ncbi.nlm.nih.gov/31110046/ · DOI 10.1074/jbc.RA119.007983
Complete structured claim and evidence
Blocking proline catabolism in human RPE impaired glucose metabolism and glutathione production.
Human proline dehydrogenase / PRODH → Glucose metabolism and glutathione production in human RPE source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
evidence_access
Primary abstract
experimental_model
Human RPE culture with pharmacological catabolism inhibition and metabolite measurements.
limitations
Pharmacological specificity and culture conditions limit inference; no human blood-proline threshold is established.
nutrient_topic
L-Proline collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Proline
plain_language
A block in proline use can affect antioxidant production indirectly.
primary_references
Proline mediates metabolic communication between retinal pigment epithelial cells and the retina. · 2019 · https://pubmed.ncbi.nlm.nih.gov/31110046/ · DOI 10.1074/jbc.RA119.007983
trigger_kind
machinery_impairment Imported condition classification; unverified.
L-Proline: synthesis, collagen processing, redox metabolism and cross-nutrient mechanisms (2026-09-19) · lines 318–324
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human RPE culture with pharmacological catabolism inhibition and metabolite measurements. · source_derived_draft · unverified_draft
## l-proline-rpe-catabolism-block A block in proline use can affect antioxidant production indirectly. Blocking proline catabolism in human RPE impaired glucose metabolism and glutathione production. Model: Human RPE culture with pharmacological catabolism inhibition and metabolite measurements. Limitations: Pharmacological specificity and culture conditions limit inference; no human blood-proline threshold is established. Evidence access: Primary abstract Proline mediates metabolic communication between retinal pigment epithelial cells and the retina. · 2019 · https://pubmed.ncbi.nlm.nih.gov/31110046/ · DOI 10.1074/jbc.RA119.007983
Complete structured claim and evidence
Human RPE used nitrogen from labeled proline to synthesize and export thirteen amino acids, including glutamate, aspartate, glutamine, alanine and serine.
L-Proline → Human RPE amino-acid synthesis and export source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary final published full text, replacing the earlier preprint
experimental_model
Human RPE matured for 20 weeks; 1 mM nitrogen-15 proline, sampling at 24 and 48 hours.
limitations
Atom transfer involves multiple enzymes; this is not thirteen direct proline-conversion reactions.
nutrient_topic
L-Proline collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Proline
plain_language
Proline supplies nitrogen as well as carbon to the retinal support system.
primary_references
Proline provides a nitrogen source in the retinal pigment epithelium to synthesize and export amino acids for the neural retina. · 2023 · https://pubmed.ncbi.nlm.nih.gov/37741457/ · DOI 10.1016/j.jbc.2023.105275
L-Proline: synthesis, collagen processing, redox metabolism and cross-nutrient mechanisms (2026-09-19) · lines 326–332
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human RPE matured for 20 weeks; 1 mM nitrogen-15 proline, sampling at 24 and 48 hours. · source_derived_draft · unverified_draft
## l-proline-rpe-nitrogen Proline supplies nitrogen as well as carbon to the retinal support system. Human RPE used nitrogen from labeled proline to synthesize and export thirteen amino acids, including glutamate, aspartate, glutamine, alanine and serine. Model: Human RPE matured for 20 weeks; 1 mM nitrogen-15 proline, sampling at 24 and 48 hours. Limitations: Atom transfer involves multiple enzymes; this is not thirteen direct proline-conversion reactions. Evidence access: Primary final published full text, replacing the earlier preprint Proline provides a nitrogen source in the retinal pigment epithelium to synthesize and export amino acids for the neural retina. · 2023 · https://pubmed.ncbi.nlm.nih.gov/37741457/ · DOI 10.1016/j.jbc.2023.105275
Complete structured claim and evidence
Prodh loss blocked proline nitrogen utilization by mouse RPE and diminished delivery of proline-derived amino-acid nitrogen to the retina.
Mouse proline dehydrogenase / Prodh → Mouse RPE-to-retina transfer of proline-derived amino-acid nitrogen source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
evidence_access
Primary final published full text
experimental_model
Mouse Prodh mutant tissue and isotope-transfer experiments, supported by coculture and in-vivo tracing.
limitations
Mouse compartmental transfer is not proof that oral proline prevents human retinal degeneration.
nutrient_topic
L-Proline collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Proline
plain_language
The retina depends on processing in a neighboring support tissue.
primary_references
Proline provides a nitrogen source in the retinal pigment epithelium to synthesize and export amino acids for the neural retina. · 2023 · https://pubmed.ncbi.nlm.nih.gov/37741457/ · DOI 10.1016/j.jbc.2023.105275
trigger_kind
machinery_impairment Imported condition classification; unverified.
L-Proline: synthesis, collagen processing, redox metabolism and cross-nutrient mechanisms (2026-09-19) · lines 334–340
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Mouse Prodh mutant tissue and isotope-transfer experiments, supported by coculture and in-vivo tracing. · source_derived_draft · unverified_draft
## l-proline-rpe-retina-nitrogen The retina depends on processing in a neighboring support tissue. Prodh loss blocked proline nitrogen utilization by mouse RPE and diminished delivery of proline-derived amino-acid nitrogen to the retina. Model: Mouse Prodh mutant tissue and isotope-transfer experiments, supported by coculture and in-vivo tracing. Limitations: Mouse compartmental transfer is not proof that oral proline prevents human retinal degeneration. Evidence access: Primary final published full text Proline provides a nitrogen source in the retinal pigment epithelium to synthesize and export amino acids for the neural retina. · 2023 · https://pubmed.ncbi.nlm.nih.gov/37741457/ · DOI 10.1016/j.jbc.2023.105275
Complete structured claim and evidence
Dietary proline improved visual function in an acute model of RPE-induced retinal degeneration.
L-Proline → Visual response in the acute mouse RPE-injury model source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
Mouse acute RPE-injury study; primary abstract.
limitations
Diet concentration and injury-protocol details are not asserted from the abstract; this does not establish treatment for chronic human AMD.
nutrient_topic
L-Proline collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Proline
plain_language
A dietary intervention helped in a specific experimental eye-injury model.
primary_references
Proline mediates metabolic communication between retinal pigment epithelial cells and the retina. · 2019 · https://pubmed.ncbi.nlm.nih.gov/31110046/ · DOI 10.1074/jbc.RA119.007983
L-Proline: synthesis, collagen processing, redox metabolism and cross-nutrient mechanisms (2026-09-19) · lines 342–348
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Mouse acute RPE-injury study; primary abstract. · source_derived_draft · unverified_draft
## l-proline-rpe-diet-model A dietary intervention helped in a specific experimental eye-injury model. Dietary proline improved visual function in an acute model of RPE-induced retinal degeneration. Model: Mouse acute RPE-injury study; primary abstract. Limitations: Diet concentration and injury-protocol details are not asserted from the abstract; this does not establish treatment for chronic human AMD. Evidence access: Primary abstract Proline mediates metabolic communication between retinal pigment epithelial cells and the retina. · 2019 · https://pubmed.ncbi.nlm.nih.gov/31110046/ · DOI 10.1074/jbc.RA119.007983
Complete structured claim and evidence
In hypoxic cancer models, increased PYCR1-dependent proline synthesis oxidized NADH and helped sustain TCA-cycle activity.
Human pyrroline-5-carboxylate reductase 1 / PYCR1 → NADH source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary full text
experimental_model
Human cancer-cell hypoxia experiments and three-dimensional/xenograft models.
limitations
A benefit to tumor-cell survival is not a health benefit of supplementation; proline production is part of the reaction that consumes NADH.
nutrient_topic
L-Proline collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Proline
plain_language
Making proline can also help rebalance mitochondrial reducing power.
primary_references
Proline synthesis through PYCR1 is required to support cancer cell proliferation and survival in oxygen-limiting conditions. · 2022 · https://pubmed.ncbi.nlm.nih.gov/35108535/ · DOI 10.1016/j.celrep.2022.110320
L-Proline: synthesis, collagen processing, redox metabolism and cross-nutrient mechanisms (2026-09-19) · lines 350–356
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human cancer-cell hypoxia experiments and three-dimensional/xenograft models. · source_derived_draft · unverified_draft
## l-proline-pycr1-hypoxic-redox Making proline can also help rebalance mitochondrial reducing power. In hypoxic cancer models, increased PYCR1-dependent proline synthesis oxidized NADH and helped sustain TCA-cycle activity. Model: Human cancer-cell hypoxia experiments and three-dimensional/xenograft models. Limitations: A benefit to tumor-cell survival is not a health benefit of supplementation; proline production is part of the reaction that consumes NADH. Evidence access: Primary full text Proline synthesis through PYCR1 is required to support cancer cell proliferation and survival in oxygen-limiting conditions. · 2022 · https://pubmed.ncbi.nlm.nih.gov/35108535/ · DOI 10.1016/j.celrep.2022.110320
Complete structured claim and evidence
PYCR1 loss increased hypoxia-associated cell death in three-dimensional cancer cultures and tumors in vivo.
Human pyrroline-5-carboxylate reductase 1 / PYCR1 → Hypoxic survival of PYCR1-manipulated human cancer cells source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
evidence_access
Primary full text
experimental_model
Human cancer-cell PYCR1 depletion/knockout and xenograft experiments.
limitations
This is a context-specific vulnerability and is not proof of systemic proline deficiency.
nutrient_topic
L-Proline collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Proline
plain_language
A cell may need the synthesis reaction itself, not merely a measured pool of the final amino acid.
primary_references
Proline synthesis through PYCR1 is required to support cancer cell proliferation and survival in oxygen-limiting conditions. · 2022 · https://pubmed.ncbi.nlm.nih.gov/35108535/ · DOI 10.1016/j.celrep.2022.110320
trigger_kind
machinery_impairment Imported condition classification; unverified.
L-Proline: synthesis, collagen processing, redox metabolism and cross-nutrient mechanisms (2026-09-19) · lines 358–364
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human cancer-cell PYCR1 depletion/knockout and xenograft experiments. · source_derived_draft · unverified_draft
## l-proline-pycr1-hypoxic-loss A cell may need the synthesis reaction itself, not merely a measured pool of the final amino acid. PYCR1 loss increased hypoxia-associated cell death in three-dimensional cancer cultures and tumors in vivo. Model: Human cancer-cell PYCR1 depletion/knockout and xenograft experiments. Limitations: This is a context-specific vulnerability and is not proof of systemic proline deficiency. Evidence access: Primary full text Proline synthesis through PYCR1 is required to support cancer cell proliferation and survival in oxygen-limiting conditions. · 2022 · https://pubmed.ncbi.nlm.nih.gov/35108535/ · DOI 10.1016/j.celrep.2022.110320
Complete structured claim and evidence
TGF-beta induced glutamine-derived proline synthesis in a Smad4-dependent fibroblast program; manipulations of mitochondrial redox potential or ATP production changed that synthesis.
TGF-beta-stimulated proline synthesis in mouse fibroblasts → L-Proline source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
TGF-beta-stimulated fibroblast experiments; primary abstract, with mouse NIH3T3 model identified in the primary study.
limitations
No dietary dose or general antifibrotic benefit is inferred.
nutrient_topic
L-Proline collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Proline
plain_language
Activated matrix-producing cells can use proline synthesis to handle metabolic demand.
primary_references
Proline biosynthesis is a vent for TGFβ-induced mitochondrial redox stress. · 2020 · https://pubmed.ncbi.nlm.nih.gov/32134147/ · DOI 10.15252/embj.2019103334
L-Proline: synthesis, collagen processing, redox metabolism and cross-nutrient mechanisms (2026-09-19) · lines 366–372
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · TGF-beta-stimulated fibroblast experiments; primary abstract, with mouse NIH3T3 model identified in the primary study. · source_derived_draft · unverified_draft
## l-proline-tgfb-proline Activated matrix-producing cells can use proline synthesis to handle metabolic demand. TGF-beta induced glutamine-derived proline synthesis in a Smad4-dependent fibroblast program; manipulations of mitochondrial redox potential or ATP production changed that synthesis. Model: TGF-beta-stimulated fibroblast experiments; primary abstract, with mouse NIH3T3 model identified in the primary study. Limitations: No dietary dose or general antifibrotic benefit is inferred. Evidence access: Primary abstract Proline biosynthesis is a vent for TGFβ-induced mitochondrial redox stress. · 2020 · https://pubmed.ncbi.nlm.nih.gov/32134147/ · DOI 10.15252/embj.2019103334
Complete structured claim and evidence
Human pancreatic cancer cells took up collagen fragments and used collagen-derived proline in metabolism under nutrient-limited culture conditions.
Collagen-bound proline residues → Collagen-derived proline metabolism in human pancreatic cancer cells source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary full text
experimental_model
Human PDAC culture and tracer experiments under limited fuel availability.
limitations
Collagen uptake, peptide digestion and proline oxidation are distinct steps; no effect of oral collagen supplements is demonstrated.
nutrient_topic
L-Proline collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Proline
plain_language
A tissue matrix can become a nutrient reservoir for cells.
primary_references
Collagen-derived proline promotes pancreatic ductal adenocarcinoma cell survival under nutrient limited conditions. · 2017 · https://pubmed.ncbi.nlm.nih.gov/28685754/ · DOI 10.1038/ncomms16031
L-Proline: synthesis, collagen processing, redox metabolism and cross-nutrient mechanisms (2026-09-19) · lines 374–380
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human PDAC culture and tracer experiments under limited fuel availability. · source_derived_draft · unverified_draft
## l-proline-pdac-collagen-fuel A tissue matrix can become a nutrient reservoir for cells. Human pancreatic cancer cells took up collagen fragments and used collagen-derived proline in metabolism under nutrient-limited culture conditions. Model: Human PDAC culture and tracer experiments under limited fuel availability. Limitations: Collagen uptake, peptide digestion and proline oxidation are distinct steps; no effect of oral collagen supplements is demonstrated. Evidence access: Primary full text Collagen-derived proline promotes pancreatic ductal adenocarcinoma cell survival under nutrient limited conditions. · 2017 · https://pubmed.ncbi.nlm.nih.gov/28685754/ · DOI 10.1038/ncomms16031
Complete structured claim and evidence
Pharmacological inhibition of Prodh impaired lung-metastasis formation in orthotopic 4T1 and EMT6.5 mouse breast-cancer models.
Mouse proline dehydrogenase / Prodh → Lung-metastasis formation in mouse breast-cancer models source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
Mouse breast-cancer models, complemented by three-dimensional culture and human tumor-expression comparisons.
limitations
This does not establish that dietary proline causes metastasis or that proline restriction is a proven treatment.
nutrient_topic
L-Proline collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Proline
plain_language
A proline-consuming pathway can support growth in a metastatic setting.
primary_references
Proline metabolism supports metastasis formation and could be inhibited to selectively target metastasizing cancer cells. · 2017 · https://pubmed.ncbi.nlm.nih.gov/28492237/ · DOI 10.1038/ncomms15267
L-Proline: synthesis, collagen processing, redox metabolism and cross-nutrient mechanisms (2026-09-19) · lines 382–388
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Mouse breast-cancer models, complemented by three-dimensional culture and human tumor-expression comparisons. · source_derived_draft · unverified_draft
## l-proline-mouse-metastatic-catabolism A proline-consuming pathway can support growth in a metastatic setting. Pharmacological inhibition of Prodh impaired lung-metastasis formation in orthotopic 4T1 and EMT6.5 mouse breast-cancer models. Model: Mouse breast-cancer models, complemented by three-dimensional culture and human tumor-expression comparisons. Limitations: This does not establish that dietary proline causes metastasis or that proline restriction is a proven treatment. Evidence access: Primary abstract Proline metabolism supports metastasis formation and could be inhibited to selectively target metastasizing cancer cells. · 2017 · https://pubmed.ncbi.nlm.nih.gov/28492237/ · DOI 10.1038/ncomms15267
Complete structured claim and evidence
Proline addition drove a reversible mesenchymal-like, motile state in embryonic stem-cell culture, accompanied by changes in H3K9 and H3K36 methylation.
L-Proline → Proline-induced mouse embryonic-stem-cell state transition source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
Mouse embryonic stem-cell culture with proline exposure; primary abstract.
limitations
This is a cell-culture state transition, not evidence that proline changes adult human identity or universally activates oncogenes.
nutrient_topic
L-Proline collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Proline
plain_language
An amino-acid exposure can alter a cell-state program in a developmental model.
primary_references
L-Proline induces a mesenchymal-like invasive program in embryonic stem cells by remodeling H3K9 and H3K36 methylation. · 2013 · https://pubmed.ncbi.nlm.nih.gov/24319666/ · DOI 10.1016/j.stemcr.2013.09.001
L-Proline: synthesis, collagen processing, redox metabolism and cross-nutrient mechanisms (2026-09-19) · lines 390–396
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Mouse embryonic stem-cell culture with proline exposure; primary abstract. · source_derived_draft · unverified_draft
## l-proline-stem-cell-state An amino-acid exposure can alter a cell-state program in a developmental model. Proline addition drove a reversible mesenchymal-like, motile state in embryonic stem-cell culture, accompanied by changes in H3K9 and H3K36 methylation. Model: Mouse embryonic stem-cell culture with proline exposure; primary abstract. Limitations: This is a cell-culture state transition, not evidence that proline changes adult human identity or universally activates oncogenes. Evidence access: Primary abstract L-Proline induces a mesenchymal-like invasive program in embryonic stem cells by remodeling H3K9 and H3K36 methylation. · 2013 · https://pubmed.ncbi.nlm.nih.gov/24319666/ · DOI 10.1016/j.stemcr.2013.09.001
Complete structured claim and evidence
Ascorbic-acid addition or proline withdrawal reversed the reported proline-induced stem-cell state and reduced the associated H3K9/H3K36 methylation pattern.
L-Ascorbate → Proline-induced mouse embryonic-stem-cell state transition source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
Mouse embryonic stem-cell model; reversible phenotype and histone-mark measurements.
limitations
The result does not establish a supplement ratio, a clinical methylation imbalance, or vitamin C depletion by ordinary proline intake.
nutrient_topic
L-Proline collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Proline
plain_language
Vitamin C and proline intersect in this experimental epigenetic response.
primary_references
L-Proline induces a mesenchymal-like invasive program in embryonic stem cells by remodeling H3K9 and H3K36 methylation. · 2013 · https://pubmed.ncbi.nlm.nih.gov/24319666/ · DOI 10.1016/j.stemcr.2013.09.001
L-Proline: synthesis, collagen processing, redox metabolism and cross-nutrient mechanisms (2026-09-19) · lines 398–404
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Mouse embryonic stem-cell model; reversible phenotype and histone-mark measurements. · source_derived_draft · unverified_draft
## l-proline-stem-cell-vitamin-c Vitamin C and proline intersect in this experimental epigenetic response. Ascorbic-acid addition or proline withdrawal reversed the reported proline-induced stem-cell state and reduced the associated H3K9/H3K36 methylation pattern. Model: Mouse embryonic stem-cell model; reversible phenotype and histone-mark measurements. Limitations: The result does not establish a supplement ratio, a clinical methylation imbalance, or vitamin C depletion by ordinary proline intake. Evidence access: Primary abstract L-Proline induces a mesenchymal-like invasive program in embryonic stem cells by remodeling H3K9 and H3K36 methylation. · 2013 · https://pubmed.ncbi.nlm.nih.gov/24319666/ · DOI 10.1016/j.stemcr.2013.09.001
Complete structured claim and evidence
Purified C. difficile proline reductase contained PrdA and selenocysteine-containing PrdB and used D-proline; its stereospecific activity is distinct from human L-proline oxidation.
Clostridioides difficile D-proline reductase complex → D-Proline source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
Purified bacterial reductase and substrate tests.
limitations
L-proline-linked fermentation requires stereochemical processing; this enzyme is not a human PRODH isoform.
nutrient_topic
L-Proline collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Proline
plain_language
Gut bacteria can use a different form of proline with different machinery.
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 406–412
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Purified bacterial reductase and substrate tests. · source_derived_draft · unverified_draft
## l-proline-microbial-stereospecificity Gut bacteria can use a different form of proline with different machinery. Purified C. difficile proline reductase contained PrdA and selenocysteine-containing PrdB and used D-proline; its stereospecific activity is distinct from human L-proline oxidation. Model: Purified bacterial reductase and substrate tests. Limitations: L-proline-linked fermentation requires stereochemical processing; this enzyme is not a human PRODH isoform. 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
Complete structured claim and evidence
Selenium supplementation was required for the increased bacterial growth yield seen with the tested Stickland amino-acid pairs; proline-related acceptors induced selenoenzyme expression.
Selenium → C. difficile growth during selenium-dependent Stickland fermentation source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
Anaerobic C. difficile culture in limiting medium; selenite supplementation and radiolabeled selenium protein analysis.
limitations
This bacterial growth mechanism does not establish that dietary selenium causes or prevents infection.
nutrient_topic
L-Proline collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Proline
plain_language
Selenium also supports some microbial amino-acid fermentation pathways.
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 414–420
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Anaerobic C. difficile culture in limiting medium; selenite supplementation and radiolabeled selenium protein analysis. · source_derived_draft · unverified_draft
## l-proline-microbial-selenium Selenium also supports some microbial amino-acid fermentation pathways. Selenium supplementation was required for the increased bacterial growth yield seen with the tested Stickland amino-acid pairs; proline-related acceptors induced selenoenzyme expression. Model: Anaerobic C. difficile culture in limiting medium; selenite supplementation and radiolabeled selenium protein analysis. Limitations: This bacterial growth mechanism does not establish that dietary selenium causes or prevents infection. 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
Complete structured claim and evidence
Zinc strongly inhibited purified C. difficile D-proline reductase, which did not require added divalent cations for its measured activity.
Zinc(II) ion → Clostridioides difficile D-proline reductase complex source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
Human P5CS links glutamate to P5C synthesis through ATP- and NADPH-dependent chemistry.
Human pyrroline-5-carboxylate synthase / ALDH18A1 → Delta-1-pyrroline-5-carboxylate / P5C source_derived_draftungraded
Experimental context and source evidence
evidence_span
{"source_cache": "artifacts/citrulline-research/11092761.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "09706fd9ec135c472473decaa612e06b3e5aa021c9b1493d77daf4fe98b8d5d2", "start_char": 0, "end_char": 1688, "text_sha256": "09706fd9ec135c472473decaa612e06b3e5aa021c9b1493d77daf4fe98b8d5d2"}
experimental_model
Patient genetics and recombinant variant expression
exposure
ALDH18A1 R84Q compared with wild-type isoforms
limitations
Rare inherited enzyme disorder; does not imply low dietary citrulline caused the clinical phenotype.
nutrient_topic
Citrulline research collection; topical membership is not evidence of a direct dietary effect. · L-Citrulline
organism
Human, two siblings and mammalian expression systems
plain_language
This supplies a precursor route connected to ornithine and arginine production.
primary_references
[citrulline-p11092761] Hyperammonemia with reduced ornithine, citrulline, arginine and proline: a new inborn error caused by a mutation in the gene encoding delta(1)-pyrroline-5-carboxylate synthase. (2000). https://pubmed.ncbi.nlm.nih.gov/11092761/ DOI: 10.1093/hmg/9.19.2853
tissue_or_cell_type
Mitochondrial P5CS and circulating amino acids
Citrulline: arginine recycling, nitrogen disposal and nutrient connections (2026-09-17) · lines 294–305
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Patient genetics and recombinant variant expression · source_derived_draft · unverified_draft
### citrulline-p5cs-reaction Human P5CS links glutamate to P5C synthesis through ATP- and NADPH-dependent chemistry. Condition category: normal nutrient_topic: Citrulline research collection; topical membership is not evidence of a direct dietary effect. plain_language: This supplies a precursor route connected to ornithine and arginine production. organism: Human, two siblings and mammalian expression systems tissue_or_cell_type: Mitochondrial P5CS and circulating amino acids experimental_model: Patient genetics and recombinant variant expression limitations: Rare inherited enzyme disorder; does not imply low dietary citrulline caused the clinical phenotype. exposure: ALDH18A1 R84Q compared with wild-type isoforms evidence_span: {"source_cache": "artifacts/citrulline-research/11092761.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "09706fd9ec135c472473decaa612e06b3e5aa021c9b1493d77daf4fe98b8d5d2", "start_char": 0, "end_char": 1688, "text_sha256": "09706fd9ec135c472473decaa612e06b3e5aa021c9b1493d77daf4fe98b8d5d2"} [citrulline-p11092761] Hyperammonemia with reduced ornithine, citrulline, arginine and proline: a new inborn error caused by a mutation in the gene encoding delta(1)-pyrroline-5-carboxylate synthase. (2000). https://pubmed.ncbi.nlm.nih.gov/11092761/ DOI: 10.1093/hmg/9.19.2853
Complete structured claim and evidence
The two R84Q siblings had hypocitrullinemia with low ornithine, arginine and proline; the variant strongly reduced expressed P5CS activity.
Human ALDH18A1 / P5CS R84Q variant → Circulating citrulline concentration source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
evidence_span
{"source_cache": "artifacts/citrulline-research/11092761.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "09706fd9ec135c472473decaa612e06b3e5aa021c9b1493d77daf4fe98b8d5d2", "start_char": 0, "end_char": 1688, "text_sha256": "09706fd9ec135c472473decaa612e06b3e5aa021c9b1493d77daf4fe98b8d5d2"}
experimental_model
Patient genetics and recombinant variant expression
exposure
ALDH18A1 R84Q compared with wild-type isoforms
limitations
Rare inherited enzyme disorder; does not imply low dietary citrulline caused the clinical phenotype.
nutrient_topic
Citrulline research collection; topical membership is not evidence of a direct dietary effect. · L-Citrulline
organism
Human, two siblings and mammalian expression systems
plain_language
Low citrulline can arise from a defective upstream enzyme.
primary_references
[citrulline-p11092761] Hyperammonemia with reduced ornithine, citrulline, arginine and proline: a new inborn error caused by a mutation in the gene encoding delta(1)-pyrroline-5-carboxylate synthase. (2000). https://pubmed.ncbi.nlm.nih.gov/11092761/ DOI: 10.1093/hmg/9.19.2853
tissue_or_cell_type
Mitochondrial P5CS and circulating amino acids
trigger_kind
machinery_impairment Imported condition classification; unverified.
Citrulline: arginine recycling, nitrogen disposal and nutrient connections (2026-09-17) · lines 320–331
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Patient genetics and recombinant variant expression · source_derived_draft · unverified_draft
### citrulline-p5cs-low-citrulline The two R84Q siblings had hypocitrullinemia with low ornithine, arginine and proline; the variant strongly reduced expressed P5CS activity. Condition category: machinery_impairment nutrient_topic: Citrulline research collection; topical membership is not evidence of a direct dietary effect. plain_language: Low citrulline can arise from a defective upstream enzyme. organism: Human, two siblings and mammalian expression systems tissue_or_cell_type: Mitochondrial P5CS and circulating amino acids experimental_model: Patient genetics and recombinant variant expression limitations: Rare inherited enzyme disorder; does not imply low dietary citrulline caused the clinical phenotype. exposure: ALDH18A1 R84Q compared with wild-type isoforms evidence_span: {"source_cache": "artifacts/citrulline-research/11092761.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "09706fd9ec135c472473decaa612e06b3e5aa021c9b1493d77daf4fe98b8d5d2", "start_char": 0, "end_char": 1688, "text_sha256": "09706fd9ec135c472473decaa612e06b3e5aa021c9b1493d77daf4fe98b8d5d2"} [citrulline-p11092761] Hyperammonemia with reduced ornithine, citrulline, arginine and proline: a new inborn error caused by a mutation in the gene encoding delta(1)-pyrroline-5-carboxylate synthase. (2000). https://pubmed.ncbi.nlm.nih.gov/11092761/ DOI: 10.1093/hmg/9.19.2853
Complete structured claim and evidence
OAT transfers the ornithine delta-amino group to 2-oxoglutarate, yielding glutamate and glutamate semialdehyde, which cyclizes to P5C.
Human ornithine aminotransferase / OAT → L-Glutamate-5-semialdehyde source_derived_draftungraded
Experimental context and source evidence
evidence_span
{"source_cache": "artifacts/citrulline-research/9514741.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "cca17abd35f0211a043dd3cc8883369e230209206ff62b62242197f90201cea0", "start_char": 0, "end_char": 2979, "text_sha256": "cca17abd35f0211a043dd3cc8883369e230209206ff62b62242197f90201cea0"}
experimental_model
Recombinant enzyme crystal structure
exposure
PLP-bound enzyme structure
limitations
The described reaction direction is ornithine transamination; this structure alone does not quantify reverse flux in human intestine.
nutrient_topic
Citrulline research collection; topical membership is not evidence of a direct dietary effect. · L-Citrulline
organism
Human OAT
plain_language
This is an ornithine-processing reaction; its direction depends on the biological setting.
primary_references
[citrulline-p9514741] Crystal structure of human recombinant ornithine aminotransferase. (1998). https://pubmed.ncbi.nlm.nih.gov/9514741/ DOI: 10.1006/jmbi.1997.1583
tissue_or_cell_type
Mitochondrial ornithine transamination
Citrulline: arginine recycling, nitrogen disposal and nutrient connections (2026-09-17) · lines 346–357
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Recombinant enzyme crystal structure · source_derived_draft · unverified_draft
### citrulline-oat-reaction OAT transfers the ornithine delta-amino group to 2-oxoglutarate, yielding glutamate and glutamate semialdehyde, which cyclizes to P5C. Condition category: normal nutrient_topic: Citrulline research collection; topical membership is not evidence of a direct dietary effect. plain_language: This is an ornithine-processing reaction; its direction depends on the biological setting. organism: Human OAT tissue_or_cell_type: Mitochondrial ornithine transamination experimental_model: Recombinant enzyme crystal structure limitations: The described reaction direction is ornithine transamination; this structure alone does not quantify reverse flux in human intestine. exposure: PLP-bound enzyme structure evidence_span: {"source_cache": "artifacts/citrulline-research/9514741.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "cca17abd35f0211a043dd3cc8883369e230209206ff62b62242197f90201cea0", "start_char": 0, "end_char": 2979, "text_sha256": "cca17abd35f0211a043dd3cc8883369e230209206ff62b62242197f90201cea0"} [citrulline-p9514741] Crystal structure of human recombinant ornithine aminotransferase. (1998). https://pubmed.ncbi.nlm.nih.gov/9514741/ DOI: 10.1006/jmbi.1997.1583
Complete structured claim and evidence
Human OAT bound pyridoxal phosphate through a Schiff base to Lys292.
PLP → Human ornithine aminotransferase / OAT source_derived_draftungraded
Experimental context and source evidence
evidence_span
{"source_cache": "artifacts/citrulline-research/9514741.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "cca17abd35f0211a043dd3cc8883369e230209206ff62b62242197f90201cea0", "start_char": 0, "end_char": 2979, "text_sha256": "cca17abd35f0211a043dd3cc8883369e230209206ff62b62242197f90201cea0"}
experimental_model
Recombinant enzyme crystal structure
exposure
PLP-bound enzyme structure
limitations
The described reaction direction is ornithine transamination; this structure alone does not quantify reverse flux in human intestine.
nutrient_topic
Citrulline research collection; topical membership is not evidence of a direct dietary effect. · L-Citrulline
organism
Human OAT
plain_language
Vitamin B6 has a defined role in the machinery handling ornithine.
primary_references
[citrulline-p9514741] Crystal structure of human recombinant ornithine aminotransferase. (1998). https://pubmed.ncbi.nlm.nih.gov/9514741/ DOI: 10.1006/jmbi.1997.1583
tissue_or_cell_type
Mitochondrial ornithine transamination
Citrulline: arginine recycling, nitrogen disposal and nutrient connections (2026-09-17) · lines 333–344
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Recombinant enzyme crystal structure · source_derived_draft · unverified_draft
### citrulline-oat-plp Human OAT bound pyridoxal phosphate through a Schiff base to Lys292. Condition category: normal nutrient_topic: Citrulline research collection; topical membership is not evidence of a direct dietary effect. plain_language: Vitamin B6 has a defined role in the machinery handling ornithine. organism: Human OAT tissue_or_cell_type: Mitochondrial ornithine transamination experimental_model: Recombinant enzyme crystal structure limitations: The described reaction direction is ornithine transamination; this structure alone does not quantify reverse flux in human intestine. exposure: PLP-bound enzyme structure evidence_span: {"source_cache": "artifacts/citrulline-research/9514741.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "cca17abd35f0211a043dd3cc8883369e230209206ff62b62242197f90201cea0", "start_char": 0, "end_char": 2979, "text_sha256": "cca17abd35f0211a043dd3cc8883369e230209206ff62b62242197f90201cea0"} [citrulline-p9514741] Crystal structure of human recombinant ornithine aminotransferase. (1998). https://pubmed.ncbi.nlm.nih.gov/9514741/ DOI: 10.1006/jmbi.1997.1583
Complete structured claim and evidence
Purified human NADK2 Δ62 converted NAD+ to NADP+ with ATP in MgCl2-containing reactions; TLC also detected ADP formation.
NADK2 Δ62 recombinant construct → NADP+ source_derived_draftungraded
Experimental context and source evidence
cross_nutrient
Magnesium is present with ATP during phosphorylation of the niacin-derived dinucleotide; this assay does not quantify effects of dietary magnesium shortage.
evidence_span
[{"source_cache": "artifacts/niacin-redox-sources/nadk2-2012.fulltext.txt", "locator": "Results", "start_char": 8475, "end_char": 9580, "file_sha256": "65209c0b4ea7220bc95afdd182e40910f2445345172956e85552d5c6db649648", "text_sha256": "c86810a1a5342cd4e7ea126e070f28ed3182d81f17ea76c0fbb3833612c0f529"}, {"source_cache": "artifacts/niacin-redox-sources/nadk2-2012.fulltext.txt", "locator": "Methods, NADK activity assay", "start_char": 26694, "end_char": 28732, "file_sha256": "65209c0b4ea7220bc95afdd182e40910f2445345172956e85552d5c6db649648", "text_sha256": "907b651f0c0aae7a31306bdc42264cdfd22fb0e236e7ab8f37900467b0b0ab72"}]
experimental_model
Purified His-tagged Δ62C5orf33/NADK2
exposure
TLC: 5 mM NAD+, 5 mM ATP, 5 mM MgCl2; 37°C
limitations
Scoped experimental observation; no dietary niacin or magnesium deficiency threshold or treatment benefit was tested.
nutrient_topic
Niacin research collection; topical membership is not evidence of a direct dietary effect. · Niacin (vitamin B3)
organism
Homo sapiens
plain_language
The mitochondrial kinase uses a phosphate-transfer reaction to create NADP+.
primary_references
[nadk2-2012] Identification and characterization of a human mitochondrial NAD kinase. (2012). https://pubmed.ncbi.nlm.nih.gov/23212377/ DOI: 10.1038/ncomms2262
tissue_or_cell_type
Purified protein
Niacin: NAD metabolism, deficiency and nutrient interactions (2026-09-17) · lines 871–883
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purified His-tagged Δ62C5orf33/NADK2 · source_derived_draft · unverified_draft
### b3-redox-nadk2-phosphorylation Purified human NADK2 Δ62 converted NAD+ to NADP+ with ATP in MgCl2-containing reactions; TLC also detected ADP formation. Condition category: normal nutrient_topic: Niacin research collection; topical membership is not evidence of a direct dietary effect. plain_language: The mitochondrial kinase uses a phosphate-transfer reaction to create NADP+. organism: Homo sapiens tissue_or_cell_type: Purified protein experimental_model: Purified His-tagged Δ62C5orf33/NADK2 limitations: Scoped experimental observation; no dietary niacin or magnesium deficiency threshold or treatment benefit was tested. exposure: TLC: 5 mM NAD+, 5 mM ATP, 5 mM MgCl2; 37°C cross_nutrient: Magnesium is present with ATP during phosphorylation of the niacin-derived dinucleotide; this assay does not quantify effects of dietary magnesium shortage. evidence_span: [{"source_cache": "artifacts/niacin-redox-sources/nadk2-2012.fulltext.txt", "locator": "Results", "start_char": 8475, "end_char": 9580, "file_sha256": "65209c0b4ea7220bc95afdd182e40910f2445345172956e85552d5c6db649648", "text_sha256": "c86810a1a5342cd4e7ea126e070f28ed3182d81f17ea76c0fbb3833612c0f529"}, {"source_cache": "artifacts/niacin-redox-sources/nadk2-2012.fulltext.txt", "locator": "Methods, NADK activity assay", "start_char": 26694, "end_char": 28732, "file_sha256": "65209c0b4ea7220bc95afdd182e40910f2445345172956e85552d5c6db649648", "text_sha256": "907b651f0c0aae7a31306bdc42264cdfd22fb0e236e7ab8f37900467b0b0ab72"}] [nadk2-2012] Identification and characterization of a human mitochondrial NAD kinase. (2012). https://pubmed.ncbi.nlm.nih.gov/23212377/ DOI: 10.1038/ncomms2262
Complete structured claim and evidence
Isotope experiments showed alanine supplying carbon and nitrogen to glutamate and proline synthesis in human lung fibroblasts, particularly during glutamine deprivation.
L-Alanine → L-Proline source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary full text
experimental_model
Human fibroblast stable-isotope tracing under specified media conditions.
limitations
Atom contribution is not a one-step alanine-to-proline reaction; other enzymes, carbon sources and cofactors remain necessary.
nutrient_topic
L-Alanine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Alanine
plain_language
One amino acid can supply material used to make another.
primary_references
TGF-β coordinates alanine synthesis and import for myofibroblast differentiation in pulmonary fibrosis. · 2026 · https://pubmed.ncbi.nlm.nih.gov/42024472/ · DOI 10.1172/jci.insight.199449
L-Alanine: carbon, nitrogen, protein synthesis and cross-nutrient mechanisms (2026-09-19) · lines 520–526
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human fibroblast stable-isotope tracing under specified media conditions. · source_derived_draft · unverified_draft
## alanine-fibroblast-proline One amino acid can supply material used to make another. Isotope experiments showed alanine supplying carbon and nitrogen to glutamate and proline synthesis in human lung fibroblasts, particularly during glutamine deprivation. Model: Human fibroblast stable-isotope tracing under specified media conditions. Limitations: Atom contribution is not a one-step alanine-to-proline reaction; other enzymes, carbon sources and cofactors remain necessary. Evidence access: Primary full text TGF-β coordinates alanine synthesis and import for myofibroblast differentiation in pulmonary fibrosis. · 2026 · https://pubmed.ncbi.nlm.nih.gov/42024472/ · DOI 10.1172/jci.insight.199449
Complete structured claim and evidence
Tracer carbon appeared in putrescine and proline; arginase inhibition reduced these labeled products.
L-Arginine → Putrescine source_derived_draftungraded
Experimental context and source evidence
evidence_access
Full-text results, Figures 2 and 6, Europe PMC PMC5075284; primary abstract.
experimental_model
Primary human activated T cells; isotope tracing and functional assays.
limitations
Flux is model-specific; not evidence of clinical wound healing.
nutrient_topic
L-Arginine collection; tissue, species, dose and formulation distinctions retained. · L-Arginine
plain_language
Arginine fed more than the NO pathway.
primary_references
L-Arginine Modulates T Cell Metabolism and Enhances Survival and Anti-tumor Activity. · 2016 · https://pubmed.ncbi.nlm.nih.gov/27745970/ · DOI 10.1016/j.cell.2016.09.031
L-Arginine: transport, metabolic branches, nutrient interactions, availability and discovery questions (2026-09-18) · lines 222–228
AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Primary human activated T cells; isotope tracing and functional assays. · source_derived_draft · unverified_draft
## arg-tcell-carbon Arginine fed more than the NO pathway. Tracer carbon appeared in putrescine and proline; arginase inhibition reduced these labeled products. Model: Primary human activated T cells; isotope tracing and functional assays. Limitations: Flux is model-specific; not evidence of clinical wound healing. Evidence access: Full-text results, Figures 2 and 6, Europe PMC PMC5075284; primary abstract. L-Arginine Modulates T Cell Metabolism and Enhances Survival and Anti-tumor Activity. · 2016 · https://pubmed.ncbi.nlm.nih.gov/27745970/ · DOI 10.1016/j.cell.2016.09.031
Complete structured claim and evidence
Inheritance and functional studies in seven families implicated nonfunctional SLC36A2 alleles in urinary glycine and imino-acid loss; two defective alleles tracked iminoglycinuria and one tracked hyperglycinuria.
Human proton-coupled amino acid transporter 2 / SLC36A2 → Human renal glycine and imino-acid reabsorption source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
evidence_access
Primary abstract
experimental_model
Human family genetics with functional transporter testing.
limitations
This is renal handling; urinary loss alone does not establish systemic nutritional deficiency.
nutrient_topic
Glycine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · Glycine
plain_language
The kidney can lose glycine because its recovery transporter is faulty.
primary_references
Iminoglycinuria and hyperglycinuria are discrete human phenotypes resulting from complex mutations in proline and glycine transporters. · 2008 · https://pubmed.ncbi.nlm.nih.gov/19033659/ · DOI 10.1172/JCI36625
trigger_kind
machinery_impairment Imported condition classification; unverified.
Glycine: supply, one-carbon allocation, receptors and cross-nutrient mechanisms (2026-09-19) · lines 66–72
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human family genetics with functional transporter testing. · source_derived_draft · unverified_draft
## glycine-renal-pat2 The kidney can lose glycine because its recovery transporter is faulty. Inheritance and functional studies in seven families implicated nonfunctional SLC36A2 alleles in urinary glycine and imino-acid loss; two defective alleles tracked iminoglycinuria and one tracked hyperglycinuria. Model: Human family genetics with functional transporter testing. Limitations: This is renal handling; urinary loss alone does not establish systemic nutritional deficiency. Evidence access: Primary abstract Iminoglycinuria and hyperglycinuria are discrete human phenotypes resulting from complex mutations in proline and glycine transporters. · 2008 · https://pubmed.ncbi.nlm.nih.gov/19033659/ · DOI 10.1172/JCI36625
Complete structured claim and evidence
SLC6A20 mutations accompanied iminoglycinuria when combined with SLC36A2 variants retaining residual transport.
Human imino-acid transporter / SLC6A20 → Phenotype with residual SLC36A2 transport source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
evidence_access
Primary abstract
experimental_model
Human family genotype/functional analysis.
limitations
Modifier evidence is not proof of ordinary dietary competition between glycine and proline.
nutrient_topic
Glycine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · Glycine
plain_language
A second transporter can change the effect of the first defect.
primary_references
Iminoglycinuria and hyperglycinuria are discrete human phenotypes resulting from complex mutations in proline and glycine transporters. · 2008 · https://pubmed.ncbi.nlm.nih.gov/19033659/ · DOI 10.1172/JCI36625
trigger_kind
machinery_impairment Imported condition classification; unverified.
Glycine: supply, one-carbon allocation, receptors and cross-nutrient mechanisms (2026-09-19) · lines 74–80
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human family genotype/functional analysis. · source_derived_draft · unverified_draft
## glycine-renal-modifier A second transporter can change the effect of the first defect. SLC6A20 mutations accompanied iminoglycinuria when combined with SLC36A2 variants retaining residual transport. Model: Human family genotype/functional analysis. Limitations: Modifier evidence is not proof of ordinary dietary competition between glycine and proline. Evidence access: Primary abstract Iminoglycinuria and hyperglycinuria are discrete human phenotypes resulting from complex mutations in proline and glycine transporters. · 2008 · https://pubmed.ncbi.nlm.nih.gov/19033659/ · DOI 10.1172/JCI36625
Complete structured claim and evidence
In chick collagen hydroxylase assays, complete proline hydroxylation was coupled to 2-oxoglutarate decarboxylation while ascorbate was not consumed in most catalytic cycles.
Chick collagen prolyl 4-hydroxylase preparation → 2-Oxoglutarate source_derived_draftungraded
Experimental context and source evidence
cross_nutrient
Vitamin C chemistry in collagen, modified-lysine/carnitine metabolism or copper-dependent peptide/catecholamine processing.
experimental_model
Purified chick prolyl and partially purified lysyl collagen hydroxylases
exposure
Peptide substrate present or absent; uncoupled 2-oxoglutarate decarboxylation assays.
limitations
This statement concerns coupled turnover; it must not be transferred to copper monooxygenases.
nutrient_topic
Vitamin C research collection; topical membership is not evidence of a direct dietary effect. · Vitamin C
organism
Gallus gallus
plain_language
Vitamin C is not a one-for-one consumed ingredient in every successful collagen hydroxylation.
primary_references
[myllyla1984] Ascorbate is consumed stoichiometrically in the uncoupled reactions catalyzed by prolyl 4-hydroxylase and lysyl hydroxylase. (1984). https://pubmed.ncbi.nlm.nih.gov/6325436/ DOI: 10.1016/s0021-9258(18)91023-9
tissue_or_cell_type
Chick embryo enzyme preparations
Vitamin C: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 585–596
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purified chick prolyl and partially purified lysyl collagen hydroxylases · source_derived_draft · unverified_draft
### vc-enzyme-coupled-ascorbate-use In chick collagen hydroxylase assays, complete proline hydroxylation was coupled to 2-oxoglutarate decarboxylation while ascorbate was not consumed in most catalytic cycles. Condition category: normal nutrient_topic: Vitamin C research collection; topical membership is not evidence of a direct dietary effect. plain_language: Vitamin C is not a one-for-one consumed ingredient in every successful collagen hydroxylation. organism: Gallus gallus tissue_or_cell_type: Chick embryo enzyme preparations experimental_model: Purified chick prolyl and partially purified lysyl collagen hydroxylases limitations: This statement concerns coupled turnover; it must not be transferred to copper monooxygenases. cross_nutrient: Vitamin C chemistry in collagen, modified-lysine/carnitine metabolism or copper-dependent peptide/catecholamine processing. exposure: Peptide substrate present or absent; uncoupled 2-oxoglutarate decarboxylation assays. [myllyla1984] Ascorbate is consumed stoichiometrically in the uncoupled reactions catalyzed by prolyl 4-hydroxylase and lysyl hydroxylase. (1984). https://pubmed.ncbi.nlm.nih.gov/6325436/ DOI: 10.1016/s0021-9258(18)91023-9
Complete structured claim and evidence
After 2-oxoglutarate-associated inactivation of chick prolyl hydroxylase, ascorbate decreased its ferric EPR signal and partly restored activity, supporting reduction of enzyme-bound Fe(III).
L-Ascorbate → Chick collagen prolyl 4-hydroxylase with oxidized enzyme-bound iron source_derived_draftungraded
Experimental context and source evidence
cross_nutrient
Vitamin C chemistry in collagen, modified-lysine/carnitine metabolism or copper-dependent peptide/catecholamine processing.
experimental_model
Purified chick collagen prolyl hydroxylase, EPR and activity measurements
exposure
400 micromolar 2-oxoglutarate; enzyme inactivation within 1 minute without ascorbate; 30-second EPR incubation at 37 C.
limitations
Protein-bound redox chemistry; no claim that serum iron or dietary iron supplementation predicts this state.
nutrient_topic
Vitamin C research collection; topical membership is not evidence of a direct dietary effect. · Vitamin C
organism
Gallus gallus
plain_language
Vitamin C can restore the iron inside an inactive collagen enzyme to a working redox state.
primary_references
[dejong1982] Prolyl 4-hydroxylase activity in relation to the oxidation state of enzyme-bound iron. The role of ascorbate in peptidyl proline hydroxylation. (1982). https://pubmed.ncbi.nlm.nih.gov/6285984/ DOI: 10.1016/0167-4838(82)90162-5
tissue_or_cell_type
Chick embryo enzyme preparation
Vitamin C: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 624–635
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purified chick collagen prolyl hydroxylase, EPR and activity measurements · source_derived_draft · unverified_draft
### vc-enzyme-bound-iron-reactivation After 2-oxoglutarate-associated inactivation of chick prolyl hydroxylase, ascorbate decreased its ferric EPR signal and partly restored activity, supporting reduction of enzyme-bound Fe(III). Condition category: normal nutrient_topic: Vitamin C research collection; topical membership is not evidence of a direct dietary effect. plain_language: Vitamin C can restore the iron inside an inactive collagen enzyme to a working redox state. organism: Gallus gallus tissue_or_cell_type: Chick embryo enzyme preparation experimental_model: Purified chick collagen prolyl hydroxylase, EPR and activity measurements limitations: Protein-bound redox chemistry; no claim that serum iron or dietary iron supplementation predicts this state. cross_nutrient: Vitamin C chemistry in collagen, modified-lysine/carnitine metabolism or copper-dependent peptide/catecholamine processing. exposure: 400 micromolar 2-oxoglutarate; enzyme inactivation within 1 minute without ascorbate; 30-second EPR incubation at 37 C. [dejong1982] Prolyl 4-hydroxylase activity in relation to the oxidation state of enzyme-bound iron. The role of ascorbate in peptidyl proline hydroxylation. (1982). https://pubmed.ncbi.nlm.nih.gov/6285984/ DOI: 10.1016/0167-4838(82)90162-5
Complete structured claim and evidence
Replacing the TFEB PPP motif with AAA partially rescued TFEB expression during GC7 treatment.
Mouse TFEB triproline-containing translation motif → Mouse transcription factor EB / Tfeb source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary full text
experimental_model
Murine TFEB constructs in NIH 3T3 cells.
limitations
Partial rescue; free proline supplementation was not tested.
nutrient_topic
Spermidine collection; molecular form, preparation, species, exposure and manipulation remain explicit. · Spermidine
plain_language
A sequence within the protein helps explain the dependency.
primary_references
Polyamines Control eIF5A Hypusination, TFEB Translation, and Autophagy to Reverse B Cell Senescence. · 2019 · https://pubmed.ncbi.nlm.nih.gov/31474573/ · DOI 10.1016/j.molcel.2019.08.005
Spermidine: biosynthesis, hypusination, transport and cross-nutrient mechanisms (2026-09-19) · lines 222–228
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Murine TFEB constructs in NIH 3T3 cells. · source_derived_draft · unverified_draft
## spermidine-tfeb-proline A sequence within the protein helps explain the dependency. Replacing the TFEB PPP motif with AAA partially rescued TFEB expression during GC7 treatment. Model: Murine TFEB constructs in NIH 3T3 cells. Limitations: Partial rescue; free proline supplementation was not tested. Evidence access: Primary full text Polyamines Control eIF5A Hypusination, TFEB Translation, and Autophagy to Reverse B Cell Senescence. · 2019 · https://pubmed.ncbi.nlm.nih.gov/31474573/ · DOI 10.1016/j.molcel.2019.08.005
Complete structured claim and evidence
DHPS transfers spermidine-derived aminobutyl onto eIF5A Lys50 to form deoxyhypusine.
DHPS → eIF5A1 with unmodified Lys50 source_derived_draftungraded
Experimental context and source evidence
experimental_model
Human DHPS structural biochemistry.
limitations
NAD cycles during catalysis; it is not represented as a net consumed substrate here. This reaction modifies lysine already in a protein. It does not show that extra oral lysine increases the reaction or improves a clinical outcome.
organism
Human
plain_language
A particular protein lysine becomes a specialized translation-factor residue.
primary_references
[dhps-2020] Half Way to Hypusine-Structural Basis for Substrate Recognition by Human Deoxyhypusine Synthase (2020). https://pubmed.ncbi.nlm.nih.gov/32235505/
tissue_or_cell_type
Not specified as a whole tissue; see experimental model.
L-Lysine: mechanism-first literature curation (2026-09-17) · lines 578–586
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human DHPS structural biochemistry. · source_derived_draft · unverified_draft
### dhps-eif5a-deoxyhypusine DHPS transfers spermidine-derived aminobutyl onto eIF5A Lys50 to form deoxyhypusine. Plain language: A particular protein lysine becomes a specialized translation-factor residue. Condition category: normal organism: Human tissue_or_cell_type: Not specified as a whole tissue; see experimental model. experimental_model: Human DHPS structural biochemistry. limitations: NAD cycles during catalysis; it is not represented as a net consumed substrate here. This reaction modifies lysine already in a protein. It does not show that extra oral lysine increases the reaction or improves a clinical outcome. [dhps-2020] Half Way to Hypusine-Structural Basis for Substrate Recognition by Human Deoxyhypusine Synthase (2020). https://pubmed.ncbi.nlm.nih.gov/32235505/
Complete structured claim and evidence
Increasing medium glycine from the millimolar range increased type-II collagen production in cultured bovine chondrocytes, with larger sustained effects than the tested proline/lysine increments.
Glycine → Type-II collagen production by bovine articular chondrocytes source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary full text
experimental_model
Bovine articular chondrocyte monolayers; 15-day concentration series and collagen ELISA.
limitations
The paper proposes dietary implications, but the experiment does not establish human glycine essentiality, osteoarthritis causation or cartilage regeneration.
nutrient_topic
Glycine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · Glycine
plain_language
Collagen-producing cells responded to extra glycine in a culture assay.
primary_references
High glycine concentration increases collagen synthesis by articular chondrocytes in vitro: acute glycine deficiency could be an important cause of osteoarthritis. · 2018 · https://pubmed.ncbi.nlm.nih.gov/30006659/ · DOI 10.1007/s00726-018-2611-x
Glycine: supply, one-carbon allocation, receptors and cross-nutrient mechanisms (2026-09-19) · lines 402–408
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Bovine articular chondrocyte monolayers; 15-day concentration series and collagen ELISA. · source_derived_draft · unverified_draft
## glycine-collagen-culture Collagen-producing cells responded to extra glycine in a culture assay. Increasing medium glycine from the millimolar range increased type-II collagen production in cultured bovine chondrocytes, with larger sustained effects than the tested proline/lysine increments. Model: Bovine articular chondrocyte monolayers; 15-day concentration series and collagen ELISA. Limitations: The paper proposes dietary implications, but the experiment does not establish human glycine essentiality, osteoarthritis causation or cartilage regeneration. Evidence access: Primary full text High glycine concentration increases collagen synthesis by articular chondrocytes in vitro: acute glycine deficiency could be an important cause of osteoarthritis. · 2018 · https://pubmed.ncbi.nlm.nih.gov/30006659/ · DOI 10.1007/s00726-018-2611-x
Complete structured claim and evidence

Availability and dependencies

Each situation shows the normal role first, then what the sources report under a specific condition. A shortfall in the diet, a fault in the machinery, and a low blood reading are kept separate because they are not the same thing.

A missing mitochondrial cofactor pool creates dependence on imported proline

Condition: machinery_impairment · NADK2 deletion in cultured mammalian cells.