L-Serine

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary abstract

experimental_model

Small human HSAN1 serine-supplementation pilot.

limitations

Biomarker lowering alone does not establish neurological recovery, and the intervention was serine rather than alanine.

nutrient_topic

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

plain_language

The human pilot measured a biochemical response.

primary_references

Oral L-serine supplementation reduces production of neurotoxic deoxysphingolipids in mice and humans with hereditary sensory autonomic neuropathy type 1. · 2011 · https://pubmed.ncbi.nlm.nih.gov/22045570/ · DOI 10.1172/JCI57549

trigger_kind

machinery_impairment Imported condition classification; unverified.

L-Alanine: carbon, nitrogen, protein synthesis and cross-nutrient mechanisms (2026-09-19) · lines 448–454

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Small human HSAN1 serine-supplementation pilot. · source_derived_draft · unverified_draft

## alanine-spt-human-serine The human pilot measured a biochemical response. A pilot study in 14 HSAN1 patients found reduced deoxysphingolipid levels during oral serine supplementation. Model: Small human HSAN1 serine-supplementation pilot. Limitations: Biomarker lowering alone does not establish neurological recovery, and the intervention was serine rather than alanine. Evidence access: Primary abstract Oral L-serine supplementation reduces production of neurotoxic deoxysphingolipids in mice and humans with hereditary sensory autonomic neuropathy type 1. · 2011 · https://pubmed.ncbi.nlm.nih.gov/22045570/ · DOI 10.1172/JCI57549

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary abstract

experimental_model

HSAN1 transgenic mouse dietary intervention.

limitations

Mouse neurological outcomes do not establish human clinical benefit.

nutrient_topic

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

plain_language

Restoring the competing normal substrate changed the abnormal lipid output.

primary_references

Oral L-serine supplementation reduces production of neurotoxic deoxysphingolipids in mice and humans with hereditary sensory autonomic neuropathy type 1. · 2011 · https://pubmed.ncbi.nlm.nih.gov/22045570/ · DOI 10.1172/JCI57549

trigger_kind

machinery_impairment Imported condition classification; unverified.

L-Alanine: carbon, nitrogen, protein synthesis and cross-nutrient mechanisms (2026-09-19) · lines 440–446

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · HSAN1 transgenic mouse dietary intervention. · source_derived_draft · unverified_draft

## alanine-spt-serine-rescue Restoring the competing normal substrate changed the abnormal lipid output. A 10% serine-enriched diet reduced deoxysphingolipids and improved selected motor and sensory outcomes in C133W SPTLC1 transgenic mice. Model: HSAN1 transgenic mouse dietary intervention. Limitations: Mouse neurological outcomes do not establish human clinical benefit. Evidence access: Primary abstract Oral L-serine supplementation reduces production of neurotoxic deoxysphingolipids in mice and humans with hereditary sensory autonomic neuropathy type 1. · 2011 · https://pubmed.ncbi.nlm.nih.gov/22045570/ · DOI 10.1172/JCI57549

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary full-text results section: serine supplementation and ALS-associated SPTLC1 variants

experimental_model

Primary full-text experiment in engineered human motor-neuron-like cells.

limitations

Measured biochemical worsening is distinct from a clinical outcome trial; this finding cannot be generalized to all ALS.

nutrient_topic

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

plain_language

Extra substrate can feed an overactive pathway.

primary_references

Childhood amyotrophic lateral sclerosis caused by excess sphingolipid synthesis. · 2021 · https://pubmed.ncbi.nlm.nih.gov/34059824/ · DOI 10.1038/s41591-021-01346-1

trigger_kind

machinery_impairment Imported condition classification; unverified.

L-Serine: synthesis, one-carbon metabolism, lipids 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 · Primary full-text experiment in engineered human motor-neuron-like cells. · source_derived_draft · unverified_draft

## l-serine-als-serine-addition Extra substrate can feed an overactive pathway. Adding excess serine further increased already elevated sphingolipid levels in mutant-SPTLC1 human iPSC-derived motor-neuron-like cells. Model: Primary full-text experiment in engineered human motor-neuron-like cells. Limitations: Measured biochemical worsening is distinct from a clinical outcome trial; this finding cannot be generalized to all ALS. Evidence access: Primary full-text results section: serine supplementation and ALS-associated SPTLC1 variants Childhood amyotrophic lateral sclerosis caused by excess sphingolipid synthesis. · 2021 · https://pubmed.ncbi.nlm.nih.gov/34059824/ · DOI 10.1038/s41591-021-01346-1

evidence_access

Primary abstract

experimental_model

18 randomized adults; 16 completed; 400 mg/kg/day versus placebo for one year followed by open-label treatment.

limitations

High-dose disease-specific research regimen, not a general supplement recommendation.

nutrient_topic

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

plain_language

Changing substrate supply changed the abnormal lipid product in this inherited disorder.

primary_references

Randomized trial of l-serine in patients with hereditary sensory and autonomic neuropathy type 1. · 2019 · https://pubmed.ncbi.nlm.nih.gov/30626650/ · DOI 10.1212/WNL.0000000000006811

L-Serine: synthesis, one-carbon metabolism, lipids 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 · 18 randomized adults; 16 completed; 400 mg/kg/day versus placebo for one year followed by open-label treatment. · source_derived_draft · unverified_draft

## l-serine-hsan-trial-lipids Changing substrate supply changed the abnormal lipid product in this inherited disorder. In the randomized HSAN1 trial, oral L-serine reduced deoxysphinganine by 59% versus an 11% increase with placebo after one year. Model: 18 randomized adults; 16 completed; 400 mg/kg/day versus placebo for one year followed by open-label treatment. Limitations: High-dose disease-specific research regimen, not a general supplement recommendation. Evidence access: Primary abstract Randomized trial of l-serine in patients with hereditary sensory and autonomic neuropathy type 1. · 2019 · https://pubmed.ncbi.nlm.nih.gov/30626650/ · DOI 10.1212/WNL.0000000000006811

evidence_access

Primary abstract

experimental_model

Same HSAN1 randomized trial as the lipid result; not independent participants.

limitations

Small rare-disease trial; benefit cannot be transferred to other neuropathies or ALS.

nutrient_topic

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

plain_language

A small controlled trial also measured a clinical outcome.

primary_references

Randomized trial of l-serine in patients with hereditary sensory and autonomic neuropathy type 1. · 2019 · https://pubmed.ncbi.nlm.nih.gov/30626650/ · DOI 10.1212/WNL.0000000000006811

L-Serine: synthesis, one-carbon metabolism, lipids 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 · Same HSAN1 randomized trial as the lipid result; not independent participants. · source_derived_draft · unverified_draft

## l-serine-hsan-trial-neuropathy A small controlled trial also measured a clinical outcome. At one year, the L-serine group improved by 1.5 CMTNS units relative to placebo; the 95% confidence interval was -2.8 to -0.1 units. Model: Same HSAN1 randomized trial as the lipid result; not independent participants. Limitations: Small rare-disease trial; benefit cannot be transferred to other neuropathies or ALS. Evidence access: Primary abstract Randomized trial of l-serine in patients with hereditary sensory and autonomic neuropathy type 1. · 2019 · https://pubmed.ncbi.nlm.nih.gov/30626650/ · DOI 10.1212/WNL.0000000000006811

availability_state

biomarker_context Imported condition classification; unverified.

evidence_access

Primary abstract

experimental_model

Human case-control metabolomics; serine 20.6% lower and deoxysphingolipids 84.2% higher.

limitations

Association does not establish a dietary cause, universal threshold or supplementation benefit.

nutrient_topic

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

plain_language

A low measured amino-acid pool was associated with an abnormal lipid signature.

primary_references

Serine and Lipid Metabolism in Macular Disease and Peripheral Neuropathy. · 2019 · https://pubmed.ncbi.nlm.nih.gov/31509666/ · DOI 10.1056/NEJMoa1815111

trigger_kind

biomarker_context Imported condition classification; unverified.

L-Serine: synthesis, one-carbon metabolism, lipids 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 case-control metabolomics; serine 20.6% lower and deoxysphingolipids 84.2% higher. · source_derived_draft · unverified_draft

## l-serine-mac-tel-association A low measured amino-acid pool was associated with an abnormal lipid signature. Among 125 MacTel type 2 patients without pathogenic SPT variants and 94 controls, circulating serine was lower and deoxysphingolipids higher in the patient group. Model: Human case-control metabolomics; serine 20.6% lower and deoxysphingolipids 84.2% higher. Limitations: Association does not establish a dietary cause, universal threshold or supplementation benefit. Evidence access: Primary abstract Serine and Lipid Metabolism in Macular Disease and Peripheral Neuropathy. · 2019 · https://pubmed.ncbi.nlm.nih.gov/31509666/ · DOI 10.1056/NEJMoa1815111

evidence_access

Primary abstract

experimental_model

Mouse macrophage metabolic manipulation and LPS stimulation.

limitations

IL-1beta transcription and inflammasome-mediated processing are different endpoints.

nutrient_topic

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

plain_language

An antioxidant-building pathway can support inflammatory gene expression.

primary_references

Serine Metabolism Supports Macrophage IL-1β Production. · 2019 · https://pubmed.ncbi.nlm.nih.gov/30773464/ · DOI 10.1016/j.cmet.2019.01.014

L-Serine: synthesis, one-carbon metabolism, lipids 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 · Mouse macrophage metabolic manipulation and LPS stimulation. · source_derived_draft · unverified_draft

## l-serine-macrophage-gsh An antioxidant-building pathway can support inflammatory gene expression. Serine-derived glycine supported glutathione synthesis required for optimal LPS-induced IL-1beta mRNA expression; inflammasome activation was not the affected step. Model: Mouse macrophage metabolic manipulation and LPS stimulation. Limitations: IL-1beta transcription and inflammasome-mediated processing are different endpoints. Evidence access: Primary abstract Serine Metabolism Supports Macrophage IL-1β Production. · 2019 · https://pubmed.ncbi.nlm.nih.gov/30773464/ · DOI 10.1016/j.cmet.2019.01.014

availability_state

nutrient_deficiency Imported condition classification; unverified.

evidence_access

Primary abstract

experimental_model

Mouse low-serine model in the MacTel study.

limitations

Mouse manipulation is distinct from the observational human plasma comparison.

nutrient_topic

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

plain_language

Reduced availability can change the products of lipid synthesis.

primary_references

Serine and Lipid Metabolism in Macular Disease and Peripheral Neuropathy. · 2019 · https://pubmed.ncbi.nlm.nih.gov/31509666/ · DOI 10.1056/NEJMoa1815111

trigger_kind

nutrient_deficiency Imported condition classification; unverified.

L-Serine: synthesis, one-carbon metabolism, lipids 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 · Mouse low-serine model in the MacTel study. · source_derived_draft · unverified_draft

## l-serine-mouse-low-serine-retina Reduced availability can change the products of lipid synthesis. Experimentally lowering serine in mice increased retinal deoxysphingolipids and compromised visual function. Model: Mouse low-serine model in the MacTel study. Limitations: Mouse manipulation is distinct from the observational human plasma comparison. Evidence access: Primary abstract Serine and Lipid Metabolism in Macular Disease and Peripheral Neuropathy. · 2019 · https://pubmed.ncbi.nlm.nih.gov/31509666/ · DOI 10.1056/NEJMoa1815111

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary abstract

experimental_model

Uncontrolled follow-up using different serine/glycine treatment regimens.

limitations

Small heterogeneous case series; no general supplement dose or guaranteed developmental rescue follows.

nutrient_topic

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

plain_language

Restoring supply can help some outcomes without reversing every consequence.

primary_references

Congenital microcephaly and seizures due to 3-phosphoglycerate dehydrogenase deficiency: outcome of treatment with amino acids. · 2002 · https://pubmed.ncbi.nlm.nih.gov/12118526/ · DOI 10.1023/a:1015624726822

trigger_kind

machinery_impairment Imported condition classification; unverified.

L-Serine: synthesis, one-carbon metabolism, lipids 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 · Uncontrolled follow-up using different serine/glycine treatment regimens. · source_derived_draft · unverified_draft

## l-serine-phgdh-treatment Restoring supply can help some outcomes without reversing every consequence. Amino-acid therapy over 3–7.5 years reduced seizure frequency in all five reported patients, with two becoming seizure-free; developmental progress was reported in only one early-treated patient. Model: Uncontrolled follow-up using different serine/glycine treatment regimens. Limitations: Small heterogeneous case series; no general supplement dose or guaranteed developmental rescue follows. Evidence access: Primary abstract Congenital microcephaly and seizures due to 3-phosphoglycerate dehydrogenase deficiency: outcome of treatment with amino acids. · 2002 · https://pubmed.ncbi.nlm.nih.gov/12118526/ · DOI 10.1023/a:1015624726822

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary abstract

experimental_model

Two siblings; reported regimens included serine 500 mg/kg/day and glycine 200 mg/kg/day.

limitations

Case comparison is not randomized proof, a universal rescue, or a dosing recommendation.

nutrient_topic

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

plain_language

Timing may matter when early development depends on local amino-acid supply.

primary_references

Phosphoserine aminotransferase deficiency: a novel disorder of the serine biosynthesis pathway. · 2007 · https://pubmed.ncbi.nlm.nih.gov/17436247/ · DOI 10.1086/517888

trigger_kind

machinery_impairment Imported condition classification; unverified.

L-Serine: synthesis, one-carbon metabolism, lipids 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 · Two siblings; reported regimens included serine 500 mg/kg/day and glycine 200 mg/kg/day. · source_derived_draft · unverified_draft

## l-serine-psat-early-treatment Timing may matter when early development depends on local amino-acid supply. Two siblings received serine plus glycine at different ages: the index child treated from 11 weeks died at seven months, whereas the sibling treated from birth had a normal reported outcome at age three. Model: Two siblings; reported regimens included serine 500 mg/kg/day and glycine 200 mg/kg/day. Limitations: Case comparison is not randomized proof, a universal rescue, or a dosing recommendation. Evidence access: Primary abstract Phosphoserine aminotransferase deficiency: a novel disorder of the serine biosynthesis pathway. · 2007 · https://pubmed.ncbi.nlm.nih.gov/17436247/ · DOI 10.1086/517888

evidence_access

Primary abstract

experimental_model

Human enzyme assays and pathway-flux analysis.

limitations

Pathway reconstruction is not a measurement of all tissues in vivo.

nutrient_topic

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

plain_language

Feedback measured on one enzyme need not control the whole pathway.

primary_references

Effect of l-serine and magnesium ions on the functional properties of human phosphoserine phosphatase and its pathogenetic variants. · 2024 · https://pubmed.ncbi.nlm.nih.gov/38278334/ · DOI 10.1016/j.bbadis.2024.167034

L-Serine: synthesis, one-carbon metabolism, lipids 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 enzyme assays and pathway-flux analysis. · source_derived_draft · unverified_draft

## l-serine-psph-feedback Feedback measured on one enzyme need not control the whole pathway. Serine inhibited isolated PSPH, but this inhibition did not control flux through the reconstructed phosphorylated pathway unless PSPH activity was severely impaired. Model: Human enzyme assays and pathway-flux analysis. Limitations: Pathway reconstruction is not a measurement of all tissues in vivo. Evidence access: Primary abstract Effect of l-serine and magnesium ions on the functional properties of human phosphoserine phosphatase and its pathogenetic variants. · 2024 · https://pubmed.ncbi.nlm.nih.gov/38278334/ · DOI 10.1016/j.bbadis.2024.167034

evidence_access

Primary abstract

experimental_model

Human cancer-cell metabolic tracing and nutrient manipulation.

limitations

This is not proof that adding serine increases methylation in every tissue.

nutrient_topic

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

plain_language

Methylation needs the ATP-making side of serine metabolism as well as one-carbon donation.

primary_references

Serine Metabolism Supports the Methionine Cycle and DNA/RNA Methylation through De Novo ATP Synthesis in Cancer Cells. · 2016 · https://pubmed.ncbi.nlm.nih.gov/26774282/ · DOI 10.1016/j.molcel.2015.12.014

L-Serine: synthesis, one-carbon metabolism, lipids 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 · Human cancer-cell metabolic tracing and nutrient manipulation. · source_derived_draft · unverified_draft

## l-serine-serine-atp-methylation Methylation needs the ATP-making side of serine metabolism as well as one-carbon donation. Serine metabolism supported the methionine cycle through de novo ATP synthesis both with and without extracellular methionine in the tested cancer cells. Model: Human cancer-cell metabolic tracing and nutrient manipulation. Limitations: This is not proof that adding serine increases methylation in every tissue. Evidence access: Primary abstract Serine Metabolism Supports the Methionine Cycle and DNA/RNA Methylation through De Novo ATP Synthesis in Cancer Cells. · 2016 · https://pubmed.ncbi.nlm.nih.gov/26774282/ · DOI 10.1016/j.molcel.2015.12.014

availability_state

nutrient_deficiency Imported condition classification; unverified.

evidence_access

Primary abstract

experimental_model

Human cancer-cell starvation experiments.

limitations

No universal oncogene activation, whole-body methylation collapse or dietary threshold is established.

nutrient_topic

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

plain_language

A shortage can alter methylation without a simple energy-sensor response.

primary_references

Serine Metabolism Supports the Methionine Cycle and DNA/RNA Methylation through De Novo ATP Synthesis in Cancer Cells. · 2016 · https://pubmed.ncbi.nlm.nih.gov/26774282/ · DOI 10.1016/j.molcel.2015.12.014

trigger_kind

nutrient_deficiency Imported condition classification; unverified.

L-Serine: synthesis, one-carbon metabolism, lipids 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 cancer-cell starvation experiments. · source_derived_draft · unverified_draft

## l-serine-serine-starvation-methylation A shortage can alter methylation without a simple energy-sensor response. Serine starvation increased the methionine/SAM ratio and reduced methyl-group transfer to DNA and RNA; ATP and AMP fell without AMPK activation. Model: Human cancer-cell starvation experiments. Limitations: No universal oncogene activation, whole-body methylation collapse or dietary threshold is established. Evidence access: Primary abstract Serine Metabolism Supports the Methionine Cycle and DNA/RNA Methylation through De Novo ATP Synthesis in Cancer Cells. · 2016 · https://pubmed.ncbi.nlm.nih.gov/26774282/ · DOI 10.1016/j.molcel.2015.12.014

availability_state

nutrient_deficiency Imported condition classification; unverified.

evidence_access

Primary abstract

experimental_model

Mouse hippocampal synaptic experiments.

limitations

L-serine supplies D-serine; this is not evidence that L-serine directly substitutes at the NMDAR coagonist site.

nutrient_topic

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

plain_language

Removing extracellular precursor can disrupt a downstream signaling response.

primary_references

The NMDA receptor activation by d-serine and glycine is controlled by an astrocytic Phgdh-dependent serine shuttle. · 2019 · https://pubmed.ncbi.nlm.nih.gov/31548413/ · DOI 10.1073/pnas.1909458116

trigger_kind

nutrient_deficiency Imported condition classification; unverified.

L-Serine: synthesis, one-carbon metabolism, lipids 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 · Mouse hippocampal synaptic experiments. · source_derived_draft · unverified_draft

## l-serine-shuttle-ltp Removing extracellular precursor can disrupt a downstream signaling response. Enzymatic removal of extracellular L-serine impaired hippocampal long-term potentiation, supporting a role for an intercellular serine supply route. Model: Mouse hippocampal synaptic experiments. Limitations: L-serine supplies D-serine; this is not evidence that L-serine directly substitutes at the NMDAR coagonist site. Evidence access: Primary abstract The NMDA receptor activation by d-serine and glycine is controlled by an astrocytic Phgdh-dependent serine shuttle. · 2019 · https://pubmed.ncbi.nlm.nih.gov/31548413/ · DOI 10.1073/pnas.1909458116

availability_state

nutrient_deficiency Imported condition classification; unverified.

evidence_access

Primary abstract

experimental_model

Cellular substrate manipulation, with a low-serine individual in an SPTLC1-ALS pedigree providing corroborating context.

limitations

Neither unrestricted supplementation nor restriction is shown to be a universal remedy.

nutrient_topic

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

plain_language

Restricting substrate can trade one abnormal lipid pattern for another.

primary_references

SPTLC1 variants associated with ALS produce distinct sphingolipid signatures through impaired interaction with ORMDL proteins. · 2022 · https://pubmed.ncbi.nlm.nih.gov/35900868/ · DOI 10.1172/JCI161908

trigger_kind

nutrient_deficiency Imported condition classification; unverified.

L-Serine: synthesis, one-carbon metabolism, lipids 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 · Cellular substrate manipulation, with a low-serine individual in an SPTLC1-ALS pedigree providing corroborating context. · source_derived_draft · unverified_draft

## l-serine-spt-low-serine-switch Restricting substrate can trade one abnormal lipid pattern for another. Limiting serine in cells expressing SPTLC1-ALS variants increased deoxysphingolipids and shifted the lipid profile toward an HSAN1-like signature. Model: Cellular substrate manipulation, with a low-serine individual in an SPTLC1-ALS pedigree providing corroborating context. Limitations: Neither unrestricted supplementation nor restriction is shown to be a universal remedy. Evidence access: Primary abstract SPTLC1 variants associated with ALS produce distinct sphingolipid signatures through impaired interaction with ORMDL proteins. · 2022 · https://pubmed.ncbi.nlm.nih.gov/35900868/ · DOI 10.1172/JCI161908

availability_state

nutrient_deficiency Imported condition classification; unverified.

evidence_access

Primary abstract

experimental_model

Human cancer-cell starvation with p53 comparisons.

limitations

The response depends on genotype and experimental conditions, not a universal ranking of serine uses.

nutrient_topic

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

plain_language

Cells can reallocate scarce substrate to survival rather than proliferation.

primary_references

Serine starvation induces stress and p53-dependent metabolic remodelling in cancer cells. · 2013 · https://pubmed.ncbi.nlm.nih.gov/23242140/ · DOI 10.1038/nature11743

trigger_kind

nutrient_deficiency Imported condition classification; unverified.

L-Serine: synthesis, one-carbon metabolism, lipids 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 cancer-cell starvation with p53 comparisons. · source_derived_draft · unverified_draft

## l-serine-starvation-p53 Cells can reallocate scarce substrate to survival rather than proliferation. Serine withdrawal induced a transient p53–p21 arrest that redirected limited serine toward glutathione synthesis and preserved antioxidant capacity in the tested human cancer cells. Model: Human cancer-cell starvation with p53 comparisons. Limitations: The response depends on genotype and experimental conditions, not a universal ranking of serine uses. Evidence access: Primary abstract Serine starvation induces stress and p53-dependent metabolic remodelling in cancer cells. · 2013 · https://pubmed.ncbi.nlm.nih.gov/23242140/ · DOI 10.1038/nature11743

evidence_access

Primary abstract

experimental_model

Primary study of activated T cells with in-vivo pathogen-driven expansion experiments in mice.

limitations

Species and activation context limit translation to human supplementation. Correction record: PubMed indexes a published erratum, PMID 28178570 / DOI 10.1016/j.cmet.2017.01.014. The notice body was not accessible during this curation, so its specific scope and impact remain unverified. Do not treat the original study as having received comprehensive integrity clearance. https://pubmed.ncbi.nlm.nih.gov/28178570/

nutrient_topic

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

plain_language

Fuel availability alone does not meet every requirement for immune-cell division.

primary_references

Serine Is an Essential Metabolite for Effector T Cell Expansion. · 2017 · https://pubmed.ncbi.nlm.nih.gov/28111214/ · DOI 10.1016/j.cmet.2016.12.011

L-Serine: synthesis, one-carbon metabolism, lipids 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 · Primary study of activated T cells with in-vivo pathogen-driven expansion experiments in mice. · source_derived_draft · unverified_draft

## l-serine-tcell-expansion Fuel availability alone does not meet every requirement for immune-cell division. Extracellular serine supported optimal activated T-cell expansion by providing glycine and one-carbon units for nucleotide biosynthesis; adequate glucose alone did not substitute. Model: Primary study of activated T cells with in-vivo pathogen-driven expansion experiments in mice. Limitations: Species and activation context limit translation to human supplementation. Correction record: PubMed indexes a published erratum, PMID 28178570 / DOI 10.1016/j.cmet.2017.01.014. The notice body was not accessible during this curation, so its specific scope and impact remain unverified. Do not treat the original study as having received comprehensive integrity clearance. https://pubmed.ncbi.nlm.nih.gov/28178570/ Evidence access: Primary abstract Serine Is an Essential Metabolite for Effector T Cell Expansion. · 2017 · https://pubmed.ncbi.nlm.nih.gov/28111214/ · DOI 10.1016/j.cmet.2016.12.011

availability_state

nutrient_deficiency Imported condition classification; unverified.

evidence_access

Primary abstract

experimental_model

Mouse dietary restriction and separate activated-cell formate add-back.

limitations

The culture rescue is not an in-vivo dietary rescue or a human treatment dose. Correction record: PubMed indexes a published erratum, PMID 28178570 / DOI 10.1016/j.cmet.2017.01.014. The notice body was not accessible during this curation, so its specific scope and impact remain unverified. Do not treat the original study as having received comprehensive integrity clearance. https://pubmed.ncbi.nlm.nih.gov/28178570/

nutrient_topic

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

plain_language

Shortage can impair an induced response without eliminating resting immune cells.

primary_references

Serine Is an Essential Metabolite for Effector T Cell Expansion. · 2017 · https://pubmed.ncbi.nlm.nih.gov/28111214/ · DOI 10.1016/j.cmet.2016.12.011

trigger_kind

nutrient_deficiency Imported condition classification; unverified.

L-Serine: synthesis, one-carbon metabolism, lipids 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 · Mouse dietary restriction and separate activated-cell formate add-back. · source_derived_draft · unverified_draft

## l-serine-tcell-restriction Shortage can impair an induced response without eliminating resting immune cells. Dietary serine restriction impaired pathogen-driven T-cell expansion in the mouse experiments without disrupting overall immune-cell homeostasis; formate rescued serine-deprived T cells in culture. Model: Mouse dietary restriction and separate activated-cell formate add-back. Limitations: The culture rescue is not an in-vivo dietary rescue or a human treatment dose. Correction record: PubMed indexes a published erratum, PMID 28178570 / DOI 10.1016/j.cmet.2017.01.014. The notice body was not accessible during this curation, so its specific scope and impact remain unverified. Do not treat the original study as having received comprehensive integrity clearance. https://pubmed.ncbi.nlm.nih.gov/28178570/ Evidence access: Primary abstract Serine Is an Essential Metabolite for Effector T Cell Expansion. · 2017 · https://pubmed.ncbi.nlm.nih.gov/28111214/ · DOI 10.1016/j.cmet.2016.12.011

experimental_model

Stable-isotope and exchange-rate measurements

exposure

Assay conditions described in the linked primary study.

limitations

Fractions depend on culture conditions.

nutrient_topic

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

organism

Homo sapiens

plain_language

Cells can make more one-carbon units than they use locally.

primary_references

[meiser-2016] Serine one-carbon catabolism with formate overflow (2016). https://pubmed.ncbi.nlm.nih.gov/27819051/ DOI: 10.1126/sciadv.1601273

tissue_or_cell_type

Cultured cancer cells and lung fibroblasts

Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1206–1216

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Stable-isotope and exchange-rate measurements · source_derived_draft · unverified_draft

### serine-formate-overflow Tested cancer cells and IMR90 fibroblasts released most serine-derived one-carbon units as formate rather than retaining them for biosynthesis. Condition category: normal nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: Cells can make more one-carbon units than they use locally. organism: Homo sapiens tissue_or_cell_type: Cultured cancer cells and lung fibroblasts experimental_model: Stable-isotope and exchange-rate measurements limitations: Fractions depend on culture conditions. exposure: Assay conditions described in the linked primary study. [meiser-2016] Serine one-carbon catabolism with formate overflow (2016). https://pubmed.ncbi.nlm.nih.gov/27819051/ DOI: 10.1126/sciadv.1601273

evidence_access

Primary abstract

experimental_model

Primary cancer-cell nutrient-restriction and metabolic tracing study.

limitations

Abstract-level extraction; model-specific result does not negate glycine-dependent growth in other culture conditions.

nutrient_topic

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

plain_language

The ability to interconvert two amino acids does not make their supplies interchangeable.

primary_references

Serine, but not glycine, supports one-carbon metabolism and proliferation of cancer cells. · 2014 · https://pubmed.ncbi.nlm.nih.gov/24813884/ · DOI 10.1016/j.celrep.2014.04.045

Glycine: supply, one-carbon allocation, receptors and cross-nutrient mechanisms (2026-09-19) · lines 170–176

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Primary cancer-cell nutrient-restriction and metabolic tracing study. · source_derived_draft · unverified_draft

## glycine-serine-required-context The ability to interconvert two amino acids does not make their supplies interchangeable. In the tested cancer cultures, exogenous glycine did not replace serine for nucleotide synthesis and proliferation; glycine restriction or glycine-cleavage depletion did not impede growth. Model: Primary cancer-cell nutrient-restriction and metabolic tracing study. Limitations: Abstract-level extraction; model-specific result does not negate glycine-dependent growth in other culture conditions. Evidence access: Primary abstract Serine, but not glycine, supports one-carbon metabolism and proliferation of cancer cells. · 2014 · https://pubmed.ncbi.nlm.nih.gov/24813884/ · DOI 10.1016/j.celrep.2014.04.045

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary abstract

experimental_model

Five-patient treatment follow-up in a rare inherited disorder.

limitations

This is not evidence that ordinary low dietary intake causes the same syndrome.

nutrient_topic

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

plain_language

An internal synthesis defect can create a clinically important shortage.

primary_references

Congenital microcephaly and seizures due to 3-phosphoglycerate dehydrogenase deficiency: outcome of treatment with amino acids. · 2002 · https://pubmed.ncbi.nlm.nih.gov/12118526/ · DOI 10.1023/a:1015624726822

trigger_kind

machinery_impairment Imported condition classification; unverified.

L-Serine: synthesis, one-carbon metabolism, lipids 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 · Five-patient treatment follow-up in a rare inherited disorder. · source_derived_draft · unverified_draft

## l-serine-phgdh-deficiency An internal synthesis defect can create a clinically important shortage. Patients with inherited PHGDH deficiency had low plasma and cerebrospinal-fluid serine, variably low glycine, microcephaly, seizures and severe developmental impairment. Model: Five-patient treatment follow-up in a rare inherited disorder. Limitations: This is not evidence that ordinary low dietary intake causes the same syndrome. Evidence access: Primary abstract Congenital microcephaly and seizures due to 3-phosphoglycerate dehydrogenase deficiency: outcome of treatment with amino acids. · 2002 · https://pubmed.ncbi.nlm.nih.gov/12118526/ · DOI 10.1023/a:1015624726822

evidence_access

Primary abstract

experimental_model

Recombinant human PSPH functional analysis.

limitations

Free phosphoserine is distinct from a phosphorylated serine residue in a protein.

nutrient_topic

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

plain_language

The last enzyme releases free serine from its phosphorylated precursor.

primary_references

Effect of l-serine and magnesium ions on the functional properties of human phosphoserine phosphatase and its pathogenetic variants. · 2024 · https://pubmed.ncbi.nlm.nih.gov/38278334/ · DOI 10.1016/j.bbadis.2024.167034

L-Serine: synthesis, one-carbon metabolism, lipids 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 · Recombinant human PSPH functional analysis. · source_derived_draft · unverified_draft

## l-serine-psph-final-step The last enzyme releases free serine from its phosphorylated precursor. Human phosphoserine phosphatase catalyzes the final, effectively irreversible dephosphorylation step of the phosphorylated serine synthesis pathway. Model: Recombinant human PSPH functional analysis. Limitations: Free phosphoserine is distinct from a phosphorylated serine residue in a protein. Evidence access: Primary abstract Effect of l-serine and magnesium ions on the functional properties of human phosphoserine phosphatase and its pathogenetic variants. · 2024 · https://pubmed.ncbi.nlm.nih.gov/38278334/ · DOI 10.1016/j.bbadis.2024.167034

evidence_access

Primary abstract

experimental_model

Human CRISPR screens, localization and purified-protein transport experiments.

limitations

This does not imply SFXN1 is the only transporter or that all cellular serine is mitochondrial.

nutrient_topic

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

plain_language

Serine must cross a compartment boundary before mitochondrial enzymes can use it.

primary_references

SFXN1 is a mitochondrial serine transporter required for one-carbon metabolism. · 2018 · https://pubmed.ncbi.nlm.nih.gov/30442778/ · DOI 10.1126/science.aat9528

transport_effect

raises Identified as an inner-mitochondrial-membrane serine importer.

transport_pool

the mitochondrial matrix Identified as an inner-mitochondrial-membrane serine importer.

L-Serine: synthesis, one-carbon metabolism, lipids 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 · Human CRISPR screens, localization and purified-protein transport experiments. · source_derived_draft · unverified_draft

## l-serine-sfxn1-import Serine must cross a compartment boundary before mitochondrial enzymes can use it. Purified SFXN1 transported serine in vitro, and human-cell genetic experiments identified it as an inner-mitochondrial-membrane serine transporter. Model: Human CRISPR screens, localization and purified-protein transport experiments. Limitations: This does not imply SFXN1 is the only transporter or that all cellular serine is mitochondrial. Evidence access: Primary abstract SFXN1 is a mitochondrial serine transporter required for one-carbon metabolism. · 2018 · https://pubmed.ncbi.nlm.nih.gov/30442778/ · DOI 10.1126/science.aat9528

experimental_model

Cell metabolomics

exposure

Engineered ALDH1L1 expression.

limitations

Pool changes alone do not quantify compartment-specific SHMT flux.

nutrient_topic

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

organism

Homo sapiens

plain_language

Changing folate-carbon disposal reshaped amino-acid pools.

primary_references

[sasaki-2023] One-carbon metabolizing enzyme ALDH1L1 influences mitochondrial metabolism through 5-aminoimidazole-4-carboxamide ribonucleotide accumulation and serine depletion, contributing to tumor suppression (2023). https://pubmed.ncbi.nlm.nih.gov/37596270/ DOI: 10.1038/s41598-023-38142-5

tissue_or_cell_type

HuH-7 cells

Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1084–1094

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

### aldh1l1-serine-glycine ALDH1L1-expressing HuH-7 cells had lower serine and higher glycine than controls. Condition category: normal nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: Changing folate-carbon disposal reshaped amino-acid pools. organism: Homo sapiens tissue_or_cell_type: HuH-7 cells experimental_model: Cell metabolomics limitations: Pool changes alone do not quantify compartment-specific SHMT flux. exposure: Engineered ALDH1L1 expression. [sasaki-2023] One-carbon metabolizing enzyme ALDH1L1 influences mitochondrial metabolism through 5-aminoimidazole-4-carboxamide ribonucleotide accumulation and serine depletion, contributing to tumor suppression (2023). https://pubmed.ncbi.nlm.nih.gov/37596270/ DOI: 10.1038/s41598-023-38142-5

cross_nutrient

Links existing B6-dependent SHMT chemistry to folate flux direction.

experimental_model

Stable-isotope tracing

exposure

Assay conditions described in the linked primary study.

limitations

Not a universal direction across tissues or nutrition states.

nutrient_topic

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

organism

Homo sapiens

plain_language

SHMT1 can consume one-carbon units instead of producing them.

primary_references

[ducker-2016] Reversal of Cytosolic One-Carbon Flux Compensates for Loss of the Mitochondrial Folate Pathway (2016). https://pubmed.ncbi.nlm.nih.gov/27211901/ DOI: 10.1016/j.cmet.2016.04.016

tissue_or_cell_type

HEK293T and HCT116 cells

Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 923–934

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

### shmt1-reverse-flux-replete In nutrient-replete HEK293T and HCT116 cells, isotope tracing showed net SHMT1 flux toward serine synthesis. Condition category: normal nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: SHMT1 can consume one-carbon units instead of producing them. organism: Homo sapiens tissue_or_cell_type: HEK293T and HCT116 cells experimental_model: Stable-isotope tracing limitations: Not a universal direction across tissues or nutrition states. exposure: Assay conditions described in the linked primary study. cross_nutrient: Links existing B6-dependent SHMT chemistry to folate flux direction. [ducker-2016] Reversal of Cytosolic One-Carbon Flux Compensates for Loss of the Mitochondrial Folate Pathway (2016). https://pubmed.ncbi.nlm.nih.gov/27211901/ DOI: 10.1016/j.cmet.2016.04.016

availability_state

nutrient_deficiency Imported condition classification; unverified.

evidence_access

Primary full text

experimental_model

Colorectal cancer model metabolic interventions and tracing.

limitations

Context-specific rerouting; it does not establish a universal protective effect of MPC inhibition.

nutrient_topic

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

plain_language

Changing use of alanine in mitochondria changed its availability to another pathway.

primary_references

Serine restriction alters sphingolipid diversity to constrain tumour growth. · 2020 · https://pubmed.ncbi.nlm.nih.gov/32788725/ · DOI 10.1038/s41586-020-2609-x

trigger_kind

nutrient_deficiency Imported condition classification; unverified.

L-Alanine: carbon, nitrogen, protein synthesis and cross-nutrient mechanisms (2026-09-19) · lines 464–470

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Colorectal cancer model metabolic interventions and tracing. · source_derived_draft · unverified_draft

## alanine-serine-mpc-interaction Changing use of alanine in mitochondria changed its availability to another pathway. Targeting mitochondrial pyruvate transport promoted alanine oxidation, reduced deoxysphingolipid production and restored growth under serine/glycine-restricted conditions. Model: Colorectal cancer model metabolic interventions and tracing. Limitations: Context-specific rerouting; it does not establish a universal protective effect of MPC inhibition. Evidence access: Primary full text Serine restriction alters sphingolipid diversity to constrain tumour growth. · 2020 · https://pubmed.ncbi.nlm.nih.gov/32788725/ · DOI 10.1038/s41586-020-2609-x

availability_state

nutrient_deficiency Imported condition classification; unverified.

evidence_access

Primary full text

experimental_model

Human colorectal cancer cultures/spheroids with nutrient restriction and isotope tracing; accompanying mouse xenografts.

limitations

Cancer nutrient-restriction experiments are not a recommendation to restrict serine or glycine.

nutrient_topic

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

plain_language

The ratio of available substrates can redirect a shared enzyme even without the inherited neuropathy setting.

primary_references

Serine restriction alters sphingolipid diversity to constrain tumour growth. · 2020 · https://pubmed.ncbi.nlm.nih.gov/32788725/ · DOI 10.1038/s41586-020-2609-x

trigger_kind

nutrient_deficiency Imported condition classification; unverified.

L-Alanine: carbon, nitrogen, protein synthesis and cross-nutrient mechanisms (2026-09-19) · lines 456–462

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human colorectal cancer cultures/spheroids with nutrient restriction and isotope tracing; accompanying mouse xenografts. · source_derived_draft · unverified_draft

## alanine-serine-restriction-lipids The ratio of available substrates can redirect a shared enzyme even without the inherited neuropathy setting. Serine/glycine restriction increased alanine-derived deoxysphingolipid synthesis in the tested colorectal cancer models and constrained growth. Model: Human colorectal cancer cultures/spheroids with nutrient restriction and isotope tracing; accompanying mouse xenografts. Limitations: Cancer nutrient-restriction experiments are not a recommendation to restrict serine or glycine. Evidence access: Primary full text Serine restriction alters sphingolipid diversity to constrain tumour growth. · 2020 · https://pubmed.ncbi.nlm.nih.gov/32788725/ · DOI 10.1038/s41586-020-2609-x

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary abstract

experimental_model

Transgenic HSAN1 mouse model; 10% enriched diet.

limitations

High-dose disease model, not a toxicity threshold for ordinary human alanine intake.

nutrient_topic

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

plain_language

High alanine exposure worsened a specific genetically altered pathway.

primary_references

Oral L-serine supplementation reduces production of neurotoxic deoxysphingolipids in mice and humans with hereditary sensory autonomic neuropathy type 1. · 2011 · https://pubmed.ncbi.nlm.nih.gov/22045570/ · DOI 10.1172/JCI57549

trigger_kind

machinery_impairment Imported condition classification; unverified.

L-Alanine: carbon, nitrogen, protein synthesis and cross-nutrient mechanisms (2026-09-19) · lines 432–438

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Transgenic HSAN1 mouse model; 10% enriched diet. · source_derived_draft · unverified_draft

## alanine-spt-mouse-alanine High alanine exposure worsened a specific genetically altered pathway. A 10% alanine-enriched diet increased deoxysphingolipids and led to severe peripheral neuropathy in mice expressing the HSAN1-associated C133W SPTLC1 transgene. Model: Transgenic HSAN1 mouse model; 10% enriched diet. Limitations: High-dose disease model, not a toxicity threshold for ordinary human alanine intake. Evidence access: Primary abstract Oral L-serine supplementation reduces production of neurotoxic deoxysphingolipids in mice and humans with hereditary sensory autonomic neuropathy type 1. · 2011 · https://pubmed.ncbi.nlm.nih.gov/22045570/ · DOI 10.1172/JCI57549

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary abstract

experimental_model

Human SPTLC1 variants expressed in HEK cells.

limitations

Variant-dependent abnormal chemistry is not a universal response to alanine intake.

nutrient_topic

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

plain_language

An enzyme can make different lipids when its substrate preference changes.

primary_references

Oral L-serine supplementation reduces production of neurotoxic deoxysphingolipids in mice and humans with hereditary sensory autonomic neuropathy type 1. · 2011 · https://pubmed.ncbi.nlm.nih.gov/22045570/ · DOI 10.1172/JCI57549

trigger_kind

machinery_impairment Imported condition classification; unverified.

L-Alanine: carbon, nitrogen, protein synthesis and cross-nutrient mechanisms (2026-09-19) · lines 424–430

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human SPTLC1 variants expressed in HEK cells. · source_derived_draft · unverified_draft

## alanine-spt-mutant-substrate An enzyme can make different lipids when its substrate preference changes. Human SPTLC1 mutant expression in HEK cells shifted substrate use toward alanine and increased production of deoxysphingolipids; amino-acid availability modulated this production. Model: Human SPTLC1 variants expressed in HEK cells. Limitations: Variant-dependent abnormal chemistry is not a universal response to alanine intake. Evidence access: Primary abstract Oral L-serine supplementation reduces production of neurotoxic deoxysphingolipids in mice and humans with hereditary sensory autonomic neuropathy type 1. · 2011 · https://pubmed.ncbi.nlm.nih.gov/22045570/ · DOI 10.1172/JCI57549

availability_state

nutrient_deficiency Imported condition classification; unverified.

cross_nutrient

B6 and folate participate in a reversible reaction; flux direction matters.

experimental_model

Thirteen healthy adults (seven men, six women; ages 20–39); glycine and leucine stable-isotope infusion.

exposure

Moderate dietary B6 restriction; plasma PLP55±4 to 23±1 nmol/L.

limitations

Do not substitute the reverse serine-to-glycine direction or identify the responsible SHMT compartment from whole-body data.

nutrient_topic

Vitamin B6 research collection; topical membership is not evidence of a direct dietary effect. · Vitamin B6

organism

Homo sapiens

plain_language

The measured direction ran faster, rather than shutting down.

primary_references

[b6-lamers2009] Moderate dietary vitamin B-6 restriction raises plasma glycine and cystathionine concentrations while minimally affecting the rates of glycine turnover and glycine cleavage in healthy men and women (2009). https://pubmed.ncbi.nlm.nih.gov/19158217/ DOI: 10.3945/jn.108.099184

tissue_or_cell_type

Human blood and whole-body measurements

trigger_kind

nutrient_deficiency Imported condition classification; unverified.

Vitamin B6: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1410–1421

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Thirteen healthy adults (seven men, six women; ages 20–39); glycine and leucine stable-isotope infusion. · source_derived_draft · unverified_draft

### b6-glycine-serine-flux-increase SHMT-mediated glycine-to-serine conversion increased 182 to 205 micromol/kg/hour during restriction, accompanied by higher plasma glycine. Condition category: nutrient_deficiency nutrient_topic: Vitamin B6 research collection; topical membership is not evidence of a direct dietary effect. plain_language: The measured direction ran faster, rather than shutting down. organism: Homo sapiens tissue_or_cell_type: Human blood and whole-body measurements experimental_model: Thirteen healthy adults (seven men, six women; ages 20–39); glycine and leucine stable-isotope infusion. limitations: Do not substitute the reverse serine-to-glycine direction or identify the responsible SHMT compartment from whole-body data. exposure: Moderate dietary B6 restriction; plasma PLP55±4 to 23±1 nmol/L. cross_nutrient: B6 and folate participate in a reversible reaction; flux direction matters. [b6-lamers2009] Moderate dietary vitamin B-6 restriction raises plasma glycine and cystathionine concentrations while minimally affecting the rates of glycine turnover and glycine cleavage in healthy men and women (2009). https://pubmed.ncbi.nlm.nih.gov/19158217/ DOI: 10.3945/jn.108.099184

cross_nutrient

Methionine-derived sulfur enters cysteine synthesis.

experimental_model

Recombinant truncated human CBS crystallography

limitations

Enzyme chemistry alone does not predict whole-body homocysteine during mild deficiency.

nutrient_topic

Vitamin B6 research collection; topical membership is not evidence of a direct dietary effect. · Vitamin B6

organism

Homo sapiens

plain_language

This B6-dependent step channels homocysteine into transsulfuration.

primary_references

[b6-cbs-2001] Structure of human cystathionine beta-synthase: a unique pyridoxal 5'-phosphate-dependent heme protein. (2001). https://pmc.ncbi.nlm.nih.gov/articles/PMC149156/ DOI: 10.1093/emboj/20.15.3910

tissue_or_cell_type

Purified recombinant protein; no intact tissue

Vitamin B6: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 517–527

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

### b6-met-cbs-condensation PLP-dependent human CBS condenses serine with homocysteine to produce cystathionine. Condition category: normal nutrient_topic: Vitamin B6 research collection; topical membership is not evidence of a direct dietary effect. plain_language: This B6-dependent step channels homocysteine into transsulfuration. organism: Homo sapiens tissue_or_cell_type: Purified recombinant protein; no intact tissue experimental_model: Recombinant truncated human CBS crystallography limitations: Enzyme chemistry alone does not predict whole-body homocysteine during mild deficiency. cross_nutrient: Methionine-derived sulfur enters cysteine synthesis. [b6-cbs-2001] Structure of human cystathionine beta-synthase: a unique pyridoxal 5'-phosphate-dependent heme protein. (2001). https://pmc.ncbi.nlm.nih.gov/articles/PMC149156/ DOI: 10.1093/emboj/20.15.3910

cross_nutrient

PLP (B6) and THF (folate) cooperate in one reaction.

experimental_model

Purified human SHMT1 and SHMT2; structures and solution oligomerization

limitations

Reaction is reversible; assembly assays do not establish flux in every cell.

nutrient_topic

Vitamin B6 research collection; topical membership is not evidence of a direct dietary effect. · Vitamin B6

organism

Homo sapiens

plain_language

The enzyme connects B6-dependent amino-acid chemistry to folate chemistry.

primary_references

[b6-shmt-2015] How pyridoxal 5'-phosphate differentially regulates human cytosolic and mitochondrial serine hydroxymethyltransferase oligomeric state (2015). https://febs.onlinelibrary.wiley.com/doi/10.1111/febs.13211 DOI: 10.1111/febs.13211

tissue_or_cell_type

Purified recombinant protein; no intact tissue

Vitamin B6: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 602–612

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purified human SHMT1 and SHMT2; structures and solution oligomerization · source_derived_draft · unverified_draft

### b6-met-shmt1-onecarbon Human SHMT1 uses PLP to couple serine-to-glycine conversion with transfer of a one-carbon unit to tetrahydrofolate. Condition category: normal nutrient_topic: Vitamin B6 research collection; topical membership is not evidence of a direct dietary effect. plain_language: The enzyme connects B6-dependent amino-acid chemistry to folate chemistry. organism: Homo sapiens tissue_or_cell_type: Purified recombinant protein; no intact tissue experimental_model: Purified human SHMT1 and SHMT2; structures and solution oligomerization limitations: Reaction is reversible; assembly assays do not establish flux in every cell. cross_nutrient: PLP (B6) and THF (folate) cooperate in one reaction. [b6-shmt-2015] How pyridoxal 5'-phosphate differentially regulates human cytosolic and mitochondrial serine hydroxymethyltransferase oligomeric state (2015). https://febs.onlinelibrary.wiley.com/doi/10.1111/febs.13211 DOI: 10.1111/febs.13211

cross_nutrient

PLP (B6) and THF (folate) cooperate in one reaction.

experimental_model

Purified human SHMT1 and SHMT2; structures and solution oligomerization

limitations

Reaction is reversible; assembly assays do not establish flux in every cell.

nutrient_topic

Vitamin B6 research collection; topical membership is not evidence of a direct dietary effect. · Vitamin B6

organism

Homo sapiens

plain_language

The enzyme connects B6-dependent amino-acid chemistry to folate chemistry.

primary_references

[b6-shmt-2015] How pyridoxal 5'-phosphate differentially regulates human cytosolic and mitochondrial serine hydroxymethyltransferase oligomeric state (2015). https://febs.onlinelibrary.wiley.com/doi/10.1111/febs.13211 DOI: 10.1111/febs.13211

tissue_or_cell_type

Purified recombinant protein; no intact tissue

Vitamin B6: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 614–624

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purified human SHMT1 and SHMT2; structures and solution oligomerization · source_derived_draft · unverified_draft

### b6-met-shmt2-onecarbon Human SHMT2 uses PLP to couple serine-to-glycine conversion with transfer of a one-carbon unit to tetrahydrofolate. Condition category: normal nutrient_topic: Vitamin B6 research collection; topical membership is not evidence of a direct dietary effect. plain_language: The enzyme connects B6-dependent amino-acid chemistry to folate chemistry. organism: Homo sapiens tissue_or_cell_type: Purified recombinant protein; no intact tissue experimental_model: Purified human SHMT1 and SHMT2; structures and solution oligomerization limitations: Reaction is reversible; assembly assays do not establish flux in every cell. cross_nutrient: PLP (B6) and THF (folate) cooperate in one reaction. [b6-shmt-2015] How pyridoxal 5'-phosphate differentially regulates human cytosolic and mitochondrial serine hydroxymethyltransferase oligomeric state (2015). https://febs.onlinelibrary.wiley.com/doi/10.1111/febs.13211 DOI: 10.1111/febs.13211

cross_nutrient

B6-dependent use of the amino acid serine and a fatty-acyl-CoA substrate.

experimental_model

Recombinant human SPT complexes; cryo-EM and cell/microsome activity assays

exposure

Product-bound cryo-EM and functional enzyme assays.

limitations

Does not show that B6 supplementation repairs myelin.

nutrient_topic

Vitamin B6 research collection; topical membership is not evidence of a direct dietary effect. · Vitamin B6

organism

Homo sapiens

plain_language

B6 supports entry into sphingolipid synthesis.

primary_references

[wang-2021-spt] Structural insights into the regulation of human serine palmitoyltransferase complexes (2021). https://pmc.ncbi.nlm.nih.gov/articles/PMC9812531/ DOI: 10.1038/s41594-020-00551-9

tissue_or_cell_type

Purified recombinant protein; no intact tissue

Vitamin B6: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1120–1131

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Recombinant human SPT complexes; cryo-EM and cell/microsome activity assays · source_derived_draft · unverified_draft

### b6-neuro-spt-sphingolipid-entry PLP-dependent human SPT condenses serine and palmitoyl-CoA into 3-ketosphinganine; the product-bound structure locates its headgroup and acyl chain. Condition category: normal nutrient_topic: Vitamin B6 research collection; topical membership is not evidence of a direct dietary effect. plain_language: B6 supports entry into sphingolipid synthesis. organism: Homo sapiens tissue_or_cell_type: Purified recombinant protein; no intact tissue experimental_model: Recombinant human SPT complexes; cryo-EM and cell/microsome activity assays limitations: Does not show that B6 supplementation repairs myelin. exposure: Product-bound cryo-EM and functional enzyme assays. cross_nutrient: B6-dependent use of the amino acid serine and a fatty-acyl-CoA substrate. [wang-2021-spt] Structural insights into the regulation of human serine palmitoyltransferase complexes (2021). https://pmc.ncbi.nlm.nih.gov/articles/PMC9812531/ DOI: 10.1038/s41594-020-00551-9

availability_state

nutrient_deficiency Imported condition classification; unverified.

experimental_model

Twenty-three healthy adults; paired pre/postprandial LC-MS/MS metabolite profiling.

exposure

28 days below 0.35 mg/day B6. Related restriction research program; do not count paper totals as independent trial replications.

limitations

Shared restriction research program; not an independent demonstration of each molecular enzyme defect.

nutrient_topic

Vitamin B6 research collection; topical membership is not evidence of a direct dietary effect. · Vitamin B6

organism

Homo sapiens

plain_language

More material accumulated at selected points in the network.

primary_references

[b6-dasilva2013] Metabolite profile analysis reveals functional effects of 28-day vitamin B-6 restriction on one-carbon metabolism and tryptophan catabolic pathways in healthy men and women (2013). https://pubmed.ncbi.nlm.nih.gov/23966327/ DOI: 10.3945/jn.113.180588

tissue_or_cell_type

Human blood and whole-body measurements

trigger_kind

nutrient_deficiency Imported condition classification; unverified.

Vitamin B6: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1449–1459

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Twenty-three healthy adults; paired pre/postprandial LC-MS/MS metabolite profiling. · source_derived_draft · unverified_draft

### b6-restriction-serine-cystathionine-profile Cystathionine increased 53% fasting and 76% postprandially; fasting serine increased 12%. Condition category: nutrient_deficiency nutrient_topic: Vitamin B6 research collection; topical membership is not evidence of a direct dietary effect. plain_language: More material accumulated at selected points in the network. organism: Homo sapiens tissue_or_cell_type: Human blood and whole-body measurements experimental_model: Twenty-three healthy adults; paired pre/postprandial LC-MS/MS metabolite profiling. limitations: Shared restriction research program; not an independent demonstration of each molecular enzyme defect. exposure: 28 days below 0.35 mg/day B6. Related restriction research program; do not count paper totals as independent trial replications. [b6-dasilva2013] Metabolite profile analysis reveals functional effects of 28-day vitamin B-6 restriction on one-carbon metabolism and tryptophan catabolic pathways in healthy men and women (2013). https://pubmed.ncbi.nlm.nih.gov/23966327/ DOI: 10.3945/jn.113.180588

evidence_access

Primary abstract

experimental_model

Cancer-cell nutrient and formate rescue experiment.

limitations

No extrapolation to treating cancer or supplement combinations in people.

nutrient_topic

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

plain_language

Another input changed whether supplied glycine could support growth.

primary_references

Serine, but not glycine, supports one-carbon metabolism and proliferation of cancer cells. · 2014 · https://pubmed.ncbi.nlm.nih.gov/24813884/ · DOI 10.1016/j.celrep.2014.04.045

Glycine: supply, one-carbon allocation, receptors and cross-nutrient mechanisms (2026-09-19) · lines 186–192

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Cancer-cell nutrient and formate rescue experiment. · source_derived_draft · unverified_draft

## glycine-formate-serine-deprived-rescue Another input changed whether supplied glycine could support growth. Formate restored nucleotide synthesis and growth in glycine-fed cells lacking serine. Model: Cancer-cell nutrient and formate rescue experiment. Limitations: No extrapolation to treating cancer or supplement combinations in people. Evidence access: Primary abstract Serine, but not glycine, supports one-carbon metabolism and proliferation of cancer cells. · 2014 · https://pubmed.ncbi.nlm.nih.gov/24813884/ · DOI 10.1016/j.celrep.2014.04.045

evidence_access

Primary abstract

experimental_model

Cancer cultures deprived of serine, glycine exposure and metabolic analysis.

limitations

No exposure threshold for humans is derived; one-carbon depletion is the pathway interpretation supported by the rescue experiment.

nutrient_topic

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

plain_language

Using glycine to rebuild missing serine can draw from the folate carbon pool.

primary_references

Serine, but not glycine, supports one-carbon metabolism and proliferation of cancer cells. · 2014 · https://pubmed.ncbi.nlm.nih.gov/24813884/ · DOI 10.1016/j.celrep.2014.04.045

Glycine: supply, one-carbon allocation, receptors and cross-nutrient mechanisms (2026-09-19) · lines 178–184

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Cancer cultures deprived of serine, glycine exposure and metabolic analysis. · source_derived_draft · unverified_draft

## glycine-glycine-reverse-flux Using glycine to rebuild missing serine can draw from the folate carbon pool. With serine absent, higher glycine concentrations inhibited growth and glycine was converted to serine, a reaction consuming one-carbon units. Model: Cancer cultures deprived of serine, glycine exposure and metabolic analysis. Limitations: No exposure threshold for humans is derived; one-carbon depletion is the pathway interpretation supported by the rescue experiment. Evidence access: Primary abstract Serine, but not glycine, supports one-carbon metabolism and proliferation of cancer cells. · 2014 · https://pubmed.ncbi.nlm.nih.gov/24813884/ · DOI 10.1016/j.celrep.2014.04.045

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary full text

experimental_model

Human leukemia cells, knockout and metabolite-rescue experiment.

limitations

Culture rescue is not a nutritional recommendation; this growth endpoint differs from zebrafish hemoglobin.

nutrient_topic

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

plain_language

Restoring a downstream one-carbon source worked where adding an amino acid did not.

primary_references

SLC25A38 is required for mitochondrial pyridoxal 5'-phosphate (PLP) accumulation. · 2025 · https://pubmed.ncbi.nlm.nih.gov/39856062/ · DOI 10.1038/s41467-025-56130-3

trigger_kind

machinery_impairment Imported condition classification; unverified.

Glycine: supply, one-carbon allocation, receptors and cross-nutrient mechanisms (2026-09-19) · lines 122–128

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human leukemia cells, knockout and metabolite-rescue experiment. · source_derived_draft · unverified_draft

## glycine-s38-formate-rescue Restoring a downstream one-carbon source worked where adding an amino acid did not. Formate at 1 mM rescued the low-B6 proliferation defect of SLC25A38-null K562 cells, while glycine, serine and folate did not under the tested conditions. Model: Human leukemia cells, knockout and metabolite-rescue experiment. Limitations: Culture rescue is not a nutritional recommendation; this growth endpoint differs from zebrafish hemoglobin. Evidence access: Primary full text SLC25A38 is required for mitochondrial pyridoxal 5'-phosphate (PLP) accumulation. · 2025 · https://pubmed.ncbi.nlm.nih.gov/39856062/ · DOI 10.1038/s41467-025-56130-3

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary full text

experimental_model

Human K562 knockout, isotope tracing and controlled B6 culture conditions.

limitations

Tracing reflects pathway flux; it does not establish direct PLP transport by SLC25A38.

nutrient_topic

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

plain_language

A mitochondrial cofactor problem reduced the cell's ability to make glycine.

primary_references

SLC25A38 is required for mitochondrial pyridoxal 5'-phosphate (PLP) accumulation. · 2025 · https://pubmed.ncbi.nlm.nih.gov/39856062/ · DOI 10.1038/s41467-025-56130-3

trigger_kind

machinery_impairment Imported condition classification; unverified.

Glycine: supply, one-carbon allocation, receptors and cross-nutrient mechanisms (2026-09-19) · lines 114–120

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human K562 knockout, isotope tracing and controlled B6 culture conditions. · source_derived_draft · unverified_draft

## glycine-s38-glycine-synthesis A mitochondrial cofactor problem reduced the cell's ability to make glycine. SLC25A38 loss reduced deuterated-serine incorporation into glycine and glycine-derived glutathione under low-B6 conditions. Model: Human K562 knockout, isotope tracing and controlled B6 culture conditions. Limitations: Tracing reflects pathway flux; it does not establish direct PLP transport by SLC25A38. Evidence access: Primary full text SLC25A38 is required for mitochondrial pyridoxal 5'-phosphate (PLP) accumulation. · 2025 · https://pubmed.ncbi.nlm.nih.gov/39856062/ · DOI 10.1038/s41467-025-56130-3

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary abstract

experimental_model

Human families and engineered cellular lipid-synthesis experiments.

limitations

This molecular subtype differs from HSAN1-associated substrate-switching variants.

nutrient_topic

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

plain_language

Some variants remove the brake rather than change the preferred amino-acid substrate.

primary_references

Childhood amyotrophic lateral sclerosis caused by excess sphingolipid synthesis. · 2021 · https://pubmed.ncbi.nlm.nih.gov/34059824/ · DOI 10.1038/s41591-021-01346-1

trigger_kind

machinery_impairment Imported condition classification; unverified.

L-Serine: synthesis, one-carbon metabolism, lipids 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 · Human families and engineered cellular lipid-synthesis experiments. · source_derived_draft · unverified_draft

## l-serine-als-spt-feedback Some variants remove the brake rather than change the preferred amino-acid substrate. Four dominantly acting SPTLC1 variants in childhood-onset ALS families disrupted ORMDL-mediated feedback, increasing canonical sphingolipid synthesis. Model: Human families and engineered cellular lipid-synthesis experiments. Limitations: This molecular subtype differs from HSAN1-associated substrate-switching variants. Evidence access: Primary abstract Childhood amyotrophic lateral sclerosis caused by excess sphingolipid synthesis. · 2021 · https://pubmed.ncbi.nlm.nih.gov/34059824/ · DOI 10.1038/s41591-021-01346-1

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary abstract

experimental_model

Human trio-exome analysis and structural prediction.

limitations

The proposed astrocyte-to-neuron transport mechanism was not directly measured in these two patients.

nutrient_topic

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

plain_language

A transport defect can matter even when amino-acid synthesis is present.

primary_references

SLC1A4 mutations cause a novel disorder of intellectual disability, progressive microcephaly, spasticity and thin corpus callosum. · 2015 · https://pubmed.ncbi.nlm.nih.gov/26138499/ · DOI 10.1111/cge.12637

trigger_kind

machinery_impairment Imported condition classification; unverified.

L-Serine: synthesis, one-carbon metabolism, lipids 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 · Human trio-exome analysis and structural prediction. · source_derived_draft · unverified_draft

## l-serine-asct1-genetic A transport defect can matter even when amino-acid synthesis is present. Two unrelated individuals with biallelic SLC1A4 variants had severe developmental delay, progressive microcephaly, seizures, spasticity and thin corpus callosum. Model: Human trio-exome analysis and structural prediction. Limitations: The proposed astrocyte-to-neuron transport mechanism was not directly measured in these two patients. Evidence access: Primary abstract SLC1A4 mutations cause a novel disorder of intellectual disability, progressive microcephaly, spasticity and thin corpus callosum. · 2015 · https://pubmed.ncbi.nlm.nih.gov/26138499/ · DOI 10.1111/cge.12637

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary abstract

experimental_model

Mouse genetic and hippocampal experiments with synthesis measurements.

limitations

This does not establish exclusive cell-type localization under every developmental or disease condition.

nutrient_topic

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

plain_language

Support cells can supply precursor while neurons perform the final conversion.

primary_references

The NMDA receptor activation by d-serine and glycine is controlled by an astrocytic Phgdh-dependent serine shuttle. · 2019 · https://pubmed.ncbi.nlm.nih.gov/31548413/ · DOI 10.1073/pnas.1909458116

trigger_kind

machinery_impairment Imported condition classification; unverified.

L-Serine: synthesis, one-carbon metabolism, lipids 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 genetic and hippocampal experiments with synthesis measurements. · source_derived_draft · unverified_draft

## l-serine-astrocyte-shuttle Support cells can supply precursor while neurons perform the final conversion. Astrocytic Phgdh inhibition reduced newly synthesized L- and D-serine; neuronal serine-racemase deletion reduced D-serine synthesis to a similar extent. Model: Mouse genetic and hippocampal experiments with synthesis measurements. Limitations: This does not establish exclusive cell-type localization under every developmental or disease condition. Evidence access: Primary abstract The NMDA receptor activation by d-serine and glycine is controlled by an astrocytic Phgdh-dependent serine shuttle. · 2019 · https://pubmed.ncbi.nlm.nih.gov/31548413/ · DOI 10.1073/pnas.1909458116

evidence_access

Primary abstract

experimental_model

Biochemical assays, primary cultures and mouse microdialysis; Asc-1 knockout abolished the release response.

limitations

Inhibition of synthesis and stimulation of release are distinct endpoints, not contradictory directions for one reaction.

nutrient_topic

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

plain_language

The same neighboring amino acid can affect both production and release in different ways.

primary_references

The NMDA receptor activation by d-serine and glycine is controlled by an astrocytic Phgdh-dependent serine shuttle. · 2019 · https://pubmed.ncbi.nlm.nih.gov/31548413/ · DOI 10.1073/pnas.1909458116

L-Serine: synthesis, one-carbon metabolism, lipids 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 · Biochemical assays, primary cultures and mouse microdialysis; Asc-1 knockout abolished the release response. · source_derived_draft · unverified_draft

## l-serine-glycine-racemase The same neighboring amino acid can affect both production and release in different ways. Intracellular glycine tonically inhibited serine racemase in the study, while glycine exposure could transiently promote D-serine release through Asc-1. Model: Biochemical assays, primary cultures and mouse microdialysis; Asc-1 knockout abolished the release response. Limitations: Inhibition of synthesis and stimulation of release are distinct endpoints, not contradictory directions for one reaction. Evidence access: Primary abstract The NMDA receptor activation by d-serine and glycine is controlled by an astrocytic Phgdh-dependent serine shuttle. · 2019 · https://pubmed.ncbi.nlm.nih.gov/31548413/ · DOI 10.1073/pnas.1909458116

availability_state

nutrient_deficiency Imported condition classification; unverified.

evidence_access

Primary abstract

experimental_model

Macrophage culture with serine restriction and metabolite add-back.

limitations

The delivered compound was cell-permeable GSH, not an assumed effect of oral glutathione.

nutrient_topic

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

plain_language

The limiting branch differs from the nucleotide requirement in dividing T cells.

primary_references

Serine Metabolism Supports Macrophage IL-1β Production. · 2019 · https://pubmed.ncbi.nlm.nih.gov/30773464/ · DOI 10.1016/j.cmet.2019.01.014

trigger_kind

nutrient_deficiency Imported condition classification; unverified.

L-Serine: synthesis, one-carbon metabolism, lipids 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 · Macrophage culture with serine restriction and metabolite add-back. · source_derived_draft · unverified_draft

## l-serine-macrophage-rescue The limiting branch differs from the nucleotide requirement in dividing T cells. Cell-permeable glutathione, but not formate, rescued IL-1beta mRNA expression under serine restriction in the macrophage experiments. Model: Macrophage culture with serine restriction and metabolite add-back. Limitations: The delivered compound was cell-permeable GSH, not an assumed effect of oral glutathione. Evidence access: Primary abstract Serine Metabolism Supports Macrophage IL-1β Production. · 2019 · https://pubmed.ncbi.nlm.nih.gov/30773464/ · DOI 10.1016/j.cmet.2019.01.014

evidence_access

Primary full text

experimental_model

Recombinant enzyme assays, including 40 micromolar 3-phosphoglycerate substrate.

limitations

NADHX is chemically damaged NADH, not simply a low NAD+ concentration.

nutrient_topic

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

plain_language

Repair of a niacin-derived cofactor protects a separate amino-acid pathway.

primary_references

Failure to repair damaged NAD(P)H blocks de novo serine synthesis in human cells. · 2025 · https://pubmed.ncbi.nlm.nih.gov/39789421/ · DOI 10.1186/s11658-024-00681-8

L-Serine: synthesis, one-carbon metabolism, lipids 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 · Recombinant enzyme assays, including 40 micromolar 3-phosphoglycerate substrate. · source_derived_draft · unverified_draft

## l-serine-nadhx-inhibition Repair of a niacin-derived cofactor protects a separate amino-acid pathway. Purified NADHX species inhibited recombinant human PHGDH, supporting direct inhibition as an explanation for the serine-synthesis defect in NAXD-deficient cells. Model: Recombinant enzyme assays, including 40 micromolar 3-phosphoglycerate substrate. Limitations: NADHX is chemically damaged NADH, not simply a low NAD+ concentration. Evidence access: Primary full text Failure to repair damaged NAD(P)H blocks de novo serine synthesis in human cells. · 2025 · https://pubmed.ncbi.nlm.nih.gov/39789421/ · DOI 10.1186/s11658-024-00681-8

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary full text

experimental_model

Human knockout cells, patient fibroblasts and isotope tracing.

limitations

The impairment depended on culture conditions and was more pronounced under galactose stress.

nutrient_topic

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

plain_language

Damaged cofactor can block a pathway even when the enzyme is still present.

primary_references

Failure to repair damaged NAD(P)H blocks de novo serine synthesis in human cells. · 2025 · https://pubmed.ncbi.nlm.nih.gov/39789421/ · DOI 10.1186/s11658-024-00681-8

trigger_kind

machinery_impairment Imported condition classification; unverified.

L-Serine: synthesis, one-carbon metabolism, lipids 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 · Human knockout cells, patient fibroblasts and isotope tracing. · source_derived_draft · unverified_draft

## l-serine-naxd-block Damaged cofactor can block a pathway even when the enzyme is still present. NAXD loss caused NADHX accumulation and impaired de novo serine synthesis in human HAP1 cells under galactose stress and in patient-derived fibroblasts. Model: Human knockout cells, patient fibroblasts and isotope tracing. Limitations: The impairment depended on culture conditions and was more pronounced under galactose stress. Evidence access: Primary full text Failure to repair damaged NAD(P)H blocks de novo serine synthesis in human cells. · 2025 · https://pubmed.ncbi.nlm.nih.gov/39789421/ · DOI 10.1186/s11658-024-00681-8

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary full text

experimental_model

Human cell add-back experiments.

limitations

Cell rescue is not established treatment for inherited NAXD disease.

nutrient_topic

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

plain_language

Two metabolic inputs partly bypassed a specific cellular vulnerability.

primary_references

Failure to repair damaged NAD(P)H blocks de novo serine synthesis in human cells. · 2025 · https://pubmed.ncbi.nlm.nih.gov/39789421/ · DOI 10.1186/s11658-024-00681-8

trigger_kind

machinery_impairment Imported condition classification; unverified.

L-Serine: synthesis, one-carbon metabolism, lipids 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 · Human cell add-back experiments. · source_derived_draft · unverified_draft

## l-serine-naxd-small-molecule-rescue Two metabolic inputs partly bypassed a specific cellular vulnerability. Nicotinamide riboside and inosine partly improved viability of galactose-grown NAXD-null HAP1 cells, with metabolomics suggesting different mechanisms involving serine synthesis. Model: Human cell add-back experiments. Limitations: Cell rescue is not established treatment for inherited NAXD disease. Evidence access: Primary full text Failure to repair damaged NAD(P)H blocks de novo serine synthesis in human cells. · 2025 · https://pubmed.ncbi.nlm.nih.gov/39789421/ · DOI 10.1186/s11658-024-00681-8

evidence_access

Primary abstract

experimental_model

Human retinal organoid exposure experiment.

limitations

The result does not establish effective serine treatment for people with MacTel.

nutrient_topic

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

plain_language

The abnormal lipid can itself damage cells in an experimental retinal model.

primary_references

Serine and Lipid Metabolism in Macular Disease and Peripheral Neuropathy. · 2019 · https://pubmed.ncbi.nlm.nih.gov/31509666/ · DOI 10.1056/NEJMoa1815111

L-Serine: synthesis, one-carbon metabolism, lipids 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 · Human retinal organoid exposure experiment. · source_derived_draft · unverified_draft

## l-serine-organoid-lipid-toxicity The abnormal lipid can itself damage cells in an experimental retinal model. Deoxysphingolipid exposure caused photoreceptor-cell death in human retinal organoids, which was prevented by tested regulators of lipid metabolism. Model: Human retinal organoid exposure experiment. Limitations: The result does not establish effective serine treatment for people with MacTel. Evidence access: Primary abstract Serine and Lipid Metabolism in Macular Disease and Peripheral Neuropathy. · 2019 · https://pubmed.ncbi.nlm.nih.gov/31509666/ · DOI 10.1056/NEJMoa1815111

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary abstract

experimental_model

Human recombinant variants; solution biochemistry with AlphaFold and molecular-dynamics model refinement.

limitations

The complete tetramer model is computationally derived; it is not an experimentally solved full-length crystal structure.

nutrient_topic

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

plain_language

The enzyme must fold and assemble correctly as well as receive its cofactor.

primary_references

On the quaternary structure of human D-3-phosphoglycerate dehydrogenase. · 2024 · https://pubmed.ncbi.nlm.nih.gov/39012001/ · DOI 10.1002/pro.5089

trigger_kind

machinery_impairment Imported condition classification; unverified.

L-Serine: synthesis, one-carbon metabolism, lipids 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 · Human recombinant variants; solution biochemistry with AlphaFold and molecular-dynamics model refinement. · source_derived_draft · unverified_draft

## l-serine-phgdh-assembly The enzyme must fold and assemble correctly as well as receive its cofactor. Alanine substitutions at the predicted human PHGDH tetramer interface disrupted assembly, stability and activity for several tested ACT-domain residues. Model: Human recombinant variants; solution biochemistry with AlphaFold and molecular-dynamics model refinement. Limitations: The complete tetramer model is computationally derived; it is not an experimentally solved full-length crystal structure. Evidence access: Primary abstract On the quaternary structure of human D-3-phosphoglycerate dehydrogenase. · 2024 · https://pubmed.ncbi.nlm.nih.gov/39012001/ · DOI 10.1002/pro.5089

evidence_access

Primary abstract

experimental_model

Recombinant human PHGDH catalytic-domain structure and enzyme assays.

limitations

The truncated dimeric structure does not define the complete native oligomer.

nutrient_topic

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

plain_language

A glycolysis intermediate can be diverted into serine production.

primary_references

Structural insights into the enzymatic activity and potential substrate promiscuity of human 3-phosphoglycerate dehydrogenase (PHGDH). · 2017 · https://pubmed.ncbi.nlm.nih.gov/29262655/ · DOI 10.18632/oncotarget.22327

L-Serine: synthesis, one-carbon metabolism, lipids 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 · Recombinant human PHGDH catalytic-domain structure and enzyme assays. · source_derived_draft · unverified_draft

## l-serine-phgdh-reaction A glycolysis intermediate can be diverted into serine production. Human PHGDH catalyzes the NAD+-dependent oxidation of 3-phosphoglycerate to phosphohydroxypyruvate, the first step of phosphorylated serine biosynthesis. Model: Recombinant human PHGDH catalytic-domain structure and enzyme assays. Limitations: The truncated dimeric structure does not define the complete native oligomer. Evidence access: Primary abstract Structural insights into the enzymatic activity and potential substrate promiscuity of human 3-phosphoglycerate dehydrogenase (PHGDH). · 2017 · https://pubmed.ncbi.nlm.nih.gov/29262655/ · DOI 10.18632/oncotarget.22327

evidence_access

Primary abstract

experimental_model

Human family genetics and fibroblast lipid-conversion measurements.

limitations

This pathway uses membrane-bound phosphatidylserine, not free serine as the direct PISD substrate.

nutrient_topic

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

plain_language

A serine-derived lipid feeds another lipid needed inside mitochondria.

primary_references

PISD is a mitochondrial disease gene causing skeletal dysplasia, cataracts, and white matter changes. · 2019 · https://pubmed.ncbi.nlm.nih.gov/30858161/ · DOI 10.26508/lsa.201900353

L-Serine: synthesis, one-carbon metabolism, lipids 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 · Human family genetics and fibroblast lipid-conversion measurements. · source_derived_draft · unverified_draft

## l-serine-pisd-decarboxylation A serine-derived lipid feeds another lipid needed inside mitochondria. Human PISD converts phosphatidylserine to phosphatidylethanolamine in the inner mitochondrial membrane; patient fibroblasts with PISD variants showed reduced conversion. Model: Human family genetics and fibroblast lipid-conversion measurements. Limitations: This pathway uses membrane-bound phosphatidylserine, not free serine as the direct PISD substrate. Evidence access: Primary abstract PISD is a mitochondrial disease gene causing skeletal dysplasia, cataracts, and white matter changes. · 2019 · https://pubmed.ncbi.nlm.nih.gov/30858161/ · DOI 10.26508/lsa.201900353

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary abstract

experimental_model

Two affected sisters, patient fibroblasts and functional variant characterization.

limitations

The other allele produced an alternative splice product; different molecular defects remain distinct.

nutrient_topic

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

plain_language

A downstream processing defect can persist despite precursor availability.

primary_references

PISD is a mitochondrial disease gene causing skeletal dysplasia, cataracts, and white matter changes. · 2019 · https://pubmed.ncbi.nlm.nih.gov/30858161/ · DOI 10.26508/lsa.201900353

trigger_kind

machinery_impairment Imported condition classification; unverified.

L-Serine: synthesis, one-carbon metabolism, lipids and cross-nutrient mechanisms (2026-09-19) · lines 430–436

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Two affected sisters, patient fibroblasts and functional variant characterization. · source_derived_draft · unverified_draft

## l-serine-pisd-failure A downstream processing defect can persist despite precursor availability. PISD patient fibroblasts had fragmented mitochondria, enlarged lysosomes and reduced maximal oxygen consumption; one variant impaired the enzyme autocatalytic processing required for activity. Model: Two affected sisters, patient fibroblasts and functional variant characterization. Limitations: The other allele produced an alternative splice product; different molecular defects remain distinct. Evidence access: Primary abstract PISD is a mitochondrial disease gene causing skeletal dysplasia, cataracts, and white matter changes. · 2019 · https://pubmed.ncbi.nlm.nih.gov/30858161/ · DOI 10.26508/lsa.201900353

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary abstract

experimental_model

Human patient fibroblast rescue experiments.

limitations

This is not evidence that oral serine or phosphatidylserine corrects PISD disease.

nutrient_topic

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

plain_language

Supplying a downstream lipid can bypass a specific defect in culture.

primary_references

PISD is a mitochondrial disease gene causing skeletal dysplasia, cataracts, and white matter changes. · 2019 · https://pubmed.ncbi.nlm.nih.gov/30858161/ · DOI 10.26508/lsa.201900353

trigger_kind

machinery_impairment Imported condition classification; unverified.

L-Serine: synthesis, one-carbon metabolism, lipids and cross-nutrient mechanisms (2026-09-19) · lines 438–444

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human patient fibroblast rescue experiments. · source_derived_draft · unverified_draft

## l-serine-pisd-lipid-rescue Supplying a downstream lipid can bypass a specific defect in culture. Lyso-PE treatment and genetic complementation restored mitochondrial and lysosomal morphology in PISD patient fibroblasts. Model: Human patient fibroblast rescue experiments. Limitations: This is not evidence that oral serine or phosphatidylserine corrects PISD disease. Evidence access: Primary abstract PISD is a mitochondrial disease gene causing skeletal dysplasia, cataracts, and white matter changes. · 2019 · https://pubmed.ncbi.nlm.nih.gov/30858161/ · DOI 10.26508/lsa.201900353

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary abstract

experimental_model

Human family genetics and recombinant mutant expression.

limitations

Fibroblast enzyme testing was inconclusive; the recombinant result is the direct functional measurement.

nutrient_topic

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

plain_language

The amino-group transfer step can become a synthesis bottleneck.

primary_references

Phosphoserine aminotransferase deficiency: a novel disorder of the serine biosynthesis pathway. · 2007 · https://pubmed.ncbi.nlm.nih.gov/17436247/ · DOI 10.1086/517888

trigger_kind

machinery_impairment Imported condition classification; unverified.

L-Serine: synthesis, one-carbon metabolism, lipids 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 family genetics and recombinant mutant expression. · source_derived_draft · unverified_draft

## l-serine-psat-genetic The amino-group transfer step can become a synthesis bottleneck. Recombinant PSAT1 Asp100Ala retained only about 15% of wild-type maximal activity in the study of two affected siblings. Model: Human family genetics and recombinant mutant expression. Limitations: Fibroblast enzyme testing was inconclusive; the recombinant result is the direct functional measurement. Evidence access: Primary abstract Phosphoserine aminotransferase deficiency: a novel disorder of the serine biosynthesis pathway. · 2007 · https://pubmed.ncbi.nlm.nih.gov/17436247/ · DOI 10.1086/517888

evidence_access

Primary full text

experimental_model

Recombinant human PSAT kinetics and substrate-bound crystal structures.

limitations

This is an enzyme reaction, not evidence that dietary glutamate or B6 is limiting in a particular person.

nutrient_topic

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

plain_language

Glutamate supplies nitrogen while active B6 enables the transfer.

primary_references

L-serine biosynthesis in the human central nervous system: Structure and function of phosphoserine aminotransferase. · 2023 · https://pubmed.ncbi.nlm.nih.gov/36851825/ · DOI 10.1002/pro.4609

L-Serine: synthesis, one-carbon metabolism, lipids 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 · Recombinant human PSAT kinetics and substrate-bound crystal structures. · source_derived_draft · unverified_draft

## l-serine-psat-nitrogen Glutamate supplies nitrogen while active B6 enables the transfer. Human PSAT1 transfers nitrogen from glutamate to phosphohydroxypyruvate, producing O-phosphoserine and 2-oxoglutarate in a reversible PLP-dependent reaction. Model: Recombinant human PSAT kinetics and substrate-bound crystal structures. Limitations: This is an enzyme reaction, not evidence that dietary glutamate or B6 is limiting in a particular person. Evidence access: Primary full text L-serine biosynthesis in the human central nervous system: Structure and function of phosphoserine aminotransferase. · 2023 · https://pubmed.ncbi.nlm.nih.gov/36851825/ · DOI 10.1002/pro.4609

evidence_access

Primary full text

experimental_model

Purified human PSAT spectroscopy, substrate addition and crystallography.

limitations

PLP is recycled in catalysis; the experiment does not show one dietary B6 molecule is consumed for each serine made.

nutrient_topic

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

plain_language

The B6 cofactor cycles between forms as it carries amino-group chemistry.

primary_references

L-serine biosynthesis in the human central nervous system: Structure and function of phosphoserine aminotransferase. · 2023 · https://pubmed.ncbi.nlm.nih.gov/36851825/ · DOI 10.1002/pro.4609

L-Serine: synthesis, one-carbon metabolism, lipids 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 · Purified human PSAT spectroscopy, substrate addition and crystallography. · source_derived_draft · unverified_draft

## l-serine-psat-plp The B6 cofactor cycles between forms as it carries amino-group chemistry. Human PSAT contained a PLP internal aldimine associated with Lys200; glutamate converted the cofactor toward its pyridoxamine-phosphate state during the first half-reaction. Model: Purified human PSAT spectroscopy, substrate addition and crystallography. Limitations: PLP is recycled in catalysis; the experiment does not show one dietary B6 molecule is consumed for each serine made. Evidence access: Primary full text L-serine biosynthesis in the human central nervous system: Structure and function of phosphoserine aminotransferase. · 2023 · https://pubmed.ncbi.nlm.nih.gov/36851825/ · DOI 10.1002/pro.4609

evidence_access

Primary abstract

experimental_model

Human enzyme crystallography; the calcium-bound structure used 0.7 M CaCl2 crystallization conditions.

limitations

The high-calcium structure does not establish inhibition by normal dietary calcium.

nutrient_topic

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

plain_language

Two minerals can bind differently to the same enzyme.

primary_references

How calcium inhibits the magnesium-dependent enzyme human phosphoserine phosphatase. · 2004 · https://pubmed.ncbi.nlm.nih.gov/15291819/ · DOI 10.1111/j.0014-2956.2004.04277.x

L-Serine: synthesis, one-carbon metabolism, lipids 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 enzyme crystallography; the calcium-bound structure used 0.7 M CaCl2 crystallization conditions. · source_derived_draft · unverified_draft

## l-serine-psph-metal Two minerals can bind differently to the same enzyme. Human PSPH uses an active-site Mg2+ ion; replacing it with Ca2+ changes coordination of catalytic Asp20 in a way that impedes nucleophilic attack. Model: Human enzyme crystallography; the calcium-bound structure used 0.7 M CaCl2 crystallization conditions. Limitations: The high-calcium structure does not establish inhibition by normal dietary calcium. Evidence access: Primary abstract How calcium inhibits the magnesium-dependent enzyme human phosphoserine phosphatase. · 2004 · https://pubmed.ncbi.nlm.nih.gov/15291819/ · DOI 10.1111/j.0014-2956.2004.04277.x

evidence_access

Primary abstract

experimental_model

Purified human wild-type and variant PSPH; kinetic interpretation of physiological ion ranges.

limitations

This qualifies physiological extrapolation from binding assays; it does not deny the earlier calcium-bound structure.

nutrient_topic

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

plain_language

A required mineral need not be the rate-limiting input when its binding site is already occupied.

primary_references

Effect of l-serine and magnesium ions on the functional properties of human phosphoserine phosphatase and its pathogenetic variants. · 2024 · https://pubmed.ncbi.nlm.nih.gov/38278334/ · DOI 10.1016/j.bbadis.2024.167034

L-Serine: synthesis, one-carbon metabolism, lipids 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 · Purified human wild-type and variant PSPH; kinetic interpretation of physiological ion ranges. · source_derived_draft · unverified_draft

## l-serine-psph-physiology A required mineral need not be the rate-limiting input when its binding site is already occupied. The 2024 human PSPH study found near-saturation with Mg2+ under physiological conditions and judged ordinary Mg2+/Ca2+ fluctuations unlikely to regulate activity substantially. Model: Purified human wild-type and variant PSPH; kinetic interpretation of physiological ion ranges. Limitations: This qualifies physiological extrapolation from binding assays; it does not deny the earlier calcium-bound structure. Evidence access: Primary abstract Effect of l-serine and magnesium ions on the functional properties of human phosphoserine phosphatase and its pathogenetic variants. · 2024 · https://pubmed.ncbi.nlm.nih.gov/38278334/ · DOI 10.1016/j.bbadis.2024.167034

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary abstract

experimental_model

Recombinant human natural variants.

limitations

Assay behavior does not independently resolve the clinical pathogenicity of every variant.

nutrient_topic

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

plain_language

Different variants in the same gene can have very different biochemical effects.

primary_references

Effect of l-serine and magnesium ions on the functional properties of human phosphoserine phosphatase and its pathogenetic variants. · 2024 · https://pubmed.ncbi.nlm.nih.gov/38278334/ · DOI 10.1016/j.bbadis.2024.167034

trigger_kind

machinery_impairment Imported condition classification; unverified.

L-Serine: synthesis, one-carbon metabolism, lipids 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 · Recombinant human natural variants. · source_derived_draft · unverified_draft

## l-serine-psph-variant Different variants in the same gene can have very different biochemical effects. The A35T PSPH substitution reduced catalytic efficiency about fiftyfold and lowered thermal stability; M52T had milder effects and D32N behaved like wild type in these assays. Model: Recombinant human natural variants. Limitations: Assay behavior does not independently resolve the clinical pathogenicity of every variant. Evidence access: Primary abstract Effect of l-serine and magnesium ions on the functional properties of human phosphoserine phosphatase and its pathogenetic variants. · 2024 · https://pubmed.ncbi.nlm.nih.gov/38278334/ · DOI 10.1016/j.bbadis.2024.167034

evidence_access

Primary full text

experimental_model

Full-length human PSS1 cryo-EM in apo, calcium-bound and calcium/serine-bound states.

limitations

The proposed chemical mechanism combines structure and mutagenesis; it is not a clinical calcium-response experiment.

nutrient_topic

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

plain_language

Calcium has a constructive catalytic role in this lipid-building enzyme.

primary_references

Structural basis for catalytic mechanism of human phosphatidylserine synthase 1. · 2025 · https://pubmed.ncbi.nlm.nih.gov/40044636/ · DOI 10.1038/s41421-025-00775-3

L-Serine: synthesis, one-carbon metabolism, lipids 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 · Full-length human PSS1 cryo-EM in apo, calcium-bound and calcium/serine-bound states. · source_derived_draft · unverified_draft

## l-serine-pss1-calcium Calcium has a constructive catalytic role in this lipid-building enzyme. Human PSS1 structures positioned calcium and serine in the catalytic pocket; structural and mutational analysis implicated His172 in the base-exchange mechanism. Model: Full-length human PSS1 cryo-EM in apo, calcium-bound and calcium/serine-bound states. Limitations: The proposed chemical mechanism combines structure and mutagenesis; it is not a clinical calcium-response experiment. Evidence access: Primary full text Structural basis for catalytic mechanism of human phosphatidylserine synthase 1. · 2025 · https://pubmed.ncbi.nlm.nih.gov/40044636/ · DOI 10.1038/s41421-025-00775-3

evidence_access

Primary full text

experimental_model

Human PSS1 proteoliposomes with POPC and radioactive serine assays.

limitations

The bound endogenous lipid density could not conclusively distinguish PC from PE; no universal exclusion of PE is asserted.

nutrient_topic

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

plain_language

Serine can replace a phospholipid headgroup to make a different membrane lipid.

primary_references

Structural basis for catalytic mechanism of human phosphatidylserine synthase 1. · 2025 · https://pubmed.ncbi.nlm.nih.gov/40044636/ · DOI 10.1038/s41421-025-00775-3

L-Serine: synthesis, one-carbon metabolism, lipids 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 PSS1 proteoliposomes with POPC and radioactive serine assays. · source_derived_draft · unverified_draft

## l-serine-pss1-exchange Serine can replace a phospholipid headgroup to make a different membrane lipid. Purified human PSS1 reconstituted with phosphatidylcholine showed serine base-exchange activity producing phosphatidylserine. Model: Human PSS1 proteoliposomes with POPC and radioactive serine assays. Limitations: The bound endogenous lipid density could not conclusively distinguish PC from PE; no universal exclusion of PE is asserted. Evidence access: Primary full text Structural basis for catalytic mechanism of human phosphatidylserine synthase 1. · 2025 · https://pubmed.ncbi.nlm.nih.gov/40044636/ · DOI 10.1038/s41421-025-00775-3

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary abstract

experimental_model

Human genetics and patient fibroblast synthesis assays.

limitations

These gain-of-function variants are not serine shortage or proof of an effect from phosphatidylserine supplements.

nutrient_topic

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

plain_language

Failure of a feedback brake can increase lipid production.

primary_references

Gain-of-function mutations in the phosphatidylserine synthase 1 (PTDSS1) gene cause Lenz-Majewski syndrome. · 2014 · https://pubmed.ncbi.nlm.nih.gov/24241535/ · DOI 10.1038/ng.2829

trigger_kind

machinery_impairment Imported condition classification; unverified.

L-Serine: synthesis, one-carbon metabolism, lipids 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 · Human genetics and patient fibroblast synthesis assays. · source_derived_draft · unverified_draft

## l-serine-pss1-feedback Failure of a feedback brake can increase lipid production. PTDSS1 variants from Lenz-Majewski syndrome markedly reduced product inhibition by phosphatidylserine and increased phosphatidylserine synthesis in patient fibroblasts. Model: Human genetics and patient fibroblast synthesis assays. Limitations: These gain-of-function variants are not serine shortage or proof of an effect from phosphatidylserine supplements. Evidence access: Primary abstract Gain-of-function mutations in the phosphatidylserine synthase 1 (PTDSS1) gene cause Lenz-Majewski syndrome. · 2014 · https://pubmed.ncbi.nlm.nih.gov/24241535/ · DOI 10.1038/ng.2829

evidence_access

Primary abstract

experimental_model

Purified epitope-tagged human PSS1/PSS2 substrate and feedback assays.

limitations

In this preparation PSS1 used both PC and PE and was not inhibited by added PS; purified-enzyme feedback cannot be assumed identical across preparations or intact cells.

nutrient_topic

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

plain_language

A second enzyme uses a different membrane-lipid starting material.

primary_references

Purification and characterization of human phosphatidylserine synthases 1 and 2. · 2009 · https://pubmed.ncbi.nlm.nih.gov/19014349/ · DOI 10.1042/BJ20081597

L-Serine: synthesis, one-carbon metabolism, lipids 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 · Purified epitope-tagged human PSS1/PSS2 substrate and feedback assays. · source_derived_draft · unverified_draft

## l-serine-pss2-exchange A second enzyme uses a different membrane-lipid starting material. Purified human PSS2 converted phosphatidylethanolamine, but not phosphatidylcholine, into phosphatidylserine; added phosphatidylserine inhibited purified PSS2. Model: Purified epitope-tagged human PSS1/PSS2 substrate and feedback assays. Limitations: In this preparation PSS1 used both PC and PE and was not inhibited by added PS; purified-enzyme feedback cannot be assumed identical across preparations or intact cells. Evidence access: Primary abstract Purification and characterization of human phosphatidylserine synthases 1 and 2. · 2009 · https://pubmed.ncbi.nlm.nih.gov/19014349/ · DOI 10.1042/BJ20081597

evidence_access

Primary abstract

experimental_model

Purified human PSTK with tRNA substrates; comparison with KTI12.

limitations

This is tRNA-bound serine chemistry, not direct conversion of free serine into free selenocysteine.

nutrient_topic

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

plain_language

A serine molecule already loaded onto a tRNA is processed into a selenium-containing amino-acid precursor.

primary_references

Same but different - Molecular comparison of human KTI12 and PSTK. · 2021 · https://pubmed.ncbi.nlm.nih.gov/33417976/ · DOI 10.1016/j.bbamcr.2020.118945

L-Serine: synthesis, one-carbon metabolism, lipids 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 · Purified human PSTK with tRNA substrates; comparison with KTI12. · source_derived_draft · unverified_draft

## l-serine-pstk-serine A serine molecule already loaded onto a tRNA is processed into a selenium-containing amino-acid precursor. Human PSTK phosphorylates serine attached to tRNA Sec as part of the specialized selenocysteine synthesis pathway. Model: Purified human PSTK with tRNA substrates; comparison with KTI12. Limitations: This is tRNA-bound serine chemistry, not direct conversion of free serine into free selenocysteine. Evidence access: Primary abstract Same but different - Molecular comparison of human KTI12 and PSTK. · 2021 · https://pubmed.ncbi.nlm.nih.gov/33417976/ · DOI 10.1016/j.bbamcr.2020.118945

evidence_access

Primary abstract

experimental_model

Purified human hepatic enzyme, activity assay and 2.5-angstrom crystal structure.

limitations

Enzyme capacity does not quantify its share of whole-body serine disposal.

nutrient_topic

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

plain_language

Serine carbon can enter central metabolism through a B6-dependent breakdown step.

primary_references

Crystal structure of the pyridoxal-5'-phosphate-dependent serine dehydratase from human liver. · 2005 · https://pubmed.ncbi.nlm.nih.gov/15689518/ · DOI 10.1110/ps.041179105

L-Serine: synthesis, one-carbon metabolism, lipids 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 · Purified human hepatic enzyme, activity assay and 2.5-angstrom crystal structure. · source_derived_draft · unverified_draft

## l-serine-sds-catabolism Serine carbon can enter central metabolism through a B6-dependent breakdown step. Human liver serine dehydratase uses PLP to convert L-serine to pyruvate and ammonia; its active holoenzyme was structurally characterized. Model: Purified human hepatic enzyme, activity assay and 2.5-angstrom crystal structure. Limitations: Enzyme capacity does not quantify its share of whole-body serine disposal. Evidence access: Primary abstract Crystal structure of the pyridoxal-5'-phosphate-dependent serine dehydratase from human liver. · 2005 · https://pubmed.ncbi.nlm.nih.gov/15689518/ · DOI 10.1110/ps.041179105

evidence_access

Primary abstract

experimental_model

Recombinant human enzymes, 2.8-angstrom SDSL structure and site-directed mutagenesis.

limitations

This is a comparison of enzyme constructs, not clinical evidence of a dietary shortage.

nutrient_topic

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

plain_language

Related enzymes are not interchangeable just because they use the same substrate.

primary_references

A catalytic mechanism that explains a low catalytic activity of serine dehydratase like-1 from human cancer cells: crystal structure and site-directed mutagenesis studies. · 2008 · https://pubmed.ncbi.nlm.nih.gov/18342636/ · DOI 10.1016/j.bbagen.2008.01.020

L-Serine: synthesis, one-carbon metabolism, lipids 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 · Recombinant human enzymes, 2.8-angstrom SDSL structure and site-directed mutagenesis. · source_derived_draft · unverified_draft

## l-serine-sdsl-distinction Related enzymes are not interchangeable just because they use the same substrate. Human serine dehydratase-like protein had lower activity than the hepatic enzyme; structures and complementary mutations implicated active-site differences, including Gly72. Model: Recombinant human enzymes, 2.8-angstrom SDSL structure and site-directed mutagenesis. Limitations: This is a comparison of enzyme constructs, not clinical evidence of a dietary shortage. Evidence access: Primary abstract A catalytic mechanism that explains a low catalytic activity of serine dehydratase like-1 from human cancer cells: crystal structure and site-directed mutagenesis studies. · 2008 · https://pubmed.ncbi.nlm.nih.gov/18342636/ · DOI 10.1016/j.bbagen.2008.01.020

evidence_access

Primary abstract

experimental_model

Human SepSecS–tRNA complex structure with enzyme assays.

limitations

Free phosphoserine and a phosphoserine residue on this specialized tRNA are not interchangeable substrates.

nutrient_topic

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

plain_language

The carrier and the cofactor are part of the reaction, not optional packaging.

primary_references

The human SepSecS-tRNASec complex reveals the mechanism of selenocysteine formation. · 2009 · https://pubmed.ncbi.nlm.nih.gov/19608919/ · DOI 10.1126/science.1173755

L-Serine: synthesis, one-carbon metabolism, lipids 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 · Human SepSecS–tRNA complex structure with enzyme assays. · source_derived_draft · unverified_draft

## l-serine-sepsecs-substrate The carrier and the cofactor are part of the reaction, not optional packaging. Human SepSecS structural and functional analysis supported correct positioning of tRNA-bound phosphoserine, but not free phosphoserine, for PLP-dependent selenocysteine formation. Model: Human SepSecS–tRNA complex structure with enzyme assays. Limitations: Free phosphoserine and a phosphoserine residue on this specialized tRNA are not interchangeable substrates. Evidence access: Primary abstract The human SepSecS-tRNASec complex reveals the mechanism of selenocysteine formation. · 2009 · https://pubmed.ncbi.nlm.nih.gov/19608919/ · DOI 10.1126/science.1173755

evidence_access

Primary abstract

experimental_model

Purified-substrate amino-acid activation and tRNA-charging assays.

limitations

Aminoacylation is not direct proof of the frequency of proteome misincorporation in humans.

nutrient_topic

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

plain_language

Chemical similarity to serine does not establish entry through the serine-loading enzyme.

primary_references

The mechanism of β-N-methylamino-l-alanine inhibition of tRNA aminoacylation and its impact on misincorporation. · 2020 · https://pubmed.ncbi.nlm.nih.gov/31862734/ · DOI 10.1074/jbc.RA119.011714

L-Serine: synthesis, one-carbon metabolism, lipids 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 · Purified-substrate amino-acid activation and tRNA-charging assays. · source_derived_draft · unverified_draft

## l-serine-serrs-bmaa-boundary Chemical similarity to serine does not establish entry through the serine-loading enzyme. Purified BMAA was not a substrate for human seryl-tRNA synthetase in the study; human alanyl-tRNA synthetase instead activated it and formed BMAA-tRNA Ala. Model: Purified-substrate amino-acid activation and tRNA-charging assays. Limitations: Aminoacylation is not direct proof of the frequency of proteome misincorporation in humans. Evidence access: Primary abstract The mechanism of β-N-methylamino-l-alanine inhibition of tRNA aminoacylation and its impact on misincorporation. · 2020 · https://pubmed.ncbi.nlm.nih.gov/31862734/ · DOI 10.1074/jbc.RA119.011714

evidence_access

Primary abstract

experimental_model

Human SerRS with two tRNA species and ten mutant/chimeric constructs.

limitations

Carrier recognition is distinct from ordinary amino-acid transport or downstream protein phosphorylation.

nutrient_topic

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

plain_language

Serine must be attached to a tRNA before it can enter a growing protein.

primary_references

Insights into substrate promiscuity of human seryl-tRNA synthetase. · 2017 · https://pubmed.ncbi.nlm.nih.gov/28808125/ · DOI 10.1261/rna.061069.117

L-Serine: synthesis, one-carbon metabolism, lipids and cross-nutrient mechanisms (2026-09-19) · lines 446–452

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human SerRS with two tRNA species and ten mutant/chimeric constructs. · source_derived_draft · unverified_draft

## l-serine-serrs-protein-route Serine must be attached to a tRNA before it can enter a growing protein. Human cytosolic SerRS attached L-serine to tRNA Ser and showed only a modest preference for it over tRNA Sec in the tested binding and serylation experiments. Model: Human SerRS with two tRNA species and ten mutant/chimeric constructs. Limitations: Carrier recognition is distinct from ordinary amino-acid transport or downstream protein phosphorylation. Evidence access: Primary abstract Insights into substrate promiscuity of human seryl-tRNA synthetase. · 2017 · https://pubmed.ncbi.nlm.nih.gov/28808125/ · DOI 10.1261/rna.061069.117

evidence_access

Primary abstract

experimental_model

Human cytosolic SerRS substrate-recognition and aminoacylation experiments.

limitations

Serylation does not itself add selenium; PSTK and SEPSECS act in later steps.

nutrient_topic

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

plain_language

The same loading enzyme feeds both ordinary protein synthesis and selenium-dependent decoding.

primary_references

Insights into substrate promiscuity of human seryl-tRNA synthetase. · 2017 · https://pubmed.ncbi.nlm.nih.gov/28808125/ · DOI 10.1261/rna.061069.117

L-Serine: synthesis, one-carbon metabolism, lipids and cross-nutrient mechanisms (2026-09-19) · lines 454–460

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human cytosolic SerRS substrate-recognition and aminoacylation experiments. · source_derived_draft · unverified_draft

## l-serine-serrs-selenium-route The same loading enzyme feeds both ordinary protein synthesis and selenium-dependent decoding. Human SerRS also attached L-serine to tRNA Sec, initiating the specialized pathway that later converts its attached amino acid into selenocysteine. Model: Human cytosolic SerRS substrate-recognition and aminoacylation experiments. Limitations: Serylation does not itself add selenium; PSTK and SEPSECS act in later steps. Evidence access: Primary abstract Insights into substrate promiscuity of human seryl-tRNA synthetase. · 2017 · https://pubmed.ncbi.nlm.nih.gov/28808125/ · DOI 10.1261/rna.061069.117

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary abstract

experimental_model

Human cell single and double knockout comparisons.

limitations

Related transporters provide redundancy; this is not a demonstrated dietary serine deficiency.

nutrient_topic

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

plain_language

Transport capacity can limit another amino acid and nucleotide production.

primary_references

SFXN1 is a mitochondrial serine transporter required for one-carbon metabolism. · 2018 · https://pubmed.ncbi.nlm.nih.gov/30442778/ · DOI 10.1126/science.aat9528

trigger_kind

machinery_impairment Imported condition classification; unverified.

L-Serine: synthesis, one-carbon metabolism, lipids 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 cell single and double knockout comparisons. · source_derived_draft · unverified_draft

## l-serine-sfxn1-loss Transport capacity can limit another amino acid and nucleotide production. SFXN1-null human cells had impaired glycine and purine synthesis; loss of both SFXN1 and SFXN3 caused stronger defects, including dependence on exogenous glycine. Model: Human cell single and double knockout comparisons. Limitations: Related transporters provide redundancy; this is not a demonstrated dietary serine deficiency. Evidence access: Primary abstract SFXN1 is a mitochondrial serine transporter required for one-carbon metabolism. · 2018 · https://pubmed.ncbi.nlm.nih.gov/30442778/ · DOI 10.1126/science.aat9528

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary abstract

experimental_model

Human cell metabolic and respiratory-chain experiments.

limitations

This does not reduce all SFXN1 phenotypes to one folate bottleneck.

nutrient_topic

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

plain_language

Two effects of the same transporter can run through different downstream routes.

primary_references

The mitochondrial carrier SFXN1 is critical for complex III integrity and cellular metabolism. · 2021 · https://pubmed.ncbi.nlm.nih.gov/33730581/ · DOI 10.1016/j.celrep.2021.108869

trigger_kind

machinery_impairment Imported condition classification; unverified.

L-Serine: synthesis, one-carbon metabolism, lipids 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 cell metabolic and respiratory-chain experiments. · source_derived_draft · unverified_draft

## l-serine-sfxn1-rescue-boundary Two effects of the same transporter can run through different downstream routes. The study attributed SFXN1-dependent complex III support to heme and 2-oxoglutarate metabolism rather than to its one-carbon-metabolism role alone. Model: Human cell metabolic and respiratory-chain experiments. Limitations: This does not reduce all SFXN1 phenotypes to one folate bottleneck. Evidence access: Primary abstract The mitochondrial carrier SFXN1 is critical for complex III integrity and cellular metabolism. · 2021 · https://pubmed.ncbi.nlm.nih.gov/33730581/ · DOI 10.1016/j.celrep.2021.108869

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary abstract

experimental_model

Human cultured-cell mitochondrial carrier characterization.

limitations

This is a transporter-loss experiment, not evidence that serine supplements raise CoQ.

nutrient_topic

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

plain_language

A transport defect can affect the respiratory chain as well as one-carbon metabolism.

primary_references

The mitochondrial carrier SFXN1 is critical for complex III integrity and cellular metabolism. · 2021 · https://pubmed.ncbi.nlm.nih.gov/33730581/ · DOI 10.1016/j.celrep.2021.108869

trigger_kind

machinery_impairment Imported condition classification; unverified.

L-Serine: synthesis, one-carbon metabolism, lipids 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 cultured-cell mitochondrial carrier characterization. · source_derived_draft · unverified_draft

## l-serine-sfxn1-respiration A transport defect can affect the respiratory chain as well as one-carbon metabolism. SFXN1 deficiency impaired complex III biogenesis, assembly and activity and compromised coenzyme Q levels. Model: Human cultured-cell mitochondrial carrier characterization. Limitations: This is a transporter-loss experiment, not evidence that serine supplements raise CoQ. Evidence access: Primary abstract The mitochondrial carrier SFXN1 is critical for complex III integrity and cellular metabolism. · 2021 · https://pubmed.ncbi.nlm.nih.gov/33730581/ · DOI 10.1016/j.celrep.2021.108869

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary abstract

experimental_model

Human SHMT2 knockout and mitochondrial ribosome profiling.

limitations

The methyl-donor route was mechanistically inferred alongside measured modification and translation defects.

nutrient_topic

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

plain_language

Serine-linked folate chemistry helps mitochondria read particular codons.

primary_references

Mitochondrial translation requires folate-dependent tRNA methylation. · 2018 · https://pubmed.ncbi.nlm.nih.gov/29364879/ · DOI 10.1038/nature25460

trigger_kind

machinery_impairment Imported condition classification; unverified.

L-Serine: synthesis, one-carbon metabolism, lipids 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 · Human SHMT2 knockout and mitochondrial ribosome profiling. · source_derived_draft · unverified_draft

## l-serine-shmt2-translation Serine-linked folate chemistry helps mitochondria read particular codons. Catalytic SHMT2 loss in human cells impaired mitochondrial tRNA modification and caused preferential ribosome stalling at AAG lysine and UUG leucine codons. Model: Human SHMT2 knockout and mitochondrial ribosome profiling. Limitations: The methyl-donor route was mechanistically inferred alongside measured modification and translation defects. Evidence access: Primary abstract Mitochondrial translation requires folate-dependent tRNA methylation. · 2018 · https://pubmed.ncbi.nlm.nih.gov/29364879/ · DOI 10.1038/nature25460

evidence_access

Primary abstract

experimental_model

Recombinant human serine racemase and serine dehydratase mutants with functional comparisons.

limitations

Engineered reaction switching does not mean the native enzymes have identical functions.

nutrient_topic

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

plain_language

One enzyme creates the D-form used in a distinct signaling pathway.

primary_references

Modulating the function of human serine racemase and human serine dehydratase by protein engineering. · 2012 · https://pubmed.ncbi.nlm.nih.gov/23112234/ · DOI 10.1093/protein/gzs078

L-Serine: synthesis, one-carbon metabolism, lipids 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 · Recombinant human serine racemase and serine dehydratase mutants with functional comparisons. · source_derived_draft · unverified_draft

## l-serine-srr-racemization One enzyme creates the D-form used in a distinct signaling pathway. Human serine racemase catalyzes the PLP-dependent formation of D-serine from L-serine; replacing Ser84 with alanine shifted its behavior toward serine dehydratase activity. Model: Recombinant human serine racemase and serine dehydratase mutants with functional comparisons. Limitations: Engineered reaction switching does not mean the native enzymes have identical functions. Evidence access: Primary abstract Modulating the function of human serine racemase and human serine dehydratase by protein engineering. · 2012 · https://pubmed.ncbi.nlm.nih.gov/23112234/ · DOI 10.1093/protein/gzs078

availability_state

nutrient_deficiency Imported condition classification; unverified.

evidence_access

Primary abstract

experimental_model

Human cancer-cell p53 comparison, with an additional in-vivo tumor model.

limitations

This is not a proven dietary cancer therapy.

nutrient_topic

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

plain_language

The same shortage can have a different outcome when stress-response machinery is missing.

primary_references

Serine starvation induces stress and p53-dependent metabolic remodelling in cancer cells. · 2013 · https://pubmed.ncbi.nlm.nih.gov/23242140/ · DOI 10.1038/nature11743

trigger_kind

nutrient_deficiency Imported condition classification; unverified.

L-Serine: synthesis, one-carbon metabolism, lipids 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 · Human cancer-cell p53 comparison, with an additional in-vivo tumor model. · source_derived_draft · unverified_draft

## l-serine-starvation-p53-loss The same shortage can have a different outcome when stress-response machinery is missing. p53-deficient cells failed to complete the adaptive response to serine withdrawal and developed oxidative stress, lower viability and impaired proliferation. Model: Human cancer-cell p53 comparison, with an additional in-vivo tumor model. Limitations: This is not a proven dietary cancer therapy. Evidence access: Primary abstract Serine starvation induces stress and p53-dependent metabolic remodelling in cancer cells. · 2013 · https://pubmed.ncbi.nlm.nih.gov/23242140/ · DOI 10.1038/nature11743

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

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

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary full text

experimental_model

Human cancer cells with FTCD depletion, metabolomics and U-13C-serine tracing.

limitations

Measured under methotrexate; do not generalize to normal folate demand or all tissues. Correction record: A 2022 author correction is indexed (PMID 35017686). The publisher-accessible record identifies corrected Fig. 1f, Extended Data Fig. 11, Supplementary Fig. 3 and source data for Figs. 1/2, including an erroneous doxorubicin replicate. Complete correction narrative was not accessible; its full impact is not independently cleared. The original study remains flagged corrected, and no comprehensive safety claim is made. https://www.nature.com/articles/s41586-021-03487-2

nutrient_topic

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

plain_language

Blocking histidine breakdown spared folate for nucleotide production in this drug-stressed setting.

primary_references

Histidine catabolism is a major determinant of methotrexate sensitivity. · 2018 · https://pubmed.ncbi.nlm.nih.gov/29995852/ · DOI 10.1038/s41586-018-0316-7

trigger_kind

machinery_impairment Imported condition classification; unverified.

L-Histidine: supply, catabolism, histamine, receptors and cross-nutrient mechanisms (2026-09-19) · lines 154–160

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human cancer cells with FTCD depletion, metabolomics and U-13C-serine tracing. · source_derived_draft · unverified_draft

## histidine-ftcd-thf-sparing Blocking histidine breakdown spared folate for nucleotide production in this drug-stressed setting. Under methotrexate, FTCD depletion preserved THF and increased serine-derived labeling of IMP and TTP relative to controls. Model: Human cancer cells with FTCD depletion, metabolomics and U-13C-serine tracing. Limitations: Measured under methotrexate; do not generalize to normal folate demand or all tissues. Correction record: A 2022 author correction is indexed (PMID 35017686). The publisher-accessible record identifies corrected Fig. 1f, Extended Data Fig. 11, Supplementary Fig. 3 and source data for Figs. 1/2, including an erroneous doxorubicin replicate. Complete correction narrative was not accessible; its full impact is not independently cleared. The original study remains flagged corrected, and no comprehensive safety claim is made. https://www.nature.com/articles/s41586-021-03487-2 Evidence access: Primary full text Histidine catabolism is a major determinant of methotrexate sensitivity. · 2018 · https://pubmed.ncbi.nlm.nih.gov/29995852/ · DOI 10.1038/s41586-018-0316-7

evidence_access

Primary abstract

experimental_model

Human cDNA cloning and transporter characterization.

limitations

Substrate overlap alone does not quantify competition during ordinary dietary intake.

nutrient_topic

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

plain_language

Several amino acids share a cellular entry and exchange route.

primary_references

Human neutral amino acid transporter ASCT1: structure of the gene (SLC1A4) and localization to chromosome 2p13-p15. · 1994 · https://pubmed.ncbi.nlm.nih.gov/7896285/ · DOI 10.1006/geno.1994.1577

transport_effect

depends A substrate-selectivity record. ASCT1 is an obligatory exchanger and no direction is stated.

transport_pool

the cytosol across the plasma membrane A substrate-selectivity record. ASCT1 is an obligatory exchanger and no direction is stated.

L-Threonine: translation, intestinal barrier, metabolism and cross-nutrient mechanisms (2026-09-19) · lines 18–24

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human cDNA cloning and transporter characterization. · source_derived_draft · unverified_draft

## l-threonine-asct1-substrate Several amino acids share a cellular entry and exchange route. Cloned human ASCT1 transported alanine, serine, cysteine and threonine rather than glutamate or aspartate. Model: Human cDNA cloning and transporter characterization. Limitations: Substrate overlap alone does not quantify competition during ordinary dietary intake. Evidence access: Primary abstract Human neutral amino acid transporter ASCT1: structure of the gene (SLC1A4) and localization to chromosome 2p13-p15. · 1994 · https://pubmed.ncbi.nlm.nih.gov/7896285/ · DOI 10.1006/geno.1994.1577

evidence_access

Primary abstract

experimental_model

Human GalNAc-T2 structural and NMR enzymology.

limitations

Free dietary threonine is not the glycosyltransferase acceptor used in this protein-modification reaction.

nutrient_topic

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

plain_language

A threonine residue already built into a protein can carry a sugar.

primary_references

Structural Analysis of a GalNAc-T2 Mutant Reveals an Induced-Fit Catalytic Mechanism for GalNAc-Ts. · 2018 · https://pubmed.ncbi.nlm.nih.gov/29601100/ · DOI 10.1002/chem.201800701

L-Threonine: translation, intestinal barrier, metabolism and cross-nutrient mechanisms (2026-09-19) · lines 186–192

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human GalNAc-T2 structural and NMR enzymology. · source_derived_draft · unverified_draft

## l-threonine-galnt2-sugar A threonine residue already built into a protein can carry a sugar. GalNAc-T2 initiates mucin-type O-glycosylation by transferring GalNAc from UDP-GalNAc to serine or threonine residues within proteins. Model: Human GalNAc-T2 structural and NMR enzymology. Limitations: Free dietary threonine is not the glycosyltransferase acceptor used in this protein-modification reaction. Evidence access: Primary abstract Structural Analysis of a GalNAc-T2 Mutant Reveals an Induced-Fit Catalytic Mechanism for GalNAc-Ts. · 2018 · https://pubmed.ncbi.nlm.nih.gov/29601100/ · DOI 10.1002/chem.201800701

evidence_access

Primary abstract

experimental_model

Human recombinant enzymes expressed in E. coli and compared biochemically.

limitations

Activity in a purified system does not quantify whole-body human threonine flux. The threonine product is alpha-ketobutyrate, distinct from the serine product pyruvate.

nutrient_topic

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

plain_language

Threonine can enter carbon metabolism through an enzyme it shares with serine.

primary_references

Enzymatic and biochemical properties of a novel human serine dehydratase isoform. · 2006 · https://pubmed.ncbi.nlm.nih.gov/16580895/ · DOI 10.1016/j.bbapap.2006.02.010

L-Threonine: translation, intestinal barrier, metabolism and cross-nutrient mechanisms (2026-09-19) · lines 250–256

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human recombinant enzymes expressed in E. coli and compared biochemically. · source_derived_draft · unverified_draft

## l-threonine-human-sds-catabolism Threonine can enter carbon metabolism through an enzyme it shares with serine. Purified human hepatic serine dehydratase showed L-threonine dehydratase activity in comparison with the human SDH-like isoform. Model: Human recombinant enzymes expressed in E. coli and compared biochemically. Limitations: Activity in a purified system does not quantify whole-body human threonine flux. The threonine product is alpha-ketobutyrate, distinct from the serine product pyruvate. Evidence access: Primary abstract Enzymatic and biochemical properties of a novel human serine dehydratase isoform. · 2006 · https://pubmed.ncbi.nlm.nih.gov/16580895/ · DOI 10.1016/j.bbapap.2006.02.010

availability_state

biomarker_context Imported condition classification; unverified.

evidence_access

Primary abstract

experimental_model

61 genetically confirmed patients versus reference data from 274 controls; stereoselective serine analysis in a smaller subset.

limitations

Association does not identify a unique transport mechanism or justify treating an isolated CSF ratio.

nutrient_topic

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

plain_language

A high amino-acid measurement can accompany a defect in a neighboring pathway.

primary_references

Cerebrospinal fluid amino acids glycine, serine, and threonine in nonketotic hyperglycinemia. · 2022 · https://pubmed.ncbi.nlm.nih.gov/35357708/ · DOI 10.1002/jimd.12500

trigger_kind

biomarker_context Imported condition classification; unverified.

L-Threonine: translation, intestinal barrier, metabolism and cross-nutrient mechanisms (2026-09-19) · lines 418–424

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · 61 genetically confirmed patients versus reference data from 274 controls; stereoselective serine analysis in a smaller subset. · source_derived_draft · unverified_draft

## l-threonine-nkh-amino-acid-pattern A high amino-acid measurement can accompany a defect in a neighboring pathway. Compared with age-adjusted controls, NKH patients had higher CSF threonine, lower serine and higher glycine. Model: 61 genetically confirmed patients versus reference data from 274 controls; stereoselective serine analysis in a smaller subset. Limitations: Association does not identify a unique transport mechanism or justify treating an isolated CSF ratio. Evidence access: Primary abstract Cerebrospinal fluid amino acids glycine, serine, and threonine in nonketotic hyperglycinemia. · 2022 · https://pubmed.ncbi.nlm.nih.gov/35357708/ · DOI 10.1002/jimd.12500

evidence_access

Primary full-text Table 5, publisher PDF

experimental_model

Table 5: three observations per transporter; heterologous human-transporter HEK cell assays.

limitations

An inhibition concentration in culture is not a dietary threshold or proof of reduced brain serine.

nutrient_topic

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

plain_language

Threonine can compete with serine in a defined transporter assay.

primary_references

D-Serine Is a Substrate for Neutral Amino Acid Transporters ASCT1/SLC1A4 and ASCT2/SLC1A5, and Is Transported by Both Subtypes in Rat Hippocampal Astrocyte Cultures. · 2016 · https://pubmed.ncbi.nlm.nih.gov/27272177/ · DOI 10.1371/journal.pone.0156551

L-Threonine: translation, intestinal barrier, metabolism and cross-nutrient mechanisms (2026-09-19) · lines 26–32

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Table 5: three observations per transporter; heterologous human-transporter HEK cell assays. · source_derived_draft · unverified_draft

## l-threonine-serine-competition-slc1a4 Threonine can compete with serine in a defined transporter assay. L-threonine inhibited radiolabeled L-serine uptake in HEK cells expressing human ASCT1, with an IC50 of 181 ± 75 micromolar. Model: Table 5: three observations per transporter; heterologous human-transporter HEK cell assays. Limitations: An inhibition concentration in culture is not a dietary threshold or proof of reduced brain serine. Evidence access: Primary full-text Table 5, publisher PDF D-Serine Is a Substrate for Neutral Amino Acid Transporters ASCT1/SLC1A4 and ASCT2/SLC1A5, and Is Transported by Both Subtypes in Rat Hippocampal Astrocyte Cultures. · 2016 · https://pubmed.ncbi.nlm.nih.gov/27272177/ · DOI 10.1371/journal.pone.0156551

evidence_access

Primary full-text Table 5, publisher PDF

experimental_model

Table 5: three observations per transporter; heterologous human-transporter HEK cell assays.

limitations

An inhibition concentration in culture is not a dietary threshold or proof of reduced brain serine.

nutrient_topic

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

plain_language

Threonine can compete with serine in a defined transporter assay.

primary_references

D-Serine Is a Substrate for Neutral Amino Acid Transporters ASCT1/SLC1A4 and ASCT2/SLC1A5, and Is Transported by Both Subtypes in Rat Hippocampal Astrocyte Cultures. · 2016 · https://pubmed.ncbi.nlm.nih.gov/27272177/ · DOI 10.1371/journal.pone.0156551

L-Threonine: translation, intestinal barrier, metabolism and cross-nutrient mechanisms (2026-09-19) · lines 34–40

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Table 5: three observations per transporter; heterologous human-transporter HEK cell assays. · source_derived_draft · unverified_draft

## l-threonine-serine-competition-slc1a5 Threonine can compete with serine in a defined transporter assay. L-threonine inhibited radiolabeled L-serine uptake in HEK cells expressing human ASCT2, with an IC50 of 228 ± 83 micromolar. Model: Table 5: three observations per transporter; heterologous human-transporter HEK cell assays. Limitations: An inhibition concentration in culture is not a dietary threshold or proof of reduced brain serine. Evidence access: Primary full-text Table 5, publisher PDF D-Serine Is a Substrate for Neutral Amino Acid Transporters ASCT1/SLC1A4 and ASCT2/SLC1A5, and Is Transported by Both Subtypes in Rat Hippocampal Astrocyte Cultures. · 2016 · https://pubmed.ncbi.nlm.nih.gov/27272177/ · DOI 10.1371/journal.pone.0156551

evidence_access

Primary abstract

experimental_model

Human mitochondrial aminoacyl-tRNA synthetase biochemistry.

limitations

This is tRNA-bound substrate discrimination, not evidence that serine supplements cause mistranslation.

nutrient_topic

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

plain_language

Proofreading removes serine accidentally attached to threonine tRNA.

primary_references

Elucidating the molecular mechanisms associated with TARS2-related mitochondrial disease. · 2022 · https://pubmed.ncbi.nlm.nih.gov/34508595/ · DOI 10.1093/hmg/ddab257

L-Threonine: translation, intestinal barrier, metabolism 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 mitochondrial aminoacyl-tRNA synthetase biochemistry. · source_derived_draft · unverified_draft

## l-threonine-tars2-editing Proofreading removes serine accidentally attached to threonine tRNA. Human TARS2 clears mischarged Ser-tRNA Thr during mitochondrial translation. Model: Human mitochondrial aminoacyl-tRNA synthetase biochemistry. Limitations: This is tRNA-bound substrate discrimination, not evidence that serine supplements cause mistranslation. Evidence access: Primary abstract Elucidating the molecular mechanisms associated with TARS2-related mitochondrial disease. · 2022 · https://pubmed.ncbi.nlm.nih.gov/34508595/ · DOI 10.1093/hmg/ddab257

evidence_access

Primary abstract

experimental_model

Recombinant enzyme and cell-extract experiments; construct species not resolved in accessed abstract.

limitations

This is a shared-machinery connection, not a demonstrated magnesium effect on D-aspartate flux.

nutrient_topic

D-Aspartate collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · D-Aspartate

plain_language

Mineral and energy cofactors affect this enzyme, but the measured substrate was serine.

primary_references

Cofactors of serine racemase that physiologically stimulate the synthesis of the N-methyl-D-aspartate (NMDA) receptor coagonist D-serine. · 2002 · https://pubmed.ncbi.nlm.nih.gov/12393813/ · DOI 10.1073/pnas.222421299

D-Aspartate: synthesis, clearance, neural and endocrine mechanisms (2026-09-19) · lines 64–70

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Recombinant enzyme and cell-extract experiments; construct species not resolved in accessed abstract. · source_derived_draft · unverified_draft

## d-aspartate-srr-mg-atp Mineral and energy cofactors affect this enzyme, but the measured substrate was serine. Mg2+ and ATP increased recombinant serine-racemase serine racemization and pyruvate production by approximately five- to ten-fold in the study assay. Model: Recombinant enzyme and cell-extract experiments; construct species not resolved in accessed abstract. Limitations: This is a shared-machinery connection, not a demonstrated magnesium effect on D-aspartate flux. Evidence access: Primary abstract Cofactors of serine racemase that physiologically stimulate the synthesis of the N-methyl-D-aspartate (NMDA) receptor coagonist D-serine. · 2002 · https://pubmed.ncbi.nlm.nih.gov/12393813/ · DOI 10.1073/pnas.222421299

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary abstract and primary figure descriptions

experimental_model

Human lung-cancer cell gene editing, metabolite ratios and carbon tracing.

limitations

A ratio is a redox proxy, and no dietary serine/aspartate deficiency threshold was measured.

nutrient_topic

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

plain_language

Redox handling connects aspartate machinery to synthesis of another amino acid.

primary_references

Aspartate availability drives differential engagement of the malate-aspartate shuttle. · 2026 · https://pubmed.ncbi.nlm.nih.gov/41759528/ · DOI 10.1016/j.molcel.2026.02.004

trigger_kind

machinery_impairment Imported condition classification; unverified.

L-Aspartate: redox transfer, nitrogen partitioning and cross-nutrient mechanisms (2026-09-19) · lines 234–240

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human lung-cancer cell gene editing, metabolite ratios and carbon tracing. · source_derived_draft · unverified_draft

## l-aspartate-shuttle-serine-link Redox handling connects aspartate machinery to synthesis of another amino acid. Loss of shuttle components reduced pyruvate/lactate ratios and glucose-derived serine synthesis in the studied human A549 models. Model: Human lung-cancer cell gene editing, metabolite ratios and carbon tracing. Limitations: A ratio is a redox proxy, and no dietary serine/aspartate deficiency threshold was measured. Evidence access: Primary abstract and primary figure descriptions Aspartate availability drives differential engagement of the malate-aspartate shuttle. · 2026 · https://pubmed.ncbi.nlm.nih.gov/41759528/ · DOI 10.1016/j.molcel.2026.02.004

availability_state

machinery_impairment Imported condition classification; unverified.

experimental_model

CRISPR and isotope tracing

exposure

Assay conditions described in the linked primary study.

limitations

Compensation depends on nutrient availability.

nutrient_topic

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

organism

Homo sapiens

plain_language

Cells can reroute carbon production after losing the mitochondrial pathway.

primary_references

[ducker-2016] Reversal of Cytosolic One-Carbon Flux Compensates for Loss of the Mitochondrial Folate Pathway (2016). https://pubmed.ncbi.nlm.nih.gov/27211901/ DOI: 10.1016/j.cmet.2016.04.016

tissue_or_cell_type

HEK293T cells

trigger_kind

machinery_impairment Imported condition classification; unverified.

Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 899–909

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

### mitochondrial-loss-cytosolic-reversal MTHFD2 deletion depleted formyl-folate availability and activated cytosolic serine-derived one-carbon production. Condition category: machinery_impairment nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: Cells can reroute carbon production after losing the mitochondrial pathway. organism: Homo sapiens tissue_or_cell_type: HEK293T cells experimental_model: CRISPR and isotope tracing limitations: Compensation depends on nutrient availability. exposure: Assay conditions described in the linked primary study. [ducker-2016] Reversal of Cytosolic One-Carbon Flux Compensates for Loss of the Mitochondrial Folate Pathway (2016). https://pubmed.ncbi.nlm.nih.gov/27211901/ DOI: 10.1016/j.cmet.2016.04.016