Component

AMP

Free nucleotide product; distinguish from AMP covalently attached to a protein.

16 recorded relationships. Experimental role, claim status and evidence remain attached to each record.

Read recorded mechanisms Open recursive mind map

How nutrients influence it

Every nutrient with a recorded effect on this component, credited to the nutrient that acted rather than the chapter that recorded it. Open a nutrient to see the findings and the conditions they were measured under.

How nutrients reach it in more than one step

Chains of two or more recorded steps that end here, grouped by the nutrient they start from. Each step is a separate finding, so a chain is a route a mechanism could take, not proof that it does.

Tracing routes…

What it does

Every recorded relationship this component is part of, grouped by its role. Plain wording comes first; the technical statement follows.

Recorded relationships

Where it participates (unsigned role)

  1. Recombinant human TPK1 catalyzes thiamine diphosphorylation with ATP and Mg2+.

    Thiamine (vitamin B1) → Thiamine diphosphate source_derived_draftungraded
    Experimental context and source evidence
    cross_nutrient
    Magnesium availability supports vitamin B1 activation or cofactor use in the specified preparation; this does not establish a dietary threshold or universal treatment failure.
    experimental_model
    Purified His-tagged recombinant human TPK1, steady-state kinetics and mutations.
    limitations
    Assay chemistry; no clinical response measured.
    nutrient_topic
    Magnesium research collection; topical membership is not evidence of a direct dietary effect. · Magnesium
    organism
    Homo sapiens
    plain_language
    The enzyme uses ATP to convert vitamin B1 into its diphosphate cofactor.
    primary_references
    [onozuka-2003-tpk1] Steady-state kinetics and mutational studies of recombinant human thiamin pyrophosphokinase (2003). https://pubmed.ncbi.nlm.nih.gov/12953792/ DOI: 10.3177/jnsv.49.156
    tissue_or_cell_type
    Purified recombinant enzyme

    Magnesium: cross-nutrient mechanisms and deficiency (2026-09-17) · lines 481–491

    AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purified His-tagged recombinant human TPK1, steady-state kinetics and mutations. · source_derived_draft · unverified_draft

    ### mg-tpk1-thiamine-to-thdp Recombinant human TPK1 catalyzes thiamine diphosphorylation with ATP and Mg2+. Condition category: normal nutrient_topic: Magnesium research collection; topical membership is not evidence of a direct dietary effect. plain_language: The enzyme uses ATP to convert vitamin B1 into its diphosphate cofactor. organism: Homo sapiens tissue_or_cell_type: Purified recombinant enzyme experimental_model: Purified His-tagged recombinant human TPK1, steady-state kinetics and mutations. limitations: Assay chemistry; no clinical response measured. cross_nutrient: Magnesium availability supports vitamin B1 activation or cofactor use in the specified preparation; this does not establish a dietary threshold or universal treatment failure. [onozuka-2003-tpk1] Steady-state kinetics and mutational studies of recombinant human thiamin pyrophosphokinase (2003). https://pubmed.ncbi.nlm.nih.gov/12953792/ DOI: 10.3177/jnsv.49.156
    Complete structured claim and evidence

  2. Acute alanine treatment increased AMPK and downstream ACC phosphorylation in rat H4IIE liver cells over the tested 0.25–10 mM range.

    L-Alanine → Rat AMP-activated protein kinase complex source_derived_draftungraded
    Experimental context and source evidence
    evidence_access
    Primary full text
    experimental_model
    Rat H4IIE cells; acute millimolar alanine exposure.
    limitations
    Phosphorylation in culture is not proof of clinical benefit or a universal response to dietary alanine.
    nutrient_topic
    L-Alanine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Alanine
    plain_language
    Alanine metabolism can generate an energy-stress signal in this experimental setting.
    primary_references
    l-Alanine activates hepatic AMP-activated protein kinase and modulates systemic glucose metabolism. · 2018 · https://pubmed.ncbi.nlm.nih.gov/30190193/ · DOI 10.1016/j.molmet.2018.08.002

    L-Alanine: carbon, nitrogen, protein synthesis and cross-nutrient mechanisms (2026-09-19) · lines 248–254

    AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Rat H4IIE cells; acute millimolar alanine exposure. · source_derived_draft · unverified_draft

    ## alanine-ampk-acute Alanine metabolism can generate an energy-stress signal in this experimental setting. Acute alanine treatment increased AMPK and downstream ACC phosphorylation in rat H4IIE liver cells over the tested 0.25–10 mM range. Model: Rat H4IIE cells; acute millimolar alanine exposure. Limitations: Phosphorylation in culture is not proof of clinical benefit or a universal response to dietary alanine. Evidence access: Primary full text l-Alanine activates hepatic AMP-activated protein kinase and modulates systemic glucose metabolism. · 2018 · https://pubmed.ncbi.nlm.nih.gov/30190193/ · DOI 10.1016/j.molmet.2018.08.002
    Complete structured claim and evidence

  3. Ammonium chloride exposure reproduced increases in AMP/ATP and AMPK/ACC phosphorylation, and pyruvate attenuated these responses.

    Ammonium chloride → Rat AMP-activated protein kinase complex source_derived_draftungraded
    Experimental context and source evidence
    evidence_access
    Primary full text
    experimental_model
    Rat H4IIE experiments; 2–5 mM ammonium chloride comparison.
    limitations
    Mimicry is not proof that ammonia is the sole mediator of alanine effects or that urea-cycle ATP use accounts for them.
    nutrient_topic
    L-Alanine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Alanine
    plain_language
    A nitrogen-handling byproduct may contribute to the energy signal.
    primary_references
    l-Alanine activates hepatic AMP-activated protein kinase and modulates systemic glucose metabolism. · 2018 · https://pubmed.ncbi.nlm.nih.gov/30190193/ · DOI 10.1016/j.molmet.2018.08.002

    L-Alanine: carbon, nitrogen, protein synthesis and cross-nutrient mechanisms (2026-09-19) · lines 280–286

    AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Rat H4IIE experiments; 2–5 mM ammonium chloride comparison. · source_derived_draft · unverified_draft

    ## alanine-ampk-ammonia A nitrogen-handling byproduct may contribute to the energy signal. Ammonium chloride exposure reproduced increases in AMP/ATP and AMPK/ACC phosphorylation, and pyruvate attenuated these responses. Model: Rat H4IIE experiments; 2–5 mM ammonium chloride comparison. Limitations: Mimicry is not proof that ammonia is the sole mediator of alanine effects or that urea-cycle ATP use accounts for them. Evidence access: Primary full text l-Alanine activates hepatic AMP-activated protein kinase and modulates systemic glucose metabolism. · 2018 · https://pubmed.ncbi.nlm.nih.gov/30190193/ · DOI 10.1016/j.molmet.2018.08.002
    Complete structured claim and evidence

  4. Alanine increased the AMP/ATP ratio and glutamate while decreasing 2-oxoglutarate and other TCA intermediate pools in rat H4IIE cells.

    L-Alanine → AMP/ATP ratio in rat H4IIE cells source_derived_draftungraded
    Experimental context and source evidence
    evidence_access
    Primary full text
    experimental_model
    Acute rat H4IIE metabolomics; AMP/ATP approximately 1.5-fold higher at 15 minutes.
    limitations
    Pool sizes are not flux measurements; increased ATP-consuming urea synthesis was proposed rather than directly proven.
    nutrient_topic
    L-Alanine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Alanine
    plain_language
    Moving amino nitrogen changed the cell’s carbon pools and energy balance.
    primary_references
    l-Alanine activates hepatic AMP-activated protein kinase and modulates systemic glucose metabolism. · 2018 · https://pubmed.ncbi.nlm.nih.gov/30190193/ · DOI 10.1016/j.molmet.2018.08.002

    L-Alanine: carbon, nitrogen, protein synthesis and cross-nutrient mechanisms (2026-09-19) · lines 264–270

    AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Acute rat H4IIE metabolomics; AMP/ATP approximately 1.5-fold higher at 15 minutes. · source_derived_draft · unverified_draft

    ## alanine-ampk-pools Moving amino nitrogen changed the cell’s carbon pools and energy balance. Alanine increased the AMP/ATP ratio and glutamate while decreasing 2-oxoglutarate and other TCA intermediate pools in rat H4IIE cells. Model: Acute rat H4IIE metabolomics; AMP/ATP approximately 1.5-fold higher at 15 minutes. Limitations: Pool sizes are not flux measurements; increased ATP-consuming urea synthesis was proposed rather than directly proven. Evidence access: Primary full text l-Alanine activates hepatic AMP-activated protein kinase and modulates systemic glucose metabolism. · 2018 · https://pubmed.ncbi.nlm.nih.gov/30190193/ · DOI 10.1016/j.molmet.2018.08.002
    Complete structured claim and evidence

  5. ENPP1 converts extracellular ATP into AMP and PPi; ANKH-expressing cells lacking ENPP1 released ATP without the accompanying PPi accumulation.

    ATP → Inorganic pyrophosphate source_derived_draftungraded
    Experimental context and source evidence
    compartment_description
    Extracellular space
    experimental_model
    ENPP1-proficient versus deficient cells
    limitations
    Other ectonucleotidases compete for ATP; PPi is not synonymous with orthophosphate.
    nutrient_topic
    Calcium research collection; topical membership is not evidence of a direct dietary effect. · Calcium
    organism
    Homo sapiens
    plain_language
    An extracellular enzyme converts exported ATP into a mineralization inhibitor.
    primary_references
    [szeri2022] The mineralization regulator ANKH mediates cellular efflux of ATP, not pyrophosphate (2022). https://pmc.ncbi.nlm.nih.gov/articles/PMC9098669/ DOI: 10.1002/jbmr.4528
    tissue_or_cell_type
    HEK293 extracellular medium

    Calcium: mechanism-first literature curation (2026-09-17) · lines 1012–1022

    AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · ENPP1-proficient versus deficient cells · source_derived_draft · unverified_draft

    ### enpp1-atp-to-pyrophosphate ENPP1 converts extracellular ATP into AMP and PPi; ANKH-expressing cells lacking ENPP1 released ATP without the accompanying PPi accumulation. Condition category: normal nutrient_topic: Calcium research collection; topical membership is not evidence of a direct dietary effect. plain_language: An extracellular enzyme converts exported ATP into a mineralization inhibitor. organism: Homo sapiens tissue_or_cell_type: HEK293 extracellular medium experimental_model: ENPP1-proficient versus deficient cells limitations: Other ectonucleotidases compete for ATP; PPi is not synonymous with orthophosphate. compartment_description: Extracellular space [szeri2022] The mineralization regulator ANKH mediates cellular efflux of ATP, not pyrophosphate (2022). https://pmc.ncbi.nlm.nih.gov/articles/PMC9098669/ DOI: 10.1002/jbmr.4528
    Complete structured claim and evidence

  6. Purified mouse TPK1 formed ATP and thiamine from ThDP plus AMP under high-AMP, magnesium-containing conditions.

    Mouse thiamine pyrophosphokinase 1 → ATP source_derived_draftungraded
    Experimental context and source evidence
    cross_nutrient
    Mg dependence remains distinct from physiological net reaction direction.
    evidence-scope
    Recombinant enzyme
    evidence_locator
    Reaction definition and sections 2.2 and 3.3
    evidence_spans
    [{"source_document": "artifacts/thiamine_transport_sources/sambon-2022-tpk1-source-record.json", "source_field": "resultList.result[0].abstractText", "start_char": 0, "end_char": 1689}]
    experimental_model
    Purified recombinant mouse TPK1; forward and reverse reactions.
    limitations
    High AMP/Mg requirements do not establish meaningful reverse flux in humans.
    nutrient_topic
    Thiamine research collection; topical membership is not evidence of a direct dietary effect. · Thiamine (vitamin B1)
    organism
    Mus musculus
    plain_language
    The activation chemistry can run backward experimentally.
    primary_references
    [sambon-2022-tpk1] Product inhibition of mammalian thiamine pyrophosphokinase is an important mechanism for maintaining thiamine diphosphate homeostasis (2022). https://doi.org/10.1016/j.bbagen.2021.130071 DOI: 10.1016/j.bbagen.2021.130071
    tissue_or_cell_type
    Recombinant enzyme

    Thiamine: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 373–386

    AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purified recombinant mouse TPK1; forward and reverse reactions. · source_derived_draft · unverified_draft

    ### b1-mouse-tpk1-reverse-reaction Purified mouse TPK1 formed ATP and thiamine from ThDP plus AMP under high-AMP, magnesium-containing conditions. Condition category: normal nutrient_topic: Thiamine research collection; topical membership is not evidence of a direct dietary effect. plain_language: The activation chemistry can run backward experimentally. organism: Mus musculus tissue_or_cell_type: Recombinant enzyme experimental_model: Purified recombinant mouse TPK1; forward and reverse reactions. limitations: High AMP/Mg requirements do not establish meaningful reverse flux in humans. cross_nutrient: Mg dependence remains distinct from physiological net reaction direction. evidence_spans: [{"source_document": "artifacts/thiamine_transport_sources/sambon-2022-tpk1-source-record.json", "source_field": "resultList.result[0].abstractText", "start_char": 0, "end_char": 1689}] evidence_locator: Reaction definition and sections 2.2 and 3.3 evidence-scope: Recombinant enzyme [sambon-2022-tpk1] Product inhibition of mammalian thiamine pyrophosphokinase is an important mechanism for maintaining thiamine diphosphate homeostasis (2022). https://doi.org/10.1016/j.bbagen.2021.130071 DOI: 10.1016/j.bbagen.2021.130071
    Complete structured claim and evidence

  7. TPK1 activation transfers ATP-derived diphosphoryl to thiamine, yielding ThDP and AMP in a magnesium-dependent reaction.

    ATP → Thiamine (vitamin B1) source_derived_draftungraded
    Experimental context and source evidence
    cross_nutrient
    Mg-dependent ATP chemistry activates B1; it does not imply every later ThDP-binding event consumes ATP.
    curation_note
    Adds explicit phosphate-transfer/AMP-product detail to the existing magnesium collection.
    evidence-scope
    Recombinant enzyme
    evidence_locator
    Abstract
    evidence_spans
    [{"source_document": "artifacts/thiamine_transport_sources/sambon-2022-tpk1-source-record.json", "source_field": "resultList.result[0].abstractText", "start_char": 0, "end_char": 1689}]
    experimental_model
    Purified His-tagged human TPK1; ATP/Mg kinetics and mutagenesis.
    limitations
    Overall chemistry does not resolve substrate-binding order.
    nutrient_topic
    Thiamine research collection; topical membership is not evidence of a direct dietary effect. · Thiamine (vitamin B1)
    organism
    Homo sapiens
    plain_language
    B1 activation uses ATP and releases AMP; it is not an ATP-to-ADP single-phosphate step.
    primary_references
    [onozuka-2003-tpk1] Steady-state kinetics and mutational studies of recombinant human thiamin pyrophosphokinase (2003). https://pubmed.ncbi.nlm.nih.gov/12953792/ DOI: 10.3177/jnsv.49.156 [sambon-2022-tpk1] Product inhibition of mammalian thiamine pyrophosphokinase is an important mechanism for maintaining thiamine diphosphate homeostasis (2022). https://doi.org/10.1016/j.bbagen.2021.130071 DOI: 10.1016/j.bbagen.2021.130071
    reaction
    thiamine + ATP -> thiamine diphosphate + AMP
    related_existing_claim_keys
    ["mg-tpk1-thiamine-to-thdp"]
    tissue_or_cell_type
    Recombinant enzyme

    Thiamine: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 339–356

    AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purified His-tagged human TPK1; ATP/Mg kinetics and mutagenesis. · source_derived_draft · unverified_draft

    ### b1-tpk1-atp-amp-stoichiometry TPK1 activation transfers ATP-derived diphosphoryl to thiamine, yielding ThDP and AMP in a magnesium-dependent reaction. Condition category: normal nutrient_topic: Thiamine research collection; topical membership is not evidence of a direct dietary effect. plain_language: B1 activation uses ATP and releases AMP; it is not an ATP-to-ADP single-phosphate step. organism: Homo sapiens tissue_or_cell_type: Recombinant enzyme experimental_model: Purified His-tagged human TPK1; ATP/Mg kinetics and mutagenesis. limitations: Overall chemistry does not resolve substrate-binding order. cross_nutrient: Mg-dependent ATP chemistry activates B1; it does not imply every later ThDP-binding event consumes ATP. reaction: thiamine + ATP -> thiamine diphosphate + AMP related_existing_claim_keys: ["mg-tpk1-thiamine-to-thdp"] curation_note: Adds explicit phosphate-transfer/AMP-product detail to the existing magnesium collection. evidence_spans: [{"source_document": "artifacts/thiamine_transport_sources/sambon-2022-tpk1-source-record.json", "source_field": "resultList.result[0].abstractText", "start_char": 0, "end_char": 1689}] evidence_locator: Abstract evidence-scope: Recombinant enzyme [onozuka-2003-tpk1] Steady-state kinetics and mutational studies of recombinant human thiamin pyrophosphokinase (2003). https://pubmed.ncbi.nlm.nih.gov/12953792/ DOI: 10.3177/jnsv.49.156 [sambon-2022-tpk1] Product inhibition of mammalian thiamine pyrophosphokinase is an important mechanism for maintaining thiamine diphosphate homeostasis (2022). https://doi.org/10.1016/j.bbagen.2021.130071 DOI: 10.1016/j.bbagen.2021.130071
    Complete structured claim and evidence

  8. Norathyriol increased the cellular AMP-to-ATP ratio in the tested HepG2 model.

    Norathyriol → AMP-to-ATP ratio in human HepG2 cells source_derived_draftungraded
    Experimental context and source evidence
    evidence_span
    {"source_cache": "artifacts/mangiferin-research/29563875.fulltext.txt", "locator": "Primary full-text span; zero-based, end-exclusive Unicode character offsets", "file_sha256": "1a48a1f92d67cd91638969bb1ec3cb9f18cb3cb4e29c7e5f2bacf627dda76415", "start_char": 35775, "end_char": 36269, "text_sha256": "9c428b34591bbbb1e453a4e5e2829b160930ef301d3b39065822f132f5a7dcd9"}
    experimental_model
    KK-Ay mouse liver experiments and mechanistic HepG2 studies
    exposure
    Norathyriol in sodium-oleate lipid-loading model; micromolar range
    limitations
    Phosphorylation and expression are scoped to experiments; no established human fatty-liver therapy or direct SIRT1 ligand claim.
    nutrient_topic
    Mangiferin research collection; topical membership is not evidence of a direct dietary effect. · Mangiferin
    organism
    Homo sapiens for HepG2 experiments; mouse findings separately scoped
    plain_language
    The energy-sensing signal changed alongside AMPK activation.
    primary_references
    [mangiferin-p29563875] Mangiferin Improves Hepatic Lipid Metabolism Mainly Through Its Metabolite-Norathyriol by Modulating SIRT-1/AMPK/SREBP-1c Signaling. (2018). https://pubmed.ncbi.nlm.nih.gov/29563875/ DOI: 10.3389/fphar.2018.00201
    tissue_or_cell_type
    HepG2 cells

    Mangiferin: metabolism, signaling and nutrient connections (2026-09-17) · lines 471–482

    AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · KK-Ay mouse liver experiments and mechanistic HepG2 studies · source_derived_draft · unverified_draft

    ### mangiferin-energy-ratio Norathyriol increased the cellular AMP-to-ATP ratio in the tested HepG2 model. Condition category: normal nutrient_topic: Mangiferin research collection; topical membership is not evidence of a direct dietary effect. plain_language: The energy-sensing signal changed alongside AMPK activation. organism: Homo sapiens for HepG2 experiments; mouse findings separately scoped tissue_or_cell_type: HepG2 cells experimental_model: KK-Ay mouse liver experiments and mechanistic HepG2 studies limitations: Phosphorylation and expression are scoped to experiments; no established human fatty-liver therapy or direct SIRT1 ligand claim. exposure: Norathyriol in sodium-oleate lipid-loading model; micromolar range evidence_span: {"source_cache": "artifacts/mangiferin-research/29563875.fulltext.txt", "locator": "Primary full-text span; zero-based, end-exclusive Unicode character offsets", "file_sha256": "1a48a1f92d67cd91638969bb1ec3cb9f18cb3cb4e29c7e5f2bacf627dda76415", "start_char": 35775, "end_char": 36269, "text_sha256": "9c428b34591bbbb1e453a4e5e2829b160930ef301d3b39065822f132f5a7dcd9"} [mangiferin-p29563875] Mangiferin Improves Hepatic Lipid Metabolism Mainly Through Its Metabolite-Norathyriol by Modulating SIRT-1/AMPK/SREBP-1c Signaling. (2018). https://pubmed.ncbi.nlm.nih.gov/29563875/ DOI: 10.3389/fphar.2018.00201
    Complete structured claim and evidence

  9. Metformin stimulated phosphorylation of Thr-172 on the AMPK alpha subunit in intact cells without affecting phosphorylation by upstream kinases in cell-free assays, and the authors presented evidence that activation was not a consequence of energy-charge depletion via complex I in the two cell types tested.

    Metformin → AMP-activated protein kinase complexes source_derived_draftungraded
    Experimental context and source evidence
    evidence_span
    {"source_cache": "artifacts/metformin-research/12145153.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "3ff2e09e56437d39718ec15046803356b0ab0d6e23c971cf21f4e2f865e263a2", "start_char": 0, "end_char": 1279, "text_sha256": "3ff2e09e56437d39718ec15046803356b0ab0d6e23c971cf21f4e2f865e263a2"}
    experimental_model
    Intact cells and cell-free upstream-kinase assays
    exposure
    Metformin compared with AICA riboside
    limitations
    A negative mechanistic result: the authors state they did not establish the definitive mechanism, only that it differs from AMP mimicry.
    nutrient_topic
    Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. · Metformin
    organism
    Rat hepatocytes and cell lines
    plain_language
    The sensor came on by a route other than a simple fall in the cell’s energy charge.
    primary_references
    [metformin-p12145153] The antidiabetic drug metformin activates the AMP-activated protein kinase cascade via an adenine nucleotide-independent mechanism. (2002). https://pubmed.ncbi.nlm.nih.gov/12145153/ DOI: 10.2337/diabetes.51.8.2420
    tissue_or_cell_type
    Hepatocytes and cultured cells

    Metformin: transport, molecular targets, gut mechanisms and nutrient interactions (2026-09-19) · lines 619–630

    AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Intact cells and cell-free upstream-kinase assays · source_derived_draft · unverified_draft

    ### metformin-nucleotide-independent Metformin stimulated phosphorylation of Thr-172 on the AMPK alpha subunit in intact cells without affecting phosphorylation by upstream kinases in cell-free assays, and the authors presented evidence that activation was not a consequence of energy-charge depletion via complex I in the two cell types tested. Condition category: normal nutrient_topic: Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. plain_language: The sensor came on by a route other than a simple fall in the cell’s energy charge. organism: Rat hepatocytes and cell lines tissue_or_cell_type: Hepatocytes and cultured cells experimental_model: Intact cells and cell-free upstream-kinase assays limitations: A negative mechanistic result: the authors state they did not establish the definitive mechanism, only that it differs from AMP mimicry. exposure: Metformin compared with AICA riboside evidence_span: {"source_cache": "artifacts/metformin-research/12145153.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "3ff2e09e56437d39718ec15046803356b0ab0d6e23c971cf21f4e2f865e263a2", "start_char": 0, "end_char": 1279, "text_sha256": "3ff2e09e56437d39718ec15046803356b0ab0d6e23c971cf21f4e2f865e263a2"} [metformin-p12145153] The antidiabetic drug metformin activates the AMP-activated protein kinase cascade via an adenine nucleotide-independent mechanism. (2002). https://pubmed.ncbi.nlm.nih.gov/12145153/ DOI: 10.2337/diabetes.51.8.2420
    Complete structured claim and evidence

  10. Loss of Oct1 raised the AMP to ATP ratio and activated AMPK, and thiamine deficiency itself enhanced phosphorylation of AMPK and its downstream target acetyl-CoA carboxylase.

    Thiamine (vitamin B1) → AMP-activated protein kinase complexes source_derived_draftungraded
    Experimental context and source evidence
    availability_state
    nutrient_deficiency Imported condition classification; unverified.
    evidence_span
    {"source_cache": "artifacts/metformin-research/24961373.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "77be4a228b3d067ca1e7ba44e8148f5fbda7956a23b42fb8281e9faf451a0e70", "start_char": 0, "end_char": 1270, "text_sha256": "77be4a228b3d067ca1e7ba44e8148f5fbda7956a23b42fb8281e9faf451a0e70"}
    experimental_model
    Oct1-knockout and human OCT1 transgenic mice, metabolomics and isotopic uptake
    exposure
    Metformin and phenformin against thiamine uptake; acute metformin in wild-type mice
    limitations
    Identifies thiamine as an endogenous OCT1 substrate and shows competitive inhibition by metformin. The steatosis phenotype is a mouse phenotype.
    nutrient_topic
    Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. · Metformin
    organism
    Mouse and human transporter
    plain_language
    Short vitamin B1 switches on the same energy sensor the drug does.
    primary_references
    [metformin-p24961373] OCT1 is a high-capacity thiamine transporter that regulates hepatic steatosis and is a target of metformin. (2014). https://pubmed.ncbi.nlm.nih.gov/24961373/ DOI: 10.1073/pnas.1314939111
    tissue_or_cell_type
    Liver and intestine
    trigger_kind
    nutrient_deficiency Imported condition classification; unverified.

    Metformin: transport, molecular targets, gut mechanisms and nutrient interactions (2026-09-19) · lines 1269–1280

    AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Oct1-knockout and human OCT1 transgenic mice, metabolomics and isotopic uptake · source_derived_draft · unverified_draft

    ### metformin-oct1-loss-ampk-thiamine Loss of Oct1 raised the AMP to ATP ratio and activated AMPK, and thiamine deficiency itself enhanced phosphorylation of AMPK and its downstream target acetyl-CoA carboxylase. Condition category: nutrient_deficiency nutrient_topic: Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. plain_language: Short vitamin B1 switches on the same energy sensor the drug does. organism: Mouse and human transporter tissue_or_cell_type: Liver and intestine experimental_model: Oct1-knockout and human OCT1 transgenic mice, metabolomics and isotopic uptake limitations: Identifies thiamine as an endogenous OCT1 substrate and shows competitive inhibition by metformin. The steatosis phenotype is a mouse phenotype. exposure: Metformin and phenformin against thiamine uptake; acute metformin in wild-type mice evidence_span: {"source_cache": "artifacts/metformin-research/24961373.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "77be4a228b3d067ca1e7ba44e8148f5fbda7956a23b42fb8281e9faf451a0e70", "start_char": 0, "end_char": 1270, "text_sha256": "77be4a228b3d067ca1e7ba44e8148f5fbda7956a23b42fb8281e9faf451a0e70"} [metformin-p24961373] OCT1 is a high-capacity thiamine transporter that regulates hepatic steatosis and is a target of metformin. (2014). https://pubmed.ncbi.nlm.nih.gov/24961373/ DOI: 10.1073/pnas.1314939111
    Complete structured claim and evidence

  11. Clinically relevant concentrations of metformin inhibited the lysosomal proton pump v-ATPase, leading to AMPK activation without effects on cellular AMP levels.

    Metformin → Lysosomal vacuolar H+-ATPase (v-ATPase) source_derived_draftungraded
    Experimental context and source evidence
    evidence_span
    {"source_cache": "artifacts/metformin-research/35197629.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "587594a8bbbf0a2baa7066264c0c46b26ded6231287176608885e736bee36983", "start_char": 0, "end_char": 1549, "text_sha256": "587594a8bbbf0a2baa7066264c0c46b26ded6231287176608885e736bee36983"}
    experimental_model
    Photoactive metformin probe, binding studies, knockouts in mice and C. elegans
    exposure
    Clinically relevant low metformin concentrations; PEN2 knockout and ATP6AP1-binding mutants
    limitations
    A direct binding partner at low dose with a micromolar dissociation constant. Lifespan and fat-content endpoints are model endpoints, not clinical outcomes.
    nutrient_topic
    Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. · Metformin
    organism
    Human cells, mouse and C. elegans
    plain_language
    The energy sensor is switched on at the lysosome rather than by a fall in cellular AMP.
    primary_references
    [metformin-p35197629] Low-dose metformin targets the lysosomal AMPK pathway through PEN2. (2022). https://pubmed.ncbi.nlm.nih.gov/35197629/ DOI: 10.1038/s41586-022-04431-8
    tissue_or_cell_type
    Lysosome, liver and intestine

    Metformin: transport, molecular targets, gut mechanisms and nutrient interactions (2026-09-19) · lines 658–669

    AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Photoactive metformin probe, binding studies, knockouts in mice and C. elegans · source_derived_draft · unverified_draft

    ### metformin-vatpase-inhibition Clinically relevant concentrations of metformin inhibited the lysosomal proton pump v-ATPase, leading to AMPK activation without effects on cellular AMP levels. Condition category: normal nutrient_topic: Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. plain_language: The energy sensor is switched on at the lysosome rather than by a fall in cellular AMP. organism: Human cells, mouse and C. elegans tissue_or_cell_type: Lysosome, liver and intestine experimental_model: Photoactive metformin probe, binding studies, knockouts in mice and C. elegans limitations: A direct binding partner at low dose with a micromolar dissociation constant. Lifespan and fat-content endpoints are model endpoints, not clinical outcomes. exposure: Clinically relevant low metformin concentrations; PEN2 knockout and ATP6AP1-binding mutants evidence_span: {"source_cache": "artifacts/metformin-research/35197629.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "587594a8bbbf0a2baa7066264c0c46b26ded6231287176608885e736bee36983", "start_char": 0, "end_char": 1549, "text_sha256": "587594a8bbbf0a2baa7066264c0c46b26ded6231287176608885e736bee36983"} [metformin-p35197629] Low-dose metformin targets the lysosomal AMPK pathway through PEN2. (2022). https://pubmed.ncbi.nlm.nih.gov/35197629/ DOI: 10.1038/s41586-022-04431-8
    Complete structured claim and evidence

  12. After pyrophosphate release, KARS1 transfers activated lysine to the tRNA-Lys 3-prime end, forming lysyl-tRNA and AMP.

    Lysyl-adenylate → Lysyl-tRNA-Lys source_derived_draftungraded
    Experimental context and source evidence
    experimental_model
    Human LysRS-tRNA-Lys3 structural and enzyme assays
    limitations
    This is tRNA charging; subsequent ribosomal peptide-bond formation is a distinct step.
    organism
    Homo sapiens
    plain_language
    Charged tRNA supplies lysine for protein synthesis.
    primary_references
    [devarkar2025] Structural basis for aminoacylation of cellular modified tRNALys3 by human lysyl-tRNA synthetase (2025). https://pubmed.ncbi.nlm.nih.gov/40036503/ DOI: 10.1093/nar/gkaf114
    tissue_or_cell_type
    Cytosolic translation machinery

    L-Lysine: mechanism-first literature curation (2026-09-17) · lines 64–72

    AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human LysRS-tRNA-Lys3 structural and enzyme assays · source_derived_draft · unverified_draft

    ### lysyl-trna-formation After pyrophosphate release, KARS1 transfers activated lysine to the tRNA-Lys 3-prime end, forming lysyl-tRNA and AMP. Plain language: Charged tRNA supplies lysine for protein synthesis. Condition category: normal organism: Homo sapiens tissue_or_cell_type: Cytosolic translation machinery experimental_model: Human LysRS-tRNA-Lys3 structural and enzyme assays limitations: This is tRNA charging; subsequent ribosomal peptide-bond formation is a distinct step. [devarkar2025] Structural basis for aminoacylation of cellular modified tRNALys3 by human lysyl-tRNA synthetase (2025). https://pubmed.ncbi.nlm.nih.gov/40036503/ DOI: 10.1093/nar/gkaf114
    Complete structured claim and evidence

  13. Human ASNS catalyzes ATP-dependent conversion of aspartate and glutamine to asparagine and glutamate through coupled glutaminase and synthetase chemistry.

    Human asparagine synthetase / ASNS → L-Asparagine source_derived_draftungraded
    Experimental context and source evidence
    evidence_access
    Primary full text
    experimental_model
    Human recombinant ASNS structural and biochemical study; reaction characterized in the study framework.
    limitations
    A functioning reaction does not guarantee that adding substrate raises the product in every tissue. Correction record: The 2019 author correction added omitted author affiliations and funding acknowledgements; no mechanism or data change was stated. PMID 31799439; DOI 10.1038/s42003-019-0690-1. https://www.nature.com/articles/s42003-019-0690-1
    nutrient_topic
    L-Aspartate collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Aspartate
    plain_language
    Making asparagine needs both aspartate and a nitrogen donor, plus energy.
    primary_references
    High-resolution crystal structure of human asparagine synthetase enables analysis of inhibitor binding and selectivity. · 2019 · https://pubmed.ncbi.nlm.nih.gov/31552298/ · DOI 10.1038/s42003-019-0587-z

    L-Aspartate: redox transfer, nitrogen partitioning 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 recombinant ASNS structural and biochemical study; reaction characterized in the study framework. · source_derived_draft · unverified_draft

    ## l-aspartate-asns-reaction Making asparagine needs both aspartate and a nitrogen donor, plus energy. Human ASNS catalyzes ATP-dependent conversion of aspartate and glutamine to asparagine and glutamate through coupled glutaminase and synthetase chemistry. Model: Human recombinant ASNS structural and biochemical study; reaction characterized in the study framework. Limitations: A functioning reaction does not guarantee that adding substrate raises the product in every tissue. Correction record: The 2019 author correction added omitted author affiliations and funding acknowledgements; no mechanism or data change was stated. PMID 31799439; DOI 10.1038/s42003-019-0690-1. https://www.nature.com/articles/s42003-019-0690-1 Evidence access: Primary full text High-resolution crystal structure of human asparagine synthetase enables analysis of inhibitor binding and selectivity. · 2019 · https://pubmed.ncbi.nlm.nih.gov/31552298/ · DOI 10.1038/s42003-019-0587-z
    Complete structured claim and evidence

  14. Aspartate supplementation relieved IMP accumulation and restored AMP and SAICAR pools in respiration-impaired 143B cells, while GMP did not similarly recover.

    L-Aspartate → Adenine nucleotide pools in respiration-impaired human 143B cells source_derived_draftungraded
    Experimental context and source evidence
    availability_state
    machinery_impairment Imported condition classification; unverified.
    evidence_access
    Primary full text
    experimental_model
    Human 143B cytochrome-b-mutant cells; metabolomics after high extracellular aspartate.
    limitations
    The GMP branch also depends on redox chemistry; high culture supplementation does not establish oral delivery.
    nutrient_topic
    L-Aspartate collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Aspartate
    plain_language
    Restoring one substrate repaired some nucleotide steps without repairing all of them.
    primary_references
    Supporting Aspartate Biosynthesis Is an Essential Function of Respiration in Proliferating Cells. · 2015 · https://pubmed.ncbi.nlm.nih.gov/26232225/ · DOI 10.1016/j.cell.2015.07.017
    trigger_kind
    machinery_impairment Imported condition classification; unverified.

    L-Aspartate: redox transfer, nitrogen partitioning and cross-nutrient mechanisms (2026-09-19) · lines 66–72

    AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human 143B cytochrome-b-mutant cells; metabolomics after high extracellular aspartate. · source_derived_draft · unverified_draft

    ## l-aspartate-purine-rescue Restoring one substrate repaired some nucleotide steps without repairing all of them. Aspartate supplementation relieved IMP accumulation and restored AMP and SAICAR pools in respiration-impaired 143B cells, while GMP did not similarly recover. Model: Human 143B cytochrome-b-mutant cells; metabolomics after high extracellular aspartate. Limitations: The GMP branch also depends on redox chemistry; high culture supplementation does not establish oral delivery. Evidence access: Primary full text Supporting Aspartate Biosynthesis Is an Essential Function of Respiration in Proliferating Cells. · 2015 · https://pubmed.ncbi.nlm.nih.gov/26232225/ · DOI 10.1016/j.cell.2015.07.017
    Complete structured claim and evidence

  15. Recombinant human PPCS ligated L-cysteine to 4′-phosphopantothenate in a nucleotide-dependent reaction forming 4′-phosphopantothenoylcysteine.

    Phosphopantothenoylcysteine synthetase / PPCS → 4-Phosphopantothenate source_derived_draftungraded
    Experimental context and source evidence
    cross_nutrient
    true
    experimental_model
    Recombinant human PPCS, PPCDC and COASY expressed in Escherichia coli; coupled enzyme assays and HPLC reconstitution
    exposure
    Coupled PPCS assay: 1.5 mM phosphopantothenate, 5 mM cysteine and 1 mM ATP or CTP; 2 mM MgCl2, pH 8.0, 37°C.
    limitations
    Human enzyme expressed in E. coli; assay substrate supply is not evidence that oral cysteine raises human CoA or that low blood cysteine gates B5 repletion.
    nutrient_topic
    Pantothenic acid (vitamin B5) research collection; topical membership is not evidence of a direct dietary effect. · Pantothenate (vitamin B5)
    organism
    Homo sapiens
    plain_language
    Cysteine supplies the sulfur-containing portion of the developing CoA molecule.
    primary_references
    [b5-bio-daugherty2002] Complete reconstitution of the human coenzyme A biosynthetic pathway via comparative genomics. (2002). https://pubmed.ncbi.nlm.nih.gov/11923312/ DOI: 10.1074/jbc.m201708200
    tissue_or_cell_type
    Purified recombinant protein; no intact tissue

    Pantothenic acid (vitamin B5): coenzyme A, deficiency and nutrient interactions (2026-09-17) · lines 522–533

    AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Recombinant human PPCS, PPCDC and COASY expressed in Escherichia coli; coupled enzyme assays and HPLC reconstitution · source_derived_draft · unverified_draft

    ### b5-bio-ppcs-ligation Recombinant human PPCS ligated L-cysteine to 4′-phosphopantothenate in a nucleotide-dependent reaction forming 4′-phosphopantothenoylcysteine. Condition category: normal nutrient_topic: Pantothenic acid (vitamin B5) research collection; topical membership is not evidence of a direct dietary effect. plain_language: Cysteine supplies the sulfur-containing portion of the developing CoA molecule. organism: Homo sapiens tissue_or_cell_type: Purified recombinant protein; no intact tissue experimental_model: Recombinant human PPCS, PPCDC and COASY expressed in Escherichia coli; coupled enzyme assays and HPLC reconstitution limitations: Human enzyme expressed in E. coli; assay substrate supply is not evidence that oral cysteine raises human CoA or that low blood cysteine gates B5 repletion. exposure: Coupled PPCS assay: 1.5 mM phosphopantothenate, 5 mM cysteine and 1 mM ATP or CTP; 2 mM MgCl2, pH 8.0, 37°C. cross_nutrient: true [b5-bio-daugherty2002] Complete reconstitution of the human coenzyme A biosynthetic pathway via comparative genomics. (2002). https://pubmed.ncbi.nlm.nih.gov/11923312/ DOI: 10.1074/jbc.m201708200
    Complete structured claim and evidence

  16. SELENOO catalyzes NAD+ hydrolysis to NMN and AMP.

    SELENOO → NAD+ source_derived_draftliterature_reviewed:direct_experimental
    Experimental context and source evidence
    cell_type
    experimental cells
    experimental_model
    Biochemical and cellular assays
    limitations
    Recent 2026 finding; no dietary-dose inference.
    organism
    mammalian

    Selenium: literature corrections and mechanism additions · lines 438–448

    Metabolic Ledger literature curation, 17 September 2026; primary papers linked individually · supports · Biochemical and cellular assays · secondary_verified · secondary_verified

    ## selenoo-hydrolyzes-nad SELENOO can split NAD into two smaller molecules. SELENOO catalyzes NAD+ hydrolysis to NMN and AMP. Organism: mammalian Cell type: experimental cells Experimental model: Biochemical and cellular assays Limitations: Recent 2026 finding; no dietary-dose inference. Primary reference: [NAD+ hydrolysis catalyzed by SelO is required for mitochondrial homeostasis](https://pubmed.ncbi.nlm.nih.gov/41806834/)
    Complete structured claim and evidence

In the sources

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    This is a research prototype built from draft material. It is not medical advice, and its statements still await verification against the original studies.

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