BRS2-1-3 - SAMe Synthesis
(Producing the Cell's Methyl-Donor Pool)
1. Mission & Overview
Mission
Maintain methionine adenosyltransferase capacity to convert methionine and ATP into SAMe, sustaining the methyl-donor pool used by downstream methyltransferases.
Intervention Dominance: Diet-Supported
-
Methionine
-
Magnesium
-
Potassium
- ATP
- One-carbon methyl-donor pool (folate, betaine, choline)
Individual KC inputs
- Vitamin B9 (folate)
- Betaine
- Choline
Overview
Methionine adenosyltransferase forms S-adenosylmethionine from methionine and ATP. [1] Magnesium and potassium ions coordinate that ATP-dependent catalysis. [1] [2] This reaction supplies the methyl donor used by many later enzymes. [1] Upstream methionine regeneration and later methyl-transfer reactions remain separate processes. Circulating SAMe and the SAM:SAH ratio describe pool balance rather than synthesis speed. [3]
- Benefits: Forming SAMe provides the common methyl donor used by many different enzymes. [4] Those later uses include DNA methylation, membrane-phospholipid formation, and neurotransmitter metabolism.
- Implementation Notes: Methionine and dietary protein are the provision routes. [1] Magnesium and potassium ions take part in the catalysis and are not separate dosing targets. [1] [2] These reaction requirements do not set an intake for raising SAMe synthesis. [1] [3]
2. Primary Biological Effects
↑ MAT-dependent SAMe formation
↑ availability of the SAMe methyl-donor pool
→ permissive support for downstream methyl-transfer reactions
3. Intervention Levers
No PM-specific optimisation protocol is currently selected.
No PM-specific lifestyle protocol is currently selected.
4. Mechanistic Basis + Scientific Findings (SFs 3)
Summary
SAMe production is the point at which methionine and intracellular ATP become a usable methyl donor. The defining event is MAT catalysis; upstream regeneration of methionine and downstream consumption of SAMe determine context but are not part of the synthesis reaction itself.
SF1 — Biochemical provenance: MAT reaction
MAT catalyses an ATP-dependent reaction in which methionine's sulfur attacks ATP's adenosyl carbon to form SAMe; phosphate products are subsequently released. Human MAT2A studies support conflicting ATP-first and rapid-equilibrium random substrate-binding models; no settled universal order is asserted. See SF1 — Biochemical provenance: MAT reaction. Human MATα2 structures capture catalytic states and active-site ion coordination [2].
Supporting evidence: SF1 — Biochemical provenance: MAT reaction.
(Direct requirements and capacity)
Methionine and ATP are reaction substrates. Magnesium and potassium ions participate in active-site phosphate coordination under biochemical and structural conditions [1, 2]. These are biochemical requirements, not evidence that ordinary dietary magnesium, potassium or methionine intake is rate-limiting. MAT isoform abundance, enzyme stability, substrate availability and feedback all contribute to cellular capacity; the reviewed evidence does not establish a simple human basal-versus-reserve dietary threshold.
SF5 — MAT2B and MAT2A stability
MAT2B association can preserve MAT2A protein or catalytic stability in purified-human-enzyme and mammalian-cell experiments. This supports a stability contribution to enzyme regulation, not an exclusive explanation of MAT2B action or a demonstrated increase in human SAMe synthesis flux. Bailey et al. (2021) [1]; 10.1038/s41419-024-07093-8 [11]; 10.1107/S2052252526005075 [12]; 10.1021/acs.biochem.0c00998 [13]
Supporting evidence: SF5 — MAT2B and MAT2A stability.
(Pool state is not synthesis flux)
SAM concentration reflects formation and consumption. The SAM:SAH ratio additionally incorporates SAH production and clearance and is commonly used as a methylation-potential index, not a direct measure of MAT flux. Accurate interpretation also depends on matrix and sample handling because SAM is unstable [3].
(Boundaries of the mechanism)
This PM governs methionine → SAMe formation through MAT. Folate/B12-dependent remethylation belongs to BRS2-FM1-PM1; betaine/BHMT remethylation to BRS2-FM1-PM2; integrated methionine-cycle throughput to BRS2-FM1-PM4; and transsulfuration to BRS2-FM2-PM5. PEMT, DNA, neurotransmitter and other methyl-transfer reactions are downstream consumers, not SAMe synthesis.
SF4 — Biochemical provenance: methionine regeneration
Within BRS2(FM1) — Methylation Cycle Efficiency, PM1 and PM2 regenerate methionine, PM3 converts it to SAMe, and PM4 represents integrated cycle flux. BRS2(KC2) — Methionine & Transsulfuration Substrate Pool supplies substrate context without proving dietary control of PM3.
Supporting evidence: SF4 — Biochemical provenance: methionine regeneration.
4.1 Scientific Findings (3)
Summary
Human MAT structural and kinetic studies identify reaction participants, while kinetic models disagree about substrate-binding order. [1] [2] These studies directly establish enzyme mechanism and biochemical requirements. They do not test ordinary dietary modulation, human in-vivo synthesis flux or downstream methylation outcomes, so those effects remain beyond the evidence summarised here.
Biochemical provenance · [C1] Rhea · [C2] Reactome · [C3] UniProt · No numerical research-synthesis score · Evidence & Audit
MAT-dependent SAMe synthesis directly requires methionine and ATP and uses active-site magnesium and potassium ions to support ATP-dependent catalysis.
What this means
This establishes the biochemical reaction and its direct requirements. It does not establish that increasing dietary methionine, magnesium or potassium increases SAMe synthesis in adequately nourished humans; ATP is an intracellular biochemical substrate, not a dietary lever.
Evidence confidence: Biochemical provenance · [C1] Rhea · [C2] Reactome · [C3] UniProt · No numerical research-synthesis score · Evidence & Audit
Finding ID: PM3-F1
Finding Statement: MAT-dependent SAMe synthesis directly requires methionine and ATP and uses active-site magnesium and potassium ions to support ATP-dependent catalysis.
Synthesised Evidence Confidence: Biochemical provenance · [C1] Rhea · [C2] Reactome · [C3] UniProt · No numerical research-synthesis score · Evidence & Audit
Synthesis: The MAT reaction and catalytic participants have curated provenance. Human MAT2A studies support conflicting ATP-first and rapid-equilibrium random substrate-binding models; no settled universal order is asserted. MAT2B stability is assessed separately in proposed F5.
Synthesis Limitations: The primary evidence uses purified recombinant protein and crystallised human enzyme rather than intact human physiology. Active-site ion requirements do not show that physiological magnesium or potassium availability ordinarily limits MAT activity. The studies do not establish a methionine intake-response relationship, a clinically meaningful reserve-capacity threshold, or a phenome outcome.
Evidence Considered:
- Study
- Purified recombinant human MAT2A steady-state kinetics, product/dead-end inhibition and isothermal titration calorimetry, with and without MAT2B.
- Population
- Purified human MAT2A/MAT2B proteins; no cells, animals or human participants.
- Result
- ATP bound before methionine; SAM was released before phosphate and pyrophosphate. MAT2B bound tightly and stabilised low-concentration MAT2A but did not significantly change the tested kinetic parameters.
- Effect / Magnitude
- ATP Kd 80 ± 30 μM and Km 50 ± 10 μM; MAT2B Kd 6 ± 1 nM. No significant catalytic-parameter change under saturating MAT2B conditions.
- Evidence Summary
- Direct human-enzyme evidence for the ordered MAT2A reaction and distinction between catalytic activity and MAT2B-mediated stability.
- Limitations
- In-vitro purified-enzyme conditions do not establish in-vivo flux limitation, dietary responsiveness, tissue-specific regulation or phenome effects.
- Evidence Source
- Bounded external search
- Reference
- [1]
- Study
- X-ray crystallography of human MATα2 with methionine, ATP analogues, SAMe, adenosine and phosphate-state ligands.
- Population
- Purified crystallised human MATα2 protein; no cells, animals or human participants.
- Result
- Structures captured methionine repositioning toward ATP C5′, SAMe/product states and phosphate-group coordination by magnesium and potassium ions.
- Effect / Magnitude
- Structures ranged from 1.1 Å to 2.34 Å resolution; no physiological effect size applies.
- Evidence Summary
- Direct structural support for the reaction chemistry and catalytic-ion requirement of human MAT.
- Limitations
- Static ligand-bound structures establish catalytic geometry, not physiological nutrient limitation, in-vivo reaction rate, dietary dose response or clinical outcome.
- Evidence Source
- Bounded external search
- Reference
- [2]
Connected / Supportive Evidence:
- Chiang et al. (1996) [4] — MechanisticWhy relevant: Foundational review establishes SAMe as a major methyl donor and places MAT synthesis upstream of transmethylation.Why excluded from the primary synthesis: It is a broad methylation review and does not independently quantify human MAT kinetics, active-site ion requirements or dietary control of synthesis flux.
- Corrillero Bravo et al. (2022) [3] — Human MechanisticWhy relevant: Measured circulating SAM, SAH and SAM:SAH after contrasting four-week dietary patterns in healthy adults.Why excluded from the primary synthesis: The biomarkers do not isolate MAT synthesis flux; group trajectories were similar, so the study does not establish a dietary lever for PM3.
Informs: Cognitive Clarity; Emotional Regulation
Mechanistic explanation: Biochemical provenance: MAT reaction
Biochemical provenance · [C4] UniProt · [C5] UniProt · [C6] Reactome · No numerical research-synthesis score · Evidence & Audit
Folate and betaine remethylation regenerate methionine upstream of MAT-dependent SAMe formation; choline can contribute through betaine.
What this means
This establishes connected precursor provision. It does not make folate, betaine or choline MAT reactants, demonstrate that more intake raises synthesis, or resolve a donor-inadequacy constraint on MAT capacity.
Evidence confidence: Biochemical provenance · [C4] UniProt · [C5] UniProt · [C6] Reactome · No numerical research-synthesis score · Evidence & Audit
Finding ID: PM3-F4
Finding Statement: Folate and betaine remethylation regenerate methionine upstream of MAT-dependent SAMe formation; choline can contribute through betaine.
Synthesised Evidence Confidence: Biochemical provenance · [C4] UniProt · [C5] UniProt · [C6] Reactome · No numerical research-synthesis score · Evidence & Audit
Synthesis: Existing reviewed PM1-F1, PM2-F1/PM2-F2 and PM3-F1 establish the successive reaction identities. Folate provides 5-methyltetrahydrofolate for B12-dependent methionine synthase, while betaine supplies the alternative BHMT reaction, predominantly in liver and kidney. Choline oxidation can supply betaine. The regenerated methionine is available to the MAT reaction. Evidence supports the route, without requiring each donor to act directly on MAT.
Synthesis Limitations: Tissue expression, alternative methionine supply and pathway compensation limit generalisation. SAMe and SAM:SAH are pool-state measurements rather than isolated synthesis rates. No established limiting effect on MAT capacity or nutrient-replete intake benefit is claimed.
Evidence Considered:
- Froese et al. (2019) [7] — Mechanistic — Establishes folate/B12 remethylation and placement before MAT synthesis; reviewed on PM1-F1.
- Obeid (2013) [8] — Mechanistic — Establishes betaine donation and choline provision in connected remethylation; reviewed on PM2-F1/F2.
- Bailey et al. (2021) [1] — Mechanistic — Establishes methionine and ATP use in human MAT2A; reviewed on PM3-F1.
- Evans et al. (2002) [9] — Cellular / Molecular — Human BHMT reaction identity; supports betaine-to-methionine provision, not dietary MAT responsiveness.
- Salvi and Gadda (2013) [10] — Cellular / Molecular — Choline oxidation through betaine aldehyde to betaine; supports route identity, not MAT flux.
Evidence Dependency:
- Bailey et al. (2021) is reused from PM3-F1 to identify MAT substrate use; it is not independent supply-chain or dietary-response evidence.
Mechanistic explanation: Biochemical provenance: methionine regeneration
· Provisionally assessed · Evidence & Audit
MAT2B association can preserve MAT2A protein or catalytic stability in purified-human-enzyme and mammalian-cell experiments. This supports a stability contribution to enzyme regulation, not an exclusive explanation of MAT2B action or a demonstrated increase in human SAMe synthesis flux.
Evidence confidence: · Provisionally assessed · Evidence & Audit
Finding ID: PM3-F5
Finding Statement: MAT2B association can preserve MAT2A protein or catalytic stability in purified-human-enzyme and mammalian-cell experiments. This supports a stability contribution to enzyme regulation, not an exclusive explanation of MAT2B action or a demonstrated increase in human SAMe synthesis flux.
Synthesised Evidence Confidence: · Provisionally assessed · Evidence & Audit
Synthesis: Purified-enzyme activity decay and mammalian-cell perturbation/rescue support a stability contribution, with non-identical endpoints. Additional allosteric/catalytic regulation remains possible.
Synthesis Limitations: Partial cross-model corroboration does not quantify MAT2B-dependent stability or SAMe flux in the human brain. Does not establish that stability is the only MAT2B mechanism: allosteric/catalytic interpretations remain relevant. No dietary methionine, folate, betaine, choline or ADHD intervention effect was assessed.
Evidence Considered:
- Study
- Supporting experimental stability evidence
- Population
- Purified human enzyme, mammalian cellular or structural experiments as specified in the source appraisal; no dietary human intervention.
- Result
- Purified human MAT2A lost activity during substrate-free incubation at 37 C; MAT2B preserved activity. Coupled phosphate and direct LC-MS assays distinguish stability from steady-state kinetic effects. Activity half-life about 2.3 minutes without MAT2B; activity retained over the 120-minute experiment with MAT2B. Technical repeats do not constitute independent replication.
- Effect / Magnitude
- Purified human MAT2A lost activity during substrate-free incubation at 37 C; MAT2B preserved activity. Coupled phosphate and direct LC-MS assays distinguish stability from steady-state kinetic effects. Activity half-life about 2.3 minutes without MAT2B; activity retained over the 120-minute experiment with MAT2B. Technical repeats do not constitute independent replication.
- Evidence Summary
- Purified human MAT2A lost activity during substrate-free incubation at 37 C; MAT2B preserved activity. Coupled phosphate and direct LC-MS assays distinguish stability from steady-state kinetic effects. Activity half-life about 2.3 minutes without MAT2B; activity retained over the 120-minute experiment with MAT2B. Technical repeats do not constitute independent replication.
- Limitations
- Partial cross-model corroboration does not quantify MAT2B-dependent stability or SAMe flux in the human brain. Does not establish that stability is the only MAT2B mechanism: allosteric/catalytic interpretations remain relevant. No dietary methionine, folate, betaine, choline or ADHD intervention effect was assessed. Scite full text; enzyme-assay Methods, inhibition, binding and stability Results appraised
- Evidence Source
- Bounded external search
- Reference
- [1]
- Study
- Independent partial corroboration of protein stability
- Population
- Purified human enzyme, mammalian cellular or structural experiments as specified in the source appraisal; no dietary human intervention.
- Result
- Separate research group: depletion, knockout and wild-type versus binding-domain-mutant rescue support MAT2B-dependent MAT2A protein stability in mammalian cell models. Protein abundance/chase differs from purified-enzyme activity decay. Mostly representative blots with two or three repeats; no pooled half-life or universal flux effect is claimed. Later tumour/diet experiments do not establish a nutritional PM recommendation.
- Effect / Magnitude
- Separate research group: depletion, knockout and wild-type versus binding-domain-mutant rescue support MAT2B-dependent MAT2A protein stability in mammalian cell models. Protein abundance/chase differs from purified-enzyme activity decay. Mostly representative blots with two or three repeats; no pooled half-life or universal flux effect is claimed. Later tumour/diet experiments do not establish a nutritional PM recommendation.
- Evidence Summary
- Separate research group: depletion, knockout and wild-type versus binding-domain-mutant rescue support MAT2B-dependent MAT2A protein stability in mammalian cell models. Protein abundance/chase differs from purified-enzyme activity decay. Mostly representative blots with two or three repeats; no pooled half-life or universal flux effect is claimed. Later tumour/diet experiments do not establish a nutritional PM recommendation.
- Limitations
- Partial cross-model corroboration does not quantify MAT2B-dependent stability or SAMe flux in the human brain. Does not establish that stability is the only MAT2B mechanism: allosteric/catalytic interpretations remain relevant. No dietary methionine, folate, betaine, choline or ADHD intervention effect was assessed. Scite full text; cell perturbation/rescue Results and cycloheximide-chase Methods appraised
- Evidence Source
- Bounded external search
- Reference
- [11]
- Study
- Contextual structural/allosteric interpretation; challenges stability-only explanations
- Population
- Purified human enzyme, mammalian cellular or structural experiments as specified in the source appraisal; no dietary human intervention.
- Result
- CryoEM conformers suggest additional allosteric regulation. Catalytic-activity arguments partly reuse earlier experiments; this is not independent replication of the stability endpoint. Does not refute a stability contribution or establish that all MAT2B effects are stability alone.
- Effect / Magnitude
- CryoEM conformers suggest additional allosteric regulation. Catalytic-activity arguments partly reuse earlier experiments; this is not independent replication of the stability endpoint. Does not refute a stability contribution or establish that all MAT2B effects are stability alone.
- Evidence Summary
- CryoEM conformers suggest additional allosteric regulation. Catalytic-activity arguments partly reuse earlier experiments; this is not independent replication of the stability endpoint. Does not refute a stability contribution or establish that all MAT2B effects are stability alone.
- Limitations
- Partial cross-model corroboration does not quantify MAT2B-dependent stability or SAMe flux in the human brain. Does not establish that stability is the only MAT2B mechanism: allosteric/catalytic interpretations remain relevant. No dietary methionine, folate, betaine, choline or ADHD intervention effect was assessed. Scite full-text conformational Results, Discussion and construct Methods appraised
- Evidence Source
- Bounded external search
- Reference
- [12]
- Study
- Contradictory substrate-order model; contextual to stability
- Population
- Purified human enzyme, mammalian cellular or structural experiments as specified in the source appraisal; no dietary human intervention.
- Result
- Steady-state, stopped-flow and isotope-exchange evidence supports rapid-equilibrium random substrate binding, conflicting with Bailey's ATP-first model. Retained as a distinct unresolved kinetic issue, not evidence against MAT2B-mediated stability.
- Effect / Magnitude
- Steady-state, stopped-flow and isotope-exchange evidence supports rapid-equilibrium random substrate binding, conflicting with Bailey's ATP-first model. Retained as a distinct unresolved kinetic issue, not evidence against MAT2B-mediated stability.
- Evidence Summary
- Steady-state, stopped-flow and isotope-exchange evidence supports rapid-equilibrium random substrate binding, conflicting with Bailey's ATP-first model. Retained as a distinct unresolved kinetic issue, not evidence against MAT2B-mediated stability.
- Limitations
- Partial cross-model corroboration does not quantify MAT2B-dependent stability or SAMe flux in the human brain. Does not establish that stability is the only MAT2B mechanism: allosteric/catalytic interpretations remain relevant. No dietary methionine, folate, betaine, choline or ADHD intervention effect was assessed. Scite full-text human MAT2A kinetic Results appraised
- Evidence Source
- Bounded external search
- Reference
- [13]
Evidence Dependency:
- Bailey et al. (2021) is also used by PM3-F1 and PM3-F4. Reuse for the stability proposition is not independent replication.
Mechanistic explanation: MAT2B and MAT2A stability
5. BRS Pathways and Connections
5.1 BRS Pathways
BRS2-FM1-PM1 — Folate/B12-Dependent Homocysteine Remethylation / BRS2-FM1-PM2 — Betaine/BHMT Remethylation
↓
BRS2-FM1-PM3 — SAMe Synthesis
↓
BRS2-FM1-PM4 — Methionine Cycle Flux
5.2 Cross-BRS Mechanism Relationships
- None listed
5.3 Local BRS Mechanism Relationships
- BRS2-FM1-PM1 — Folate/B12-Dependent Homocysteine Remethylation — Remethylates homocysteine to methionine that can enter SAM synthesis. Upstream methionine supply, not the MAT step itself.
- BRS2-FM1-PM2 — Betaine/BHMT Remethylation — Alternative remethylation route to methionine. Parallel supply, not SAM synthetase activity.
- BRS2-FM1-PM4 — Methionine Cycle Flux — Consumes and regenerates methionine around SAM-using reactions. Shared one-carbon resource, not this PM’s synthesis reaction.
7. Phenome Connections
These mappings are translational relationships, not single-mechanism outcome claims. Phenomes are emergent functional patterns supported by multiple interacting PMs across the BRAIN Framework.
Each Phenome relationship has two independent ratings. They are not combined or averaged.
Biology → Phenome Relationship Strength
How direct and important is this biological mechanism expected to be to the Phenome within the BRAIN model?
Evidence Confidence
How strongly does the adjudicated evidence support this particular biology → Phenome relationship?
- Biology → Phenome Relationship Strength: Medium
- Evidence Confidence: Low–Medium
- Rationale: SAMe supplies methyl groups used by many downstream pathways relevant to neural function, but this is an inferred downstream bridge rather than evidence that MAT-dependent SAMe synthesis itself modulates Cognitive Clarity. The attached methylation review establishes SAMe's donor role, not a cognitive outcome or endogenous synthesis-flux effect Chiang et al. (1996) [4]. Circulating SAMe or SAM:SAH measurements cannot isolate MAT synthesis from utilisation and clearance Corrillero Bravo et al. (2022) [3]. Direct relationship evidence remains a gap.
Supporting evidence
Not scored · Evidence & Audit
The repository-attached methylation evidence establishes SAMe's donor role but does not directly demonstrate that endogenous MAT-dependent SAMe synthesis capacity modulates Cognitive Clarity.
What this means
General dependence of cognition-relevant pathways on methyl donors must not be presented as direct phenome evidence for PM3.
Evidence confidence: Not scored · Evidence & Audit
Finding ID: PM3-F3
Finding Statement: The repository-attached methylation evidence establishes SAMe's donor role but does not directly demonstrate that endogenous MAT-dependent SAMe synthesis capacity modulates Cognitive Clarity.
Synthesised Evidence Confidence: Not scored · Evidence & Audit
Synthesis: The foundational review establishes SAMe as a central methyl donor used in numerous downstream reactions. That broad biochemical role supports plausibility but does not isolate MAT synthesis capacity, measure cognitive clarity, or show that changing synthesis flux changes a cognitive outcome. The PM3-to-Cognitive Clarity relationship therefore remains a mechanistic inference with a direct-evidence gap.
Synthesis Limitations: This conclusion is bounded to the attached corpus plus targeted construct clarification. It does not exclude cognitive consequences in severe inherited disorders or downstream methylation studies; those contexts would not by themselves establish ordinary PM3 modulation.
Evidence Considered:
- Chiang et al. (1996) [4] — Mechanistic — Establishes SAMe as a principal methyl donor across downstream chemistry but does not measure Cognitive Clarity or endogenous MAT synthesis flux.
Informs: Cognitive Clarity
- Biology → Phenome Relationship Strength: Low–Medium
- Evidence Confidence: Low
- Rationale: SAMe-dependent methylation is biologically relevant to downstream neurotransmitter and membrane chemistry, but the attached mood-disorder review concerns exogenous SAMe and combined folate/B12 treatment rather than endogenous MAT activity or SAMe synthesis flux Cicero and Minervino (2022) [5]. It therefore does not directly demonstrate that this PM modulates Emotional Regulation; the relationship remains an indirect framework bridge with a direct-evidence gap.
Supporting evidence
Not scored · Evidence & Audit
The repository-attached mood-disorder evidence does not directly demonstrate an effect of endogenous MAT-dependent SAMe synthesis capacity on Emotional Regulation.
What this means
The Emotional Regulation relationship is biologically plausible downstream of methyl-donor chemistry but remains indirect for this PM.
Evidence confidence: Not scored · Evidence & Audit
Finding ID: PM3-F2
Finding Statement: The repository-attached mood-disorder evidence does not directly demonstrate an effect of endogenous MAT-dependent SAMe synthesis capacity on Emotional Regulation.
Synthesised Evidence Confidence: Not scored · Evidence & Audit
Synthesis: The attached review supports clinical interest in administered SAMe and combined one-carbon nutrients for mood disorders, but its intervention construct is exogenous treatment and its outcomes are mood symptoms. It does not manipulate MAT, quantify endogenous SAMe synthesis flux, or isolate PM3 from upstream folate/B12 remethylation and downstream methyltransferase biology. The PM3-to-Emotional Regulation proposition is therefore an inferred downstream bridge rather than a directly demonstrated relationship.
Synthesis Limitations: This is an adjudicated gap within the bounded attached corpus, not proof that no relationship exists. The source is a narrative clinical review, mixes interventions and pathway levels, and does not provide a PM3-specific causal test.
Evidence Considered:
- Cicero and Minervino (2022) [5] — Human Outcome — Reviews exogenous SAMe with folate/B12 in mood-disorder treatment but does not measure MAT activity or endogenous SAMe synthesis flux.
Informs: Emotional Regulation
Stage 2A/2B dietary-target assessment — 23 October 2026
REVIEW REQUIRED. MAT conversion of methionine and ATP to SAM.
Methionine and reaction metals are already recorded. Historical No fields on metals cannot be silently reversed because extra-intake benefit is absent or because a structure contains the metal. Assess supply/homeostasis against the same MAT dependency separately; preserve every old decision. Dietary protein duplicates a delivery category and is flagged, not removed.
New implementation: 0 dietary-input admissions (0 completed Unset candidates), 0 practices, 0 biochemical participants, 0 unscored Findings. Existing accepted inputs, source assessments, mission, KCs, Phenome relationships and scores are retained.
Source-to-claim boundary: Assessment source. Stop after adjudicating the stated material candidate and tracing supported delivery. Keep uncertain specificity, formulation, anatomical or measurement links explicit; no negative evidence is inferred from incomplete retrieval.
8. References
- [1] Bailey et al. (2021) — Human MAT2A ordered kinetic mechanism
- [2] Murray et al. (2016) — Human MAT catalytic structures
- [3] Corrillero Bravo et al. (2022) — SAM and SAH measurement and dietary intervention
- [4] Chiang et al. (1996) — S-Adenosylmethionine and methylation
- [5] Cicero and Minervino (2022) — SAMe, folate and B12 in mood disorders
- [6] FAO (2013) — Dietary protein quality evaluation (DIAAS)
- [7] Froese et al. (2019) — Vitamin B12, Folate and Methionine Remethylation
- [8] Obeid (2013) — Metabolic Burden of Methyl Donor Deficiency
- [9] Evans et al. (2002) — Human BHMT structure and catalytic zinc
- [10] Salvi and Gadda (2013) — Choline dehydrogenase and betaine formation
- [11] 10.1038/s41419-024-07093-8
- [12] 10.1107/S2052252526005075
- [13] 10.1021/acs.biochem.0c00998
PM-local source records
10.1021/acs.biochem.1c00672. Supporting experimental stability evidence. Scite full text; enzyme-assay Methods, inhibition, binding and stability Results appraised
10.1038/s41419-024-07093-8. Independent partial corroboration of protein stability. Scite full text; cell perturbation/rescue Results and cycloheximide-chase Methods appraised
10.1107/S2052252526005075. Contextual structural/allosteric interpretation; challenges stability-only explanations. Scite full-text conformational Results, Discussion and construct Methods appraised
10.1021/acs.biochem.0c00998. Contradictory substrate-order model; contextual to stability. Scite full-text human MAT2A kinetic Results appraised
Curated biochemical references
- [C1] Rhea: L-methionine + ATP + water = S-adenosyl-L-methionine + phosphate + diphosphate. RHEA:21080. Reaction identity; not dietary responsiveness. Accessed 2026-10-18. Authoritative record · Return to biochemical context
- [C2] Reactome: MAT2B:MAT2A:K+:2Mg2+ transfers Ado from ATP to L-Met. R-HSA-5603114. Human reaction and catalytic participants; no claim about dietary control of flux. Accessed 2026-10-18. Authoritative record · Return to biochemical context
- [C3] UniProt: S-adenosylmethionine synthase isoform type-2 (human MAT2A). P31153. Entry version 237; reaction and magnesium/potassium annotations. Individual annotation evidence varies. Accessed 2026-10-18. Authoritative record · Return to biochemical context
- [C4] UniProt: Methionine synthase (human MTR). Q99707. Entry version 230; folate/cobalamin-dependent methionine regeneration. Accessed 2026-10-18. Authoritative record · Return to biochemical context
- [C5] UniProt: Betaine-homocysteine S-methyltransferase 1 (human BHMT). Q93088. Entry version 211; betaine-to-homocysteine methyl transfer, mainly hepatic/renal context. Accessed 2026-10-18. Authoritative record · Return to biochemical context
- [C6] Reactome: Choline catabolism. R-HSA-6798163. Multistep choline-to-betaine pathway; CHDH alone does not complete oxidation. Accessed 2026-10-18. Authoritative record · Return to biochemical context
No validated structured conversion route is currently projected for this PM. This does not remove or reclassify its existing dietary inputs.
Mapping state: admitted-food-targets-resolved.