Methionine (S-adenosylmethionine) cycle module

A taxon-neutral decomposition of the methionine / S-adenosylmethionine (SAM) cycle, the core methyl-group-cycling pathway that interconverts methionine, S-adenosyl-L-methionine, S-adenosyl-L-homocysteine, and homocysteine, with exits to transsulfuration (via cystathionine beta-synthase) and remethylation inputs from folate (via methionine synthase) and choline/betaine (via BHMT). This module is intentionally structured in two layers. The CATALYTIC layer (enzymatic steps) grounds each step to a GO molecular-function term, the same EC <-> GO MF alignment used by the gluconeogenesis module. The REGULATORY layer is captured as connections of type POSITIVELY_REGULATES / NEGATIVELY_REGULATES whose predicate is grounded to a Systems Biology Ontology (SBO) term that distinguishes the MECHANISM (competitive vs allosteric), with the effector represented as a ChEBI-grounded metabolite-pool node. This regulatory wiring (small-molecule effector -> enzyme, with mechanism and sign) is information GO cannot express: GO annotations attach to gene products, the effectors here are metabolites, and GO has no competitive-vs-allosteric distinction. The regulatory structure is transcribed from the biosustain Maud kinetic model `data/methionine/methionine_cycle.toml`. A notable showcase is METAT, where two isozyme forms of methionine adenosyltransferase catalyse the SAME reaction but are OPPOSITELY regulated by SAM: MAT-I is competitively product-inhibited by SAM, whereas MAT-III is allosterically activated by SAM. Isozyme-specific regulation of this kind is the central thing GO flattens away. The core chemistry (SAM synthesis, transmethylation, SAH hydrolysis, homocysteine remethylation) is universal; the lineage-specific pieces are modelled as optional parts or variants. Fungi such as budding and fission yeast run the cycle with single-chain SAM synthetases (two paralogues in S. cerevisiae), a single adenosylhomocysteinase, and a cobalamin-independent (MetE-type) methionine synthase that uses 5-methyltetrahydropteroyl triglutamate; they have no glycine N-methyltransferase or betaine-homocysteine methyltransferase, whereas mammals use the cobalamin-dependent MetH-type enzyme plus hepatic BHMT and GNMT. The 5'-methylthioadenosine (MTA) salvage route back to methionine is a separate module (methionine_salvage_mta_cycle).

MODULE:methionine_cycleDRAFTMetabolic Pathwaymodules/methionine_cycle.yaml
methionine cycleGO:0033353
YeastPathways:PWY-5041
S-adenosyl-L-methionine cycle II
Source pathway for the S. cerevisiae realisation: SAM1/SAM2 methionine adenosyltransferase, an uncatalysed generic SAM-dependent methylation (RXN-7605), SAH1 adenosylhomocysteinase and MET6 cobalamin-independent methionine synthase. All four gene assignments were retained. The frame omits the MTHFR step that supplies 5-methyl-THF (MET13, with minor MET12) and the CYS4 transsulfuration exit, which are added here as exemplars of existing parts.
YeastPathways:SAM-PWY
S-adenosyl-L-methionine biosynthesis
Single-reaction YeastCyc frame (SAM1/SAM2 methionine adenosyltransferase); folded into the SAM-forming step of this module rather than modelled separately.
PMID:9409150
Metabolism of sulfur amino acids in Saccharomyces cerevisiae.
Review of yeast sulfur amino acid metabolism, including the SAM synthetases, SAH hydrolysis and methionine synthase; cited by YeastCyc for PWY-5041 and SAM-PWY.
Sulfur amino acid biosynthesis in Saccharomyces cerevisiae involves a large number of enzymes required for the de novo biosynthesis of methionine and cysteine and the recycling of organic sulfur metabolites.
PMID:3316224
SAM1, the structural gene for one of the S-adenosylmethionine synthetases in Saccharomyces cerevisiae. Sequence and expression.
S. cerevisiae has two SAM synthetase genes, SAM1 and SAM2, homologous to E. coli MetK.
Saccharomyces cerevisiae contains two genes, SAM1 and SAM2, encoding functional S-adenosylmethionine synthetases.
PMID:1903502
The synthesis of the two S-adenosyl-methionine synthetases is differently regulated in Saccharomyces cerevisiae.
SAM1 and SAM2 are differentially regulated paralogues catalysing the same reaction.
the expression of SAM1 and SAM2 is regulated differently
PMID:18591246
S-adenosyl-L-homocysteine hydrolase, key enzyme of methylation metabolism, regulates phosphatidylcholine synthesis and triacylglycerol homeostasis in yeast: implications for homocysteine as a risk factor of atherosclerosis.
Sah1 is the sole route for SAH removal in yeast; its depletion raises SAH and inhibits SAM-dependent methylation.
In eukaryotes, S-adenosyl-L-homocysteine hydrolase (Sah1) offers a single way for degradation of S-adenosyl-L-homocysteine
PMID:10600168
Saccharomyces cerevisiae expresses two genes encoding isozymes of methylenetetrahydrofolate reductase.
MET13 is the physiologically required yeast MTHFR; MET12 encodes a second, dispensable isozyme.
single disruption of MET13 resulted in methionine auxotrophy
PMID:11729203
Metabolic engineering in yeast demonstrates that S-adenosylmethionine controls flux through the methylenetetrahydrofolate reductase reaction in vivo.
Yeast Met13 MTHFR is SAM-inhibited like the mammalian enzyme, so the SAM -> MTHFR feedback edge holds in fungi.
Like mammalian MTHFRs, the yeast MTHFR encoded by the MET13 gene is NADPH-dependent and is inhibited by AdoMet in vitro.
GO:0033353
L-methionine cycle
The module is grounded in the GO biological-process term for the methionine / S-adenosylmethionine cycle (exact synonym "S-adenosylmethionine cycle").
file:models/methionine/methionine_cycle.regulation.toml
biosustain Methionine_model (Maud kinetic model)
Reaction set, isozymes, and the allosteric/competitive regulation wiring are transcribed from the Maud model data/methionine/methionine_cycle.toml.
19Nodes
11Parts
2Variant Sets
7Variants
11Annotons
23Connections

Executable models all models

Kinetic external
Maud kinetic model of the methionine cycle (biosustain)
methionine_cycle.regulation.toml · maud_methionine_mapping.yaml

Derived QC

Recommended-field compliance

100.0% recommended fields populated

All recommended fields populated.

Module deep research

✗ none found

No MODULE:methionine_cycle deep-research report alongside the module YAML.

Leaf nodes lacking representative members

7 leaf node(s) with no concrete protein grounding:

Template conformance

✓ every declared conforms_to bundle matches its template motif.

Function consistency and core coverage

18 gene-function check(s) reflected in core functions · 0 conflict(s) · 4 evidence or coverage gap(s) (34 comparison(s))

Retained noncore functions are reported separately; they do not require promotion to core functions. Support from representative genes does not establish conservation across the whole family. Missing reviews or identifiers leave a claim unverified.

AnnotonParticipantFunctionAssessment
mat1_activity MAT-I (MAT1A-encoded high-K_m hepatic isozyme)
UniProtKB:Q00266
Gene 		methionine adenosyltransferase activity
GO:0004478 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
mat3_activity MAT-III (MAT1A-encoded low-affinity hepatic isozyme)
UniProtKB:Q00266
Gene 		methionine adenosyltransferase activity
GO:0004478 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
mat_single_chain_activity SAM1 (S. cerevisiae)
UniProtKB:P10659
Family Representative 		methionine adenosyltransferase activity
GO:0004478 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
mat_single_chain_activity SAM2 (S. cerevisiae)
UniProtKB:P19358
Family Representative 		methionine adenosyltransferase activity
GO:0004478 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
mat_single_chain_activity sam1 (S. pombe)
UniProtKB:O60198
Family Representative 		methionine adenosyltransferase activity
GO:0004478 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
mat_single_chain_activity MAT2A (human)
UniProtKB:P31153
Family Representative 		methionine adenosyltransferase activity
GO:0004478 		Review Missing
No ai-review exists for this protein; its function and core-function coverage cannot yet be checked.
mat_single_chain_activity metK (Escherichia coli K-12)
UniProtKB:P0A817
Family Representative 		methionine adenosyltransferase activity
GO:0004478 		Review Missing
No ai-review exists for this protein; its function and core-function coverage cannot yet be checked.
meth_activity ANY_WITH_FUNCTION
Gene 		methyltransferase activity
GO:0008168 		Participant Unchecked
No direct UniProt participant to compare. Abstract selectors and complex-wide activities cannot be inferred from donor or subunit gene reviews.
gnmt_activity ANY_WITH_FUNCTION
Gene 		glycine N-methyltransferase activity
GO:0017174 		Participant Unchecked
No direct UniProt participant to compare. Abstract selectors and complex-wide activities cannot be inferred from donor or subunit gene reviews.
ahc_activity SAH1 (S. cerevisiae)
UniProtKB:P39954
Family Representative 		adenosylhomocysteinase activity
GO:0004013 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
ahc_activity sah1 (S. pombe, SPBC8D2.18c)
UniProtKB:O13639
Family Representative 		adenosylhomocysteinase activity
GO:0004013 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
ahc_activity AHCY (human)
UniProtKB:P23526
Family Representative 		adenosylhomocysteinase activity
GO:0004013 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
ms_activity MTR (human)
UniProtKB:Q99707
Family Representative 		methionine synthase activity
GO:0008705 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
ms_activity metH (Escherichia coli K-12)
UniProtKB:P13009
Family Representative 		methionine synthase activity
GO:0008705 		Review Missing
No ai-review exists for this protein; its function and core-function coverage cannot yet be checked.
mete_activity MET6 (S. cerevisiae)
UniProtKB:P05694
Family Representative 		5-methyltetrahydropteroyltriglutamate-homocysteine S-methyltransferase activity
GO:0003871 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
mete_activity met26 (S. pombe)
UniProtKB:Q9UT19
Family Representative 		5-methyltetrahydropteroyltriglutamate-homocysteine S-methyltransferase activity
GO:0003871 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
mete_activity metE (Escherichia coli K-12)
UniProtKB:P25665
Family Representative 		5-methyltetrahydropteroyltriglutamate-homocysteine S-methyltransferase activity
GO:0003871 		Review Missing
No ai-review exists for this protein; its function and core-function coverage cannot yet be checked.
bhmt_activity ANY_WITH_FUNCTION
Gene 		betaine-homocysteine S-methyltransferase activity
GO:0047150 		Participant Unchecked
No direct UniProt participant to compare. Abstract selectors and complex-wide activities cannot be inferred from donor or subunit gene reviews.
cbs_activity CYS4 (S. cerevisiae)
UniProtKB:P32582
Family Representative 		cystathionine beta-synthase activity
GO:0004122 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
cbs_activity CBS (human)
UniProtKB:P35520
Family Representative 		cystathionine beta-synthase activity
GO:0004122 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
mthfr_activity MET13 (S. cerevisiae)
UniProtKB:P53128
Family Representative 		methylenetetrahydrofolate reductase [NAD(P)H] activity
GO:0004489 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
mthfr_activity MET12 (S. cerevisiae)
UniProtKB:P46151
Family Representative 		methylenetetrahydrofolate reductase [NAD(P)H] activity
GO:0004489 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
mthfr_activity met9 (S. pombe)
UniProtKB:Q10258
Family Representative 		methylenetetrahydrofolate reductase [NAD(P)H] activity
GO:0004489 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
mthfr_activity met11 (S. pombe)
UniProtKB:O74927
Family Representative 		methylenetetrahydrofolate reductase [NAD(P)H] activity
GO:0004489 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
mthfr_activity MTHFR (human)
UniProtKB:P42898
Family Representative 		methylenetetrahydrofolate reductase [NAD(P)H] activity
GO:0004489 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
mat_single_chain_activity S-adenosylmethionine synthetase family
PANTHER:PTHR11964
Family 		methionine adenosyltransferase activity
GO:0004478 		Family Supported
Family review supports GO:0004478 FAMILY_WIDE. Asserted by methionine_cycle, sam_cycle and bacterial_methionine_cycle; accepted by SAM1, SAM2, sam1, MAT1A, P. putida MetK and the poplar SAMS paralogs.
ahc_activity adenosylhomocysteinase family
PANTHER:PTHR23420:SF0
Family 		adenosylhomocysteinase activity
GO:0004013 		Family Supported
Family review supports GO:0004013 for PANTHER:PTHR23420:SF0. Catalytic subfamilies only. methionine_cycle, sam_cycle and bacterial_methionine_cycle select the base family, which also takes in AHCYL1/2.
ahc_activity adenosylhomocysteinase family
PANTHER:PTHR23420:SF17
Family 		adenosylhomocysteinase activity
GO:0004013 		Family Supported
Family review supports GO:0004013 for PANTHER:PTHR23420:SF17. Catalytic subfamilies only. methionine_cycle, sam_cycle and bacterial_methionine_cycle select the base family, which also takes in AHCYL1/2.
ahc_activity adenosylhomocysteinase family
PANTHER:PTHR23420:SF29
Family 		adenosylhomocysteinase activity
GO:0004013 		Family Supported
Family review supports GO:0004013 for PANTHER:PTHR23420:SF29. Catalytic subfamilies only. methionine_cycle, sam_cycle and bacterial_methionine_cycle select the base family, which also takes in AHCYL1/2.
ahc_activity adenosylhomocysteinase family
PANTHER:PTHR23420:SF16
Family 		adenosylhomocysteinase activity
GO:0004013 		Family Supported
Family review supports GO:0004013 for PANTHER:PTHR23420:SF16. Catalytic subfamilies only. methionine_cycle, sam_cycle and bacterial_methionine_cycle select the base family, which also takes in AHCYL1/2.
ms_activity cobalamin-dependent methionine synthase
PANTHER:PTHR45833
Family 		methionine synthase activity
GO:0008705 		Family Supported
Family review supports GO:0008705 FAMILY_WIDE. Asserted by methionine_cycle, homocysteine_metabolism and bacterial_methionine_cycle; accepted by MTR and P. putida metH.
mete_activity cobalamin-independent methionine synthase (MetE)
PANTHER:PTHR30519
Family 		5-methyltetrahydropteroyltriglutamate-homocysteine S-methyltransferase activity
GO:0003871 		Family Supported
Family review supports GO:0003871 FAMILY_WIDE. Asserted by methionine_cycle and bacterial_methionine_cycle; accepted by MET6, met26 and P. putida MetE. The truncated PP_4637 is left UNDECIDED by its review.
cbs_activity cystathionine beta-synthase family
PANTHER:PTHR10314:SF194
Family 		cystathionine beta-synthase activity
GO:0004122 		Family Supported
Family review supports GO:0004122 for PANTHER:PTHR10314:SF194. Canonical serine-dependent CBS activity is placed at the eukaryotic node PTN000034107, inside SF194, which contains the reviewed canonical CBS members. Atypical OAS-dependent MccA in SF242 also carries a CBS name, but its demonstrated OAS/homocysteine chemistry does not by itself establish GO:0004122. SF194 also holds bacterial CysK proteins, which are cysteine synthases rather than canonical CBS and do not receive the PTN000034107 IBA; they are listed as member exceptions. methionine_cycle and fungal_sulfur_amino_acid_transsulfuration select SF194; homocysteine_metabolism selects the base family, which also takes in the cysteine synthases, threonine synthases and desulfhydrases.
mthfr_activity eukaryotic methylenetetrahydrofolate reductase
PANTHER:PTHR45754
Family 		methylenetetrahydrofolate reductase [NAD(P)H] activity
GO:0004489 		Family Supported
Family review supports GO:0004489 FAMILY_WIDE. Asserted by methionine_cycle, homocysteine_metabolism and folate_one_carbon_interconversion; accepted by every reviewed member.

Feedback loops (advisory, prose-driven: a regulator counts as "feedback" when its own description says so)

✓ every negative regulator described as feedback has an upstream edge closing the loop.

  • mlthf_pool ⊣ gnmt_activity [input]
    mlthf_pool is a negative regulator with no upstream edge (not described as feedback)
  • amet_pool ⊣ mthfr_activity [input]
    amet_pool is a negative regulator with no upstream edge (not described as feedback)
  • ahcys_pool ⊣ meth_activity [input]
    ahcys_pool is a negative regulator with no upstream edge (not described as feedback)

Gene-review completeness (17/21 grounded genes reviewed)

12 complete review(s) · 8 with deep research · 4 missing review · 9 reviewed but lacking deep research

Gene Review Complete Deep research
AHCY P23526 ✓ 26/27 ✗
CBS P35520 ✓ 89/101 ✓
CYS4 P32582 ✓ ✓ ✓
MAT1A Q00266 ✓ ✓ ✗
met11 O74927 ✓ ✓ ✗
MET12 P46151 ✓ 26/28 ✓
MET13 P53128 ✓ ✓ ✓
met26 Q9UT19 ✓ ✓ ✗
MET6 P05694 ✓ ✓ ✓
met9 Q10258 ✓ ✓ ✗
MTHFR P42898 ✓ ✓ ✗
MTR Q99707 ✓ ✓ ✗
metK (Escherichia coli K-12) P0A817 ✗ — —
metH (Escherichia coli K-12) P13009 ✗ — —
metE (Escherichia coli K-12) P25665 ✗ — —
MAT2A (human) P31153 ✗ — —
pi047 O13639 ✓ ✓ ✗
SAH1 P39954 ✓ ✓ ✓
sam1 O60198 ✓ ✓ ✗
SAM1 P10659 ✓ 32/33 ✓
SAM2 P19358 ✓ 28/29 ✓

Details

Methionine (SAM) cycleMetabolic Pathwaymethionine_cycle
methionine cycleGO:0033353

Layering: catalytic steps ground to GO molecular-function terms (GO:0004478, GO:0008168, GO:0017174, GO:0004013, GO:0008705, GO:0047150, GO:0004122, GO:0004489); the pathway grounds to GO:0033353. The regulatory layer is deliberately NOT expressed in GO. Each regulatory edge is a connection typed POSITIVELY/NEGATIVELY_REGULATES whose predicate is grounded to SBO so the competitive-vs-allosteric MECHANISM is explicit (SBO:0000206 competitive inhibitor, SBO:0000636 allosteric activator, SBO:0000639 allosteric inhibitor), with the effector grounded to ChEBI. This is the information that falls outside GO scope: a metabolite cannot bear a GO annotation, and GO has no representation of inhibition mechanism. The MAT-I vs MAT-III split (same GO MF GO:0004478, opposite SAM regulation) is the canonical illustration. Quantitative kinetics (K_m, k_cat, K_i, Hill/MWC parameters) from the Maud model are intentionally out of scope for this module and belong with the model / SABIO-RK-style resources. YeastPathways alignment (PWY-5041, SAM-PWY): the SGD frames supply the fungal exemplars SAM1/SAM2 (single-chain MAT variant), SAH1 (adenosylhomocysteinase), and MET6 (cobalamin-independent methionine synthase). MET6 catalyses GO:0003871 with the triglutamate folate donor, not GO:0008705 (the monoglutamate MetH-type reaction), so it is modelled as a separate remethylation variant rather than added under ms_route. The single-reaction SAM-PWY frame is folded into the SAM-forming step. MET13 / MET12 (MTHFR) and CYS4 (CBS) are added as yeast exemplars of existing parts although the PWY-5041 frame does not list them. GNMT and BHMT are vertebrate-specific; the GNMT part is optional and the BHMT route is one of several ONE_OR_MORE remethylation/exit variants. The YeastPathways GO-CAM (gomodel:YeastPathways_PWY-5041) agrees with this module for all four activities (MF terms GO:0004478, GO:0004013, GO:0003871; cytosol); it has no node for the generic methylation reaction, which YeastCyc leaves without a catalyst. The crosswalk also listed PomBase model gomodel:69c59f8a00000584 for this module. That model is titled "L-methionine cycle (GO:0033353)" but its activities are the 5'-methylthioadenosine salvage enzymes (mta1 MTA phosphorylase, mri1, mde1/mta3, utr4, adi1), none of the SAM/SAH/homocysteine interconversions in the GO:0033353 definition. It is therefore associated with the methionine_salvage_mta_cycle module (process GO:0071267 L-methionine salvage) instead, and is not linked here. Fission yeast exemplars here (sam1, sah1, met26, met9, met11) are taken from UniProt and PAINT IBD donor lists rather than from a PomBase GO-CAM.

Connections

mat1_activity -> meth_step Provides Input For
SAM produced by methionine adenosyltransferase is the methyl donor for transmethylation.
mat3_activity -> meth_step Provides Input For
SAM produced by methionine adenosyltransferase is the methyl donor for transmethylation.
mat1_activity -> gnmt_step Provides Input For
SAM is also consumed by glycine N-methyltransferase (overflow disposal).
mat3_activity -> gnmt_step Provides Input For
SAM is also consumed by glycine N-methyltransferase (overflow disposal).
mat_single_chain_activity -> meth_step Provides Input For
SAM made by MAT2A/MetK/SAM1-type synthetases is the methyl donor for transmethylation.
meth_step -> ahc_step Provides Input For
Transmethylation produces SAH, the substrate of adenosylhomocysteinase.
gnmt_step -> ahc_step Provides Input For
GNMT produces SAH, the substrate of adenosylhomocysteinase.
ahc_step -> homocysteine_fate Provides Input For
SAH hydrolysis yields homocysteine, the branch-point metabolite.
ms_route -> metat_step Provides Input For
Folate-dependent remethylation regenerates methionine, closing the cycle.
mete_route -> metat_step Provides Input For
Cobalamin-independent remethylation (MetE/MET6) regenerates methionine, closing the cycle.
bhmt_route -> metat_step Provides Input For
Betaine-dependent remethylation regenerates methionine, closing the cycle.
mthfr_step -> ms_route Provides Input For
MTHFR supplies 5-methyltetrahydrofolate consumed by methionine synthase.
mthfr_step -> mete_route Provides Input For
MTHFR supplies the 5-methyltetrahydrofolate that, after polyglutamylation, is the methyl donor for MetE-type methionine synthase.
amet_pool -> mat3_activity Positively Regulates
allosteric activationSBO:0000636
SAM allosterically activates MAT-III (feed-forward). Contrast with MAT-I, which SAM competitively inhibits - same reaction, opposite isozyme logic.
file:models/methionine/methionine_cycle.regulation.toml
Maud methionine_cycle.toml [allosteric]
MAT3 activated by amet (allosteric).
met_pool -> mat3_activity Positively Regulates
allosteric activationSBO:0000636
Methionine feed-forward activates MAT-III.
file:models/methionine/methionine_cycle.regulation.toml
Maud methionine_cycle.toml [allosteric]
MAT3 activated by met-L (allosteric).
amet_pool -> gnmt_activity Positively Regulates
allosteric activationSBO:0000636
SAM allosterically activates GNMT, opening the SAM overflow valve when methyl donor is in excess.
file:models/methionine/methionine_cycle.regulation.toml
Maud methionine_cycle.toml [allosteric]
GNMT1 activated by amet (allosteric).
mlthf_pool -> gnmt_activity Negatively Regulates
allosteric inhibitionSBO:0000639
5,10-methylenetetrahydrofolate allosterically inhibits GNMT, linking folate status to SAM disposal.
file:models/methionine/methionine_cycle.regulation.toml
Maud methionine_cycle.toml [allosteric]
GNMT1 inhibited by mlthf (allosteric).
amet_pool -> cbs_activity Positively Regulates
allosteric activationSBO:0000636
SAM allosterically activates CBS, diverting homocysteine to transsulfuration when methyl donor is abundant.
file:models/methionine/methionine_cycle.regulation.toml
Maud methionine_cycle.toml [allosteric]
CBS1 activated by amet (allosteric).
amet_pool -> mthfr_activity Negatively Regulates
allosteric inhibitionSBO:0000639
SAM allosterically inhibits MTHFR, throttling folate-dependent remethylation when SAM is high.
file:models/methionine/methionine_cycle.regulation.toml
Maud methionine_cycle.toml [allosteric]
MTHFR1 inhibited by amet (allosteric).
ahcys_pool -> mthfr_activity Positively Regulates
allosteric activationSBO:0000636
SAH allosterically activates MTHFR, restoring remethylation flux when the methylation index falls.
file:models/methionine/methionine_cycle.regulation.toml
Maud methionine_cycle.toml [allosteric]
MTHFR1 activated by ahcys (allosteric).
amet_pool -> mat1_activity Negatively Regulates
competitive inhibitionSBO:0000206
SAM competitively (product-feedback) inhibits MAT-I - opposite sign to its allosteric activation of MAT-III.
file:models/methionine/methionine_cycle.regulation.toml
Maud methionine_cycle.toml [competitive_inhibition]
MAT1 (reaction METAT) competitively inhibited by amet.
ahcys_pool -> meth_activity Negatively Regulates
competitive inhibitionSBO:0000206
SAH competitively inhibits bulk transmethylation (classic product inhibition / methylation index).
file:models/methionine/methionine_cycle.regulation.toml
Maud methionine_cycle.toml [competitive_inhibition]
METH-Gen (reaction METH) competitively inhibited by ahcys.
ahcys_pool -> gnmt_activity Negatively Regulates
competitive inhibitionSBO:0000206
SAH competitively inhibits GNMT.
file:models/methionine/methionine_cycle.regulation.toml
Maud methionine_cycle.toml [competitive_inhibition]
GNMT1 (reaction GNMT) competitively inhibited by ahcys.
Part 1: SAM-forming step (methionine activation)
Methionine -> S-adenosyl-L-methionineReactionmetat_step

Methionine adenosyltransferase (EC 2.5.1.6) condenses methionine and ATP to S-adenosyl-L-methionine (SAM), the universal methyl donor. The isozyme forms differ in their feedback logic, so they are modelled as variants to carry isozyme-specific regulation. Outside vertebrate liver the step is carried by MAT2A-type / MetK-type synthetases (including both yeast paralogues), modelled as a third variant.

methionine adenosyltransferase reaction
Variant set: Methionine adenosyltransferase isozyme/oligomeric forms by isozyme / oligomeric form (One Or More)
MAT-I (high-capacity hepatic form)Reactionmat1_form

Annotons

MAT-I methionine adenosyltransferase activity
mat1_activity
Participant: Gene Product: MAT-I (MAT1A-encoded high-K_m hepatic isozyme)
Gene Product:
MAT-I (MAT1A-encoded high-K_m hepatic isozyme)UniProtKB:Q00266 High-K_m hepatic methionine adenosyltransferase form. Subject to competitive product (SAM) inhibition in the kinetic model.

Function

methionine adenosyltransferase activityGO:0004478
Substrates: L-methionine ATP
Products: S-adenosyl-L-methionine phosphate diphosphate
MAT-III (low-affinity hepatic form)Reactionmat3_form

Annotons

MAT-III methionine adenosyltransferase activity
mat3_activity
Participant: Gene Product: MAT-III (MAT1A-encoded low-affinity hepatic isozyme)
Gene Product:
MAT-III (MAT1A-encoded low-affinity hepatic isozyme)UniProtKB:Q00266 Low-affinity hepatic methionine adenosyltransferase form, allosterically activated by its own product SAM and by methionine (feed-forward), the opposite of MAT-I.

Function

methionine adenosyltransferase activityGO:0004478
Substrates: L-methionine ATP
Products: S-adenosyl-L-methionine phosphate diphosphate
MAT2A-type / MetK-type SAM synthetase (non-hepatic, fungal, bacterial)Reactionmat_single_chain_form

The general form of the step outside vertebrate liver. Budding yeast has two nearly identical, differentially regulated paralogues (SAM1, SAM2); fission yeast has one (sam1).

Annotons

Methionine adenosyltransferase (MAT2A/MetK/SAM1-type)
mat_single_chain_activity
Participant: Family: S-adenosylmethionine synthetase family
Family:
S-adenosylmethionine synthetase familyPANTHER:PTHR11964
Representative Members: SAM1 (S. cerevisiae)UniProtKB:P10659 SAM2 (S. cerevisiae)UniProtKB:P19358 sam1 (S. pombe)UniProtKB:O60198 MAT2A (human)UniProtKB:P31153 metK (Escherichia coli K-12)UniProtKB:P0A817
Required Function:
methionine adenosyltransferase activityGO:0004478

Function

methionine adenosyltransferase activityGO:0004478
Substrates: L-methionine ATP
Products: S-adenosyl-L-methionine phosphate diphosphate

Locations

cytosolGO:0005829
Part 2: bulk transmethylation (SAM-dependent methyltransferases)
SAM-dependent transmethylation (general)Reactionmeth_step

Lumped node for the many SAM-dependent methyltransferases (EC 2.1.1.-) that transfer SAM's methyl group to acceptors (DNA, protein, small molecules), yielding S-adenosyl-L-homocysteine (SAH). Competitively product-inhibited by SAH in the kinetic model.

Annotons

SAM-dependent methyltransferase activity (general)
meth_activity
Participant: Any With Function: methyltransferase activity
Required Function:
methyltransferase activityGO:0008168

Function

methyltransferase activityGO:0008168
Substrates: S-adenosyl-L-methionine methyl acceptor
Products: S-adenosyl-L-homocysteine methylated acceptor
Part 3: SAM disposal / glycine sink (optional)

Vertebrate (chiefly hepatic) overflow valve. Fungi such as S. cerevisiae and S. pombe have no GNMT orthologue, so the cycle closes without this step there.

Glycine N-methyltransferase (SAM:SAH buffering)Reactiongnmt_step

Glycine N-methyltransferase (EC 2.1.1.20) methylates glycine to sarcosine, acting as the overflow valve that buffers the SAM:SAH ratio. Allosterically inhibited by 5,10-methylenetetrahydrofolate and competitively inhibited by SAH; activated by SAM.

Annotons

Glycine N-methyltransferase activity
gnmt_activity
Participant: Any With Function: glycine N-methyltransferase activity
Required Function:
glycine N-methyltransferase activityGO:0017174

Function

glycine N-methyltransferase activityGO:0017174
Substrates: S-adenosyl-L-methionine glycine
Products: S-adenosyl-L-homocysteine sarcosine
Part 4: SAH hydrolysis
S-adenosyl-L-homocysteine -> L-homocysteineReactionahc_step

Adenosylhomocysteinase (EC 3.3.1.1) hydrolyses SAH to L-homocysteine and adenosine, relieving SAH product inhibition of methyltransferases.

Annotons

Adenosylhomocysteinase activity
ahc_activity
Participant: Family: adenosylhomocysteinase family
Family:
adenosylhomocysteinase family
Representative Members: SAH1 (S. cerevisiae)UniProtKB:P39954 sah1 (S. pombe, SPBC8D2.18c)UniProtKB:O13639 AHCY (human)UniProtKB:P23526
Required Function:
adenosylhomocysteinase activityGO:0004013

Function

adenosylhomocysteinase activityGO:0004013
Substrates: S-adenosyl-L-homocysteine
Products: L-homocysteine adenosine

Locations

cytosolGO:0005829
Part 5: homocysteine fate (remethylation vs transsulfuration)
Homocysteine fate branchReactionhomocysteine_fate

Homocysteine is either remethylated back to methionine (folate-dependent via methionine synthase, or betaine-dependent via BHMT) or committed to transsulfuration via cystathionine beta-synthase.

Variant set: Homocysteine disposal routes by metabolic fate (One Or More)
Folate-dependent remethylation, cobalamin-dependent (MetH/MTR-type methionine synthase)Reactionms_route

Cobalamin-dependent methionine synthase using monoglutamyl 5-methyltetrahydrofolate (animals, many bacteria). Absent from yeasts, which use the MetE-type enzyme below.

Annotons

Methionine synthase activity
ms_activity
Participant: Family: cobalamin-dependent methionine synthase
Family:
cobalamin-dependent methionine synthasePANTHER:PTHR45833
Representative Members: MTR (human)UniProtKB:Q99707 metH (Escherichia coli K-12)UniProtKB:P13009
Required Function:
methionine synthase activityGO:0008705

Function

methionine synthase activityGO:0008705
Substrates: L-homocysteine 5-methyltetrahydrofolate
Products: L-methionine tetrahydrofolate
Folate-dependent remethylation, cobalamin-independent (MetE-type methionine synthase)Reactionmete_route

Cobalamin-independent, zinc-dependent methionine synthase that requires the polyglutamylated (triglutamate) methyl-folate donor. This is the only remethylation route in budding and fission yeast (MET6, met26), and is also used by plants and many bacteria.

Annotons

Cobalamin-independent methionine synthase activity
mete_activity
Participant: Family: cobalamin-independent methionine synthase (MetE)
Family:
cobalamin-independent methionine synthase (MetE)PANTHER:PTHR30519
Representative Members: MET6 (S. cerevisiae)UniProtKB:P05694 met26 (S. pombe)UniProtKB:Q9UT19 metE (Escherichia coli K-12)UniProtKB:P25665
Required Function:
5-methyltetrahydropteroyltriglutamate-homocysteine S-methyltransferase activityGO:0003871

Function

5-methyltetrahydropteroyltriglutamate-homocysteine S-methyltransferase activityGO:0003871
Substrates: L-homocysteine 5-methyltetrahydropteroyl tri-L-glutamate
Products: L-methionine tetrahydropteroyl tri-L-glutamate

Locations

cytosolGO:0005829
Betaine-dependent remethylation (BHMT)Reactionbhmt_route

Vertebrate (liver/kidney) route; absent from fungi.

Annotons

Betaine-homocysteine S-methyltransferase activity
bhmt_activity
Participant: Any With Function: betaine-homocysteine S-methyltransferase activity
Required Function:
betaine-homocysteine S-methyltransferase activityGO:0047150

Function

betaine-homocysteine S-methyltransferase activityGO:0047150
Substrates: L-homocysteine glycine betaine
Products: L-methionine N,N-dimethylglycine
Transsulfuration commitment (cystathionine beta-synthase)Reactioncbs_route

Exit from the cycle toward cysteine biosynthesis; allosterically activated by SAM.

Annotons

Cystathionine beta-synthase activity
cbs_activity
Participant: Family: cystathionine beta-synthase family
Family:
cystathionine beta-synthase familyPANTHER:PTHR10314:SF194
Representative Members: CYS4 (S. cerevisiae)UniProtKB:P32582 CBS (human)UniProtKB:P35520
Required Function:
cystathionine beta-synthase activityGO:0004122

Function

cystathionine beta-synthase activityGO:0004122
Substrates: L-homocysteine L-serine
Products: L-cystathionine
Part 6: folate methyl input arm
Methylenetetrahydrofolate reductase (5-methyl-THF supply)Reactionmthfr_step

Methylenetetrahydrofolate reductase (EC 1.5.1.20) reduces 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, the methyl donor consumed by methionine synthase. Allosterically inhibited by SAM and activated by SAH, coupling folate flux to methyl-group demand.

Annotons

Methylenetetrahydrofolate reductase activity
mthfr_activity
Participant: Family: eukaryotic methylenetetrahydrofolate reductase
Family:
eukaryotic methylenetetrahydrofolate reductasePANTHER:PTHR45754
Representative Members: MET13 (S. cerevisiae)UniProtKB:P53128 MET12 (S. cerevisiae)UniProtKB:P46151 met9 (S. pombe)UniProtKB:Q10258 met11 (S. pombe)UniProtKB:O74927 MTHFR (human)UniProtKB:P42898
Required Function:
methylenetetrahydrofolate reductase [NAD(P)H] activityGO:0004489

Function

methylenetetrahydrofolate reductase [NAD(P)H] activityGO:0004489
Substrates: 5,10-methylenetetrahydrofolate NAD(P)H
Products: 5-methyltetrahydrofolate NAD(P)+
Part 7: regulatory effector pools (metabolite endpoints for regulation edges) (optional)

These nodes are NOT catalytic steps. They represent the small-molecule effector pools that serve as the source endpoints of the regulatory connections below. They are grounded to ChEBI rather than GO, because the regulators are metabolites and cannot bear GO annotations.

Regulatory effector poolsModuleregulatory_effectors
Part: methyl-donor effector
S-adenosyl-L-methionine (SAM) poolamet_pool
S-adenosyl-L-methionineCHEBI:15414
Part: demethylated-donor effector
S-adenosyl-L-homocysteine (SAH) poolahcys_pool
S-adenosyl-L-homocysteineCHEBI:16680
Part: folate effector
5,10-methylenetetrahydrofolate poolmlthf_pool
5,10-methylenetetrahydrofolateCHEBI:1989
Part: amino-acid effector
L-methionine poolmet_pool
L-methionineCHEBI:16643