L-methionine biosynthesis (from homoserine)

De novo biosynthesis of L-methionine from L-homoserine through three ordered stages: homoserine activation, sulfur incorporation to form L-homocysteine, and methylation of L-homocysteine. Bacteria can activate homoserine with an acetyl or succinyl group, incorporate sulfur through two-step trans-sulfuration or one-step direct sulfhydrylation, and complete the pathway with a cobalamin-independent or cobalamin-dependent methionine synthase. Substrate-matched alternatives are retained explicitly because enzyme-family membership alone does not reliably distinguish acetyl from succinyl chemistry or forward biosynthetic from related PLP-dependent lyase reactions.

MODULE:methionine_biosynthesisDRAFTMetabolic Pathwaymodules/methionine_biosynthesis.yaml
methionine biosynthesisGO:0071265
GO:0071265
L-methionine biosynthetic process
Module grounded in the GO biological-process term for L-methionine biosynthesis.
KEGG:map00270
Cysteine and methionine metabolism
Step alternatives (metA/metX; trans-sulfuration vs direct sulfhydrylation; metE/metH) follow the KEGG/MetaCyc methionine biosynthesis routes; per-genome presence is resolved via KEGG Orthology (see oracle).
file:modules/methionine_biosynthesis-deep-research-openscientist.md
OpenScientist module research for L-methionine biosynthesis
OpenScientist framed methionine biosynthesis from homoserine as a Boolean satisfiability problem with required acylation, sulfur-incorporation, and methylation steps, each having route alternatives.
file:projects/P_PUTIDA/deep-research/PSEPK__methionine_biosynthesis__ppu00270-deep-research-openscientist.md
OpenScientist PSEPK ppu00270 methionine-biosynthesis research
OpenScientist concluded that the PSEPK module is satisfiable via MetXS/MetZ direct sulfhydrylation and terminal methionine synthase activity, with a secondary MetB/PP_4348 trans-sulfuration route and important caution around partial MetE-like candidates.
PMID:28581482
Parallel evolution of non-homologous isofunctional enzymes in methionine biosynthesis.
Experimental profiling of acyl-L-homoserine transferases establishes that acetyl- versus succinyl-CoA specificity cannot be assigned safely from a broad MetA/MetX-family classification alone.
file:genes/PSEPK/metXS/metXS-ai-review.yaml
PSEPK metXS gene review
Q88CT3 is an experimentally supported homoserine O-succinyltransferase exemplar despite belonging to a MetX-fold acyltransferase family that does not determine acyl-donor specificity.
file:genes/PSEPK/metZ/metZ-ai-review.yaml
PSEPK metZ gene review
Q88LD4 supports the substrate-matched O-succinylhomoserine direct sulfhydrylation route while illustrating the poor reaction specificity of the broader trans-sulfuration PANTHER family.
file:genes/PSEPK/metH/metH-ai-review.yaml
PSEPK metH gene review
Q88KB5 supplies a complete cobalamin-dependent methionine synthase exemplar for the terminal methylation stage.

The boundary begins with L-homoserine and ends with L-methionine. Upstream aspartate-family synthesis of homoserine, sulfur assimilation, cobalamin supply, methionine salvage, the methionine/SAM cycle, and transcriptional or riboswitch regulation are outside the module. PANTHER terms orient exact exemplars but do not override experimentally established substrate specificity. Family identifiers are omitted where the locally available family does not distinguish the leaf chemistry. No PTN is asserted because an appropriate ancestral function-bearing node has not been established locally for every route.

13Nodes
5Parts
3Variant Sets
7Variants
8Annotons
6Connections

Derived QC

Recommended-field compliance

100.0% recommended fields populated

All recommended fields populated.

Module deep research

✓ present

  • methionine_biosynthesis-deep-research-openscientist.md (openscientist)

Leaf nodes lacking representative members

✓ every leaf node grounds to a representative protein.

Template conformance

✓ every declared conforms_to bundle matches its template motif.

Reaction chaining (advisory)

✓ every PRECEDES step chains, or its break is acknowledged via chaining_status.

  • acylation → sulfur_incorporation [NOT_CHECKED]
  • sulfur_incorporation → methylation [NOT_CHECKED]

Gene-review completeness (3/9 grounded genes reviewed)

3 complete review(s) · 3 with deep research · 6 missing review · 0 reviewed but lacking deep research

Gene Review Complete Deep research
metH Q88KB5 ✓ ✓ ✓
metXS Q88CT3 ✓ ✓ ✓
metZ Q88LD4 ✓ ✓ ✓
MetB (Escherichia coli K-12) P00935 ✗ — —
MetC (Escherichia coli K-12) P06721 ✗ — —
MetH (Escherichia coli K-12) P13009 ✗ — —
MetE (Escherichia coli K-12) P25665 ✗ — —
MetX (Mycobacterium tuberculosis) P9WJY9 ✗ — —
MetY (Corynebacterium glutamicum) Q79VI4 ✗ — —

Details

L-methionine biosynthesisMetabolic Pathwaymethionine_biosynthesis
methionine biosynthesisGO:0071265

The module records biochemical alternatives, not universal gene-name requirements. Homoserine acyltransferase and Cys/Met PLP-enzyme families can contain members with different substrates or reaction directions, and some proteins are bifunctional across the nominal routes. Exact activity evidence therefore takes precedence over a family label when instantiating the template in a genome. A MetH-only implementation is conditional on cobalamin availability. Per-genome candidates are keyed by KEGG Orthology: metA=K00651, metX=K00641, metB=K01739, metC=K01760, metY=K01740, metE=K00549, and metH=K00548. MetZ/O-succinylhomoserine sulfhydrylase and partial MetE-like proteins require species-aware review beyond those KO mappings. See modules/experimental/gluconeogenesis-context/kegg_oracle.py and modules/experimental/gluconeogenesis-context/resolve_genomes.py for per-genome route resolution and gap detection.

Connections

Homoserine O-succinyltransferase supplies O-succinyl-L-homoserine to the MetZ direct-sulfhydrylation route.
Homoserine O-acetyltransferase supplies O-acetyl-L-homoserine to the MetY direct-sulfhydrylation route.
acylation -> trans_sulfuration Provides Input For
Trans-sulfuration uses an activated homoserine substrate; the accepted acetyl or succinyl form depends on the organism's MetB chemistry.
Homoserine activation precedes sulfur incorporation at the reusable stage level; the more specific edges above preserve substrate matching.
Part 1: acylation of homoserine (succinyl or acetyl)
Homoserine activation by acylationMetabolic Pathwayacylation
Variant set: Homoserine acyltransferase by acyl donor (One Or More)
O-succinylhomoserine formationReactiono_succinyl_activation

Annotons

Homoserine O-succinyltransferase
homoserine_o_succinyltransferase_activity
Participant: Family: metA (homoserine O-succinyltransferase)
Gene:
metA (homoserine O-succinyltransferase)
Family:
homoserine O-succinyltransferases with verified donor specificity No family identifier is asserted because MetA- and MetX-fold acyltransferases can independently evolve acetyl- or succinyl-CoA specificity.
Representative Members: MetXS (PSEPK)UniProtKB:Q88CT3

Function

homoserine O-succinyltransferase activityGO:0008899

Activates homoserine to O-succinyl-L-homoserine.

O-acetylhomoserine formationReactiono_acetyl_activation

Annotons

Homoserine O-acetyltransferase
homoserine_o_acetyltransferase_activity
Participant: Family: metX (homoserine O-acetyltransferase)
Gene:
metX (homoserine O-acetyltransferase)
Family:
homoserine O-acetyltransferases No family identifier is asserted because acyl-donor specificity is not reliably delimited by the available MetA/MetX family classifications.
Representative Members: MetX (Mycobacterium tuberculosis)UniProtKB:P9WJY9

Function

homoserine O-acetyltransferase activityGO:0004414

Activates homoserine to O-acetyl-L-homoserine.

Part 2: sulfur incorporation to homocysteine (trans-sulfuration or direct)
Sulfur incorporation to homocysteineMetabolic Pathwaysulfur_incorporation
Variant set: Sulfur-incorporation route by sulfur source (One Or More)
Trans-sulfuration (metB + metC)Metabolic Pathwaytrans_sulfuration

Two enzymes, drawing sulfur from cysteine via cystathionine.

Connections

metB_node -> metC_node Provides Input For
Cystathionine formed by MetB is the substrate cleaved by MetC to produce L-homocysteine.
Part 1: cystathionine formation
Cystathionine gamma-synthaseReactionmetB_node

Annotons

metB: cystathionine gamma-synthase
metB_activity
Participant: Family: metB (cystathionine gamma-synthase)
Gene:
metB (cystathionine gamma-synthase)
Family:
cystathionine gamma-synthases
Representative Members: MetB (Escherichia coli K-12)UniProtKB:P00935

Function

cystathionine gamma-synthase activityGO:0003962
Part 2: cystathionine cleavage to homocysteine
Cystathionine beta-lyaseReactionmetC_node

Annotons

metC: cystathionine beta-lyase
metC_activity
Participant: Family: metC (cystathionine beta-lyase)
Gene:
metC (cystathionine beta-lyase)
Family:
cystathionine beta-lyases The official -RELATED subfamily label is broader than a definitive activity assignment. The characterized P06721 exemplar and leaf molecular function provide the reaction-specific grounding.
Representative Members: MetC (Escherichia coli K-12)UniProtKB:P06721

Function

cystathionine beta-lyase activityGO:0047804
Direct sulfhydrylation of O-acetylhomoserine (metY)Reactiondirect_sulfhydrylation

One enzyme, using free sulfide on O-acetyl-homoserine.

Annotons

metY: O-acetylhomoserine sulfhydrylase
metY_activity
Participant: Family: metY (O-acetylhomoserine sulfhydrylase)
Gene:
metY (O-acetylhomoserine sulfhydrylase)
Family:
O-acetylhomoserine sulfhydrylases No family identifier is asserted because the available homocysteine/cysteine synthase family does not by itself establish O-acetylhomoserine specificity.
Representative Members: MetY (Corynebacterium glutamicum)UniProtKB:Q79VI4

Function

O-acetylhomoserine aminocarboxypropyltransferase activityGO:0003961
Direct sulfhydrylation of O-succinylhomoserine (metZ)Reactiondirect_sulfhydrylation_metZ

One enzyme, using free sulfide on O-succinylhomoserine to form L-homocysteine. This route must be paired with a homoserine O-succinyltransferase rather than an O-acetyltransferase.

Annotons

metZ: O-succinylhomoserine sulfhydrylase
metZ_activity
Participant: Family: metZ (O-succinylhomoserine sulfhydrylase)
Gene:
metZ (O-succinylhomoserine sulfhydrylase)
Family:
O-succinylhomoserine sulfhydrylases No family identifier is asserted because the available trans-sulfuration PANTHER family spans multiple reaction directions and sulfur-incorporation routes.
Representative Members: MetZ (PSEPK)UniProtKB:Q88LD4

Function

O-succinylhomoserine sulfhydrylase activityGO:0016765

Converts O-succinyl-L-homoserine and sulfide to L-homocysteine; GO:0016765 captures the EC 2.5.1 transfer class; the exact O-succinylhomoserine reaction is stated here because GO lacks a more specific live molecular-function term.

Part 3: methylation of homocysteine to methionine (cobalamin-independent or -dependent)
Homocysteine methylation to methionineMetabolic Pathwaymethylation
Variant set: Methionine synthase by cobalamin dependence (One Or More)
Cobalamin-independent synthase (metE)ReactionmetE_variant

Annotons

metE: cobalamin-independent methionine synthase
metE_activity
Participant: Family: metE (cobalamin-independent methionine synthase)
Gene:
metE (cobalamin-independent methionine synthase)
Family:
cobalamin-independent methionine synthases A PANTHER identifier is deliberately omitted because the locally assigned PTHR30519 groups complete MetE enzymes with partial MetE-like proteins and does not by itself establish catalytic competence.
Representative Members: MetE (Escherichia coli K-12)UniProtKB:P25665

Function

5-methyltetrahydropteroyltriglutamate-homocysteine S-methyltransferase activityGO:0003871
Cobalamin-dependent synthase (metH)ReactionmetH_variant

Annotons

metH: cobalamin-dependent methionine synthase
metH_activity
Participant: Family: metH (cobalamin-dependent methionine synthase)
Gene:
metH (cobalamin-dependent methionine synthase)
Family:
cobalamin-dependent methionine synthases
Representative Members: MetH (PSEPK)UniProtKB:Q88KB5 MetH (Escherichia coli K-12)UniProtKB:P13009

Function

methionine synthase activityGO:0008705