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. Fungi such as Saccharomyces cerevisiae and Schizosaccharomyces pombe activate homoserine with an acetyl group, rely mainly on direct sulfhydrylation of O-acetylhomoserine with sulfide from sulfate assimilation, can also make homocysteine from cysteine by trans-sulfuration, and finish with a cobalamin-independent methionine synthase that requires a polyglutamylated 5-methyltetrahydrofolate. Plants use a cobalamin-independent synthase and a trans-sulfuration route whose cystathionine gamma-synthase takes O-phospho-L-homoserine rather than an acylated homoserine.

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. ALIGN with YeastPathways (2026-10; PWY3O-954, PWY-5344, PWY3O-238). The module concept moved from GO:0071265 to its child GO:0071266 'de novo' L-methionine biosynthetic process, and the MetY leaf function from GO:0003961 to its child GO:0051009 O-acetylhomoserine sulfhydrylase activity, which is the exact reaction. Fungal exemplars were added without changing the route structure: MET2 and S. pombe met6 (acetyl activation), MET17 and S. pombe met17 (direct sulfhydrylation), STR2, S. pombe met3, STR3 and S. pombe cbl1 (trans-sulfuration), and MET6 and S. pombe met26 (cobalamin-independent synthase). Plant CGS1 and CBL were added to the trans-sulfuration enzymes. YeastCyc assessment: the HOM3, HOM2 and HOM6 reactions in PWY3O-954 are the upstream aspartate-family trunk, modelled in aspartate_family_threonine_biosynthesis. MET2, MET17 and MET6 are correct. STR2 and STR3, which make homocysteine from cysteine (PMID:10821189), are missing from the YeastCyc gene lists although the pathway comment describes that route. MET7 (folylpolyglutamate synthase) is required because Met6 uses only polyglutamylated 5-methyltetrahydrofolate (PMID:10799479), but it supplies a co-substrate and is kept outside the module, like sulfide supply and the MET13/MET12 methylenetetrahydrofolate reductases that make the methyl donor. All yeast activities are cytosolic in the GO-CAMs; no compartment is asserted because plant steps up to cystathionine are plastidial. Known structural gap: plants activate homoserine by phosphorylation (homoserine kinase), and their cystathionine gamma-synthase uses O-phospho-L-homoserine (PMID:9636232). That route is not yet a variant of the acylation step because tests/test_module_logic.py fixes the route/gene inventory of this template; homoserine kinase is modelled in aspartate_family_threonine_biosynthesis. GO-CAM disagreements: (a) SGD models type MET17 with the broader GO:0003961, whereas PomBase uses GO:0051009; (b) YeastPathways_P4-PWY-1 (threonine superpathway) chains MET6 -> MET17 -> MET2 -> THR1 with causally-upstream edges, the reverse of the biosynthetic order; (c) the PomBase model places S. pombe met3 (cystathionine gamma-synthase) in GO:0019344 cysteine biosynthesis although gamma-synthase forms homocysteine precursors, and it has no cystathionine beta-lyase activity; (d) the PomBase model includes two uncharacterised FAD-binding proteins (SPAC1783.01, SPBC12C2.03c) typed as GO:0030586 [methionine synthase] reductase, upstream of the cobalamin-independent met26. That reductase reactivates cobalamin-dependent MetH-type synthases, and S. pombe has no MetH, so these activities are not adopted.