Annotation: from legacy to revised
| Legacy (H37Rv / Mycobrowser) | methionine synthase |
|---|
| MTBC0 PGAP re-annotation | methionine synthase |
|---|
| Revised (this work) | Methionine synthase. Pfam: S-methyl_trans (PF02574.23), Pterin_bind (PF00809.29), B12-binding_2 (PF02607.23), B12-binding (PF02310.25), Met_synt_B12 (PF02965.23). |
|---|
Auto-curated: this verdict and function were generated by rules from
PGAP + Pfam + Foldseek and have not been hand-reviewed.
Curated reference (UniProt)
| UniProt |
O33259
SwissProt · reviewed
· Evidence at protein level
|
|---|
| UniProt name | Methionine synthase |
|---|
| EC (curated) |
EC 2.1.1.13
|
|---|
| Curated function | Catalyzes the transfer of a methyl group from methyl-cobalamin to homocysteine, yielding enzyme-bound cob(I)alamin and methionine. Subsequently, remethylates the cofactor using methyltetrahydrofolate (By similarity). |
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Functional vocabulary (eggNOG-mapper, orthology transfer)
| COG category |
E Amino acid transport and metabolism
|
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| Preferred name | metH |
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| eggNOG description | Methionine synthase |
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| Orthologous group | COG0646 |
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| EC number |
EC 2.1.1.13
|
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| KEGG orthology |
K00548
|
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| KEGG pathways |
map00270, map00450, map00670, map01100, map01110, map01230
|
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| KEGG modules |
M00017
|
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| Gene Ontology (53) |
GO:0000096, GO:0000097, GO:0003674, GO:0003824, GO:0005575, GO:0005618, GO:0005622, GO:0005623, GO:0005737, GO:0005829, GO:0005886, GO:0006082 +41 more
|
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Orthology-based transfer (eggNOG 5.0.2, diamond). EC/KO/GO/CAZy are
computed annotations, not manual curation; cross-check against the primary literature
before treating a specific reaction as established.
Conservation & selection (intra-MTBC, 145 209 strains)
pseudogene candidate
| pN/pS |
0.498 · purifying
|
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| Polymorphic sites (≥ 0.1% of strains) |
12 synonymous, 17 missense, 1 nonsense, 2 frameshift
|
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| Disruption |
3 distinct premature-stop/frameshift site(s); most common in
1.87% of strains
(2717) · clonal
|
|---|
pN/pS from segregating SNPs (singletons removed) normalised by possible sites.
Low pN/pS = purifying selection (a strong signal that a "hypothetical" is a real, constrained gene).
A high pN/pS is ambiguous: relaxed constraint or positive selection (drug resistance, antigenic
variation) inflate it; e.g. rpoB/katG/pncA score high here for resistance, not loss of function. A
clonal disruption (one allele over a clade) suggests lineage pseudogenisation; a
convergent one (many independent alleles) is typical of resistance loss-of-function.
Domains (Pfam, hmmscan --cut_ga)
| Pfam | Accession | i-Evalue | Residues | Description |
|---|
S-methyl_trans | PF02574.23 |
3.1e-76 | 22–312 |
Homocysteine S-methyltransferase |
Pterin_bind | PF00809.29 |
2.1e-48 | 347–583 |
Pterin binding enzyme |
B12-binding_2 | PF02607.23 |
5.5e-23 | 644–717 |
B12 binding domain |
B12-binding | PF02310.25 |
3.9e-19 | 730–849 |
B12 binding domain |
Met_synt_B12 | PF02965.23 |
3.0e-30 | 978–1192 |
Vitamin B12 dependent methionine synthase, activation domain |
Functional interaction network (STRING v12, guilt-by-association)
| Partner | Product | Score | No text-mining | Channels (≥400) |
|---|
Rv2172c hyp |
hypothetical protein |
990 |
977 |
coexpression:964 textmining:583 |
Rv1079 metB |
cystathionine gamma-synthase |
987 |
969 |
coexpression:644 database:900 textmining:618 |
Rv0391 metZ |
O-succinylhomoserine sulfhydrylase |
982 |
969 |
coexpression:644 database:900 textmining:445 |
Rv1133c metE |
5-methyltetrahydropteroyltriglutamate--homocysteine methyltransferase |
996 |
956 |
coexpression:521 database:900 textmining:930 |
Rv3340 metC |
O-acetylhomoserine sulfhydrylase |
984 |
940 |
database:900 textmining:755 |
Rv3248c sahH |
adenosylhomocysteinase |
971 |
940 |
database:900 textmining:554 |
Rv2211c gcvT |
aminomethyltransferase |
966 |
935 |
database:900 textmining:516 |
Rv1392 metK |
S-adenosylmethionine synthetase |
968 |
932 |
database:900 textmining:554 |
Rv1007c metS |
methionine--tRNA ligase |
921 |
914 |
database:900 |
Rv1294 thrA |
homoserine dehydrogenase |
958 |
913 |
coexpression:428 database:800 textmining:542 |
Rv1077 cbs |
cystathionine beta-synthase |
937 |
911 |
database:900 |
Rv2458 mmuM |
homocysteine S-methyltransferase MmuM |
957 |
910 |
database:900 textmining:548 |
Rv0957 purH |
bifunctional phosphoribosylaminoimidazolecarboxamide formyltransferase/inosinemonophosphate cyclohydrolase |
914 |
908 |
database:900 |
Rv2964 purU |
formyltetrahydrofolate deformylase |
914 |
907 |
database:900 |
Rv1406 fmt |
methionyl-tRNA formyltransferase |
922 |
905 |
database:900 |
STRING combines evidence channels (neighborhood, fusion, cooccurrence, coexpression,
experimental, database, text-mining) into a 0–1000 score. The ctx
badge marks edges carried by the genomic-context channels (conserved neighborhood, fusion,
phylogenetic co-occurrence), which are independent of orthology and structure and the strongest signal for an
unknown gene. The no text-mining column recomputes the score from data alone, so a link that does not
depend on the literature is visible. Association is a function hypothesis, not proof: corroborate with
the operon context and the primary literature before assigning a function.
Evidence
- Legacy H37Rv annotation: methionine synthase
- MTBC0 PGAP product: methionine synthase
- Pfam (hmmscan --cut_ga): S-methyl_trans PF02574.23 (E=3e-76), Pterin_bind PF00809.29 (E=2e-48), B12-binding_2 PF02607.23 (E=6e-23), B12-binding PF02310.25 (E=4e-19), Met_synt_B12 PF02965.23 (E=3e-30)
- (auto-curated by rules from PGAP + Pfam + Foldseek; not hand-reviewed)
Sources
- Ancestral sequence & coordinates: Harrison LB et al. (2024),
An imputed ancestral reference genome for the MTBC,
doi:10.1101/2023.09.07.556366
- Product annotation: NCBI PGAP on MTBC0; legacy from H37Rv NC_000962.3 (RefSeq NP_216640.1)
- Domains: Pfam-A via hmmscan --cut_ga — S-methyl_trans (PF02574.23), Pterin_bind (PF00809.29), B12-binding_2 (PF02607.23), B12-binding (PF02310.25), Met_synt_B12 (PF02965.23)
- Sequence-level signal: ESM Atlas (EvolutionaryScale × BioHub) — exploratory
- Controlled vocabulary: eggNOG-mapper 2.1.12 (Cantalapiedra et al. 2021,
doi:10.1093/molbev/msab293), eggNOG 5.0 DB
(Huerta-Cepas et al. 2019) — OG
COG0646
- Curated reference: UniProt
O33259
(SwissProt, reviewed; Evidence at protein level)
- Intra-MTBC selection: pN/pS and disruption from SPDI variants of
145 209 MTBC strains (this work, local collection vs H37Rv NC_000962.3)
- Interaction network: STRING v12.0 (Szklarczyk et al. 2023,
doi:10.1093/nar/gkac1000), taxon 83332, CC-BY 4.0 —
151 functional partner(s)
- Primary literature: none located yet; annotation rests on the domain/homology sources above.
Ancestral MTBC0 protein sequence
>mtbc0_002256|Rv2124c|metH
MTAADKHLYDTDLLDVLSQRVMVGDGAMGTQLQAADLTLDDFRGLEGCNEILNETRPDVLETIHRNYFEAGADAVETNTFGCNLSNLGDYDIADRIRDLSQKGTAIARRVADELGSPDRKRYVLGSMGPGTKLPTLGHTEYAVIRDAYTEAALGMLDGGADAILVETCQDLLQLKAAVLGSRRAMTRAGRHIPVFAHVTVETTGTMLLGSEIGAALTAVEPLGVDMIGLNCATGPAEMSEHLRHLSRHARIPVSVMPNAGLPVLGAKGAEYPLLPDELAEALAGFIAEFGLSLVGGCCGTTPAHIREVAAAVANIKRPERQVSYEPSVSSLYTAIPFAQDASVLVIGERTNANGSKGFREAMIAEDYQKCLDIAKDQTRDGAHLLDLCVDYVGRDGVADMKALASRLATSSTLPIMLDSTETAVLQAGLEHLGGRCAINSVNYEDGDGPESRFAKTMALVAEHGAAVVALTIDEEGQARTAQKKVEIAERLINDITGNWGVDESSILIDTLTFTIATGQEESRRDGIETIEAIRELKKRHPDVQTTLGLSNISFGLNPAARQVLNSVFLHECQEAGLDSAIVHASKILPMNRIPEEQRNVALDLVYDRRREDYDPLQELMRLFEGVSAASSKEDRLAELAGLPLFERLAQRIVDGERNGLDADLDEAMTQKPPLQIINEHLLAGMKTVGELFGSGQMQLPFVLQSAEVMKAAVAYLEPHMERSDDDSGKGRIVLATVKGDVHDIGKNLVDIILSNNGYEVVNIGIKQPIATILEVAEDKSADVVGMSGLLVKSTVVMKENLEEMNTRGVAEKFPVLLGGAALTRSYVENDLAEIYQGEVHYARDAFEGLKLMDTIMSAKRGEAPDENSPEAIKAREKEAERKARHQRSKRIAAQRKAAEEPVEVPERSDVAADIEVPAPPFWGSRIVKGLAVADYTGLLDERALFLGQWGLRGQRGGEGPSYEDLVETEGRPRLRYWLDRLSTDGILAHAAVVYGYFPAVSEGNDIVVLTEPKPDAPVRYRFHFPRQQRGRFLCIADFIRSRELAAERGEVDVLPFQLVTMGQPIADFANELFASNAYRDYLEVHGIGVQLTEALAEYWHRRIREELKFSGDRAMAAEDPEAKEDYFKLGYRGARFAFGYGACPDLEDRAKMMALLEPERIGVTLSEELQLHPEQSTDAFVLHHPEAKYFNV
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