Annotation: from legacy to revised
| Legacy (H37Rv / Mycobrowser) | 2-isopropylmalate synthase |
|---|
| MTBC0 PGAP re-annotation | 2-isopropylmalate synthase |
|---|
| Revised (this work) | 2-isopropylmalate synthase. Pfam: HMGL-like (PF00682.26), IPMS_D2 (PF22615.2), LeuA_dimer (PF08502.16). |
|---|
Auto-curated: this verdict and function were generated by rules from
PGAP + Pfam + Foldseek and have not been hand-reviewed.
Curated reference (UniProt)
| UniProt |
P9WQB3
SwissProt · reviewed
· Evidence at protein level
|
|---|
| UniProt name | 2-isopropylmalate synthase |
|---|
| EC (curated) |
EC 2.3.3.13
|
|---|
| Curated function | Catalyzes the condensation of the acetyl group of acetyl-CoA with 3-methyl-2-oxobutanoate (alpha-ketoisovalerate) to form 3-carboxy-3-hydroxy-4-methylpentanoate (2-isopropylmalate). Active on small alpha-keto acids such as 3-methyl-2-oxobutanoate, pyruvate, alpha-ketovalerate, and alpha-ketobutyrate; only uses acetyl-CoA. Complements an E.coli deletion. |
|---|
Functional vocabulary (eggNOG-mapper, orthology transfer)
| COG category |
E Amino acid transport and metabolism
|
|---|
| Preferred name | leuA |
|---|
| eggNOG description | Catalyzes the condensation of the acetyl group of acetyl-CoA with 3-methyl-2-oxobutanoate (2-oxoisovalerate) to form 3-carboxy-3-hydroxy-4-methylpentanoate (2-isopropylmalate) |
|---|
| Orthologous group | COG0119 |
|---|
| EC number |
EC 2.3.3.13
|
|---|
| KEGG orthology |
K01649
|
|---|
| KEGG pathways |
map00290, map00620, map01100, map01110, map01210, map01230
|
|---|
| KEGG modules |
M00432
|
|---|
| Gene Ontology (51) |
GO:0000287, GO:0003674, GO:0003824, GO:0003852, GO:0005488, GO:0005575, GO:0005576, GO:0005623, GO:0005886, GO:0006082, GO:0006520, GO:0006551 +39 more
|
|---|
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)
| pN/pS |
0.257 · purifying
|
|---|
| Polymorphic sites (≥ 0.1% of strains) |
9 synonymous, 7 missense, 0 nonsense, 0 frameshift
|
|---|
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 |
|---|
HMGL-like | PF00682.26 |
9.0e-75 | 73–352 |
HMGL-like |
IPMS_D2 | PF22615.2 |
4.1e-35 | 369–442 |
Alpha-isopropylmalate synthase, post-catalytic domain-like |
LeuA_dimer | PF08502.16 |
1.7e-16 | 474–574 |
LeuA allosteric (dimerisation) domain |
Functional interaction network (STRING v12, guilt-by-association)
| Partner | Product | Score | No text-mining | Channels (≥400) |
|---|
Rv3535c hsaG |
acetaldehyde dehydrogenase |
985 |
984 |
experimental:788 database:900 |
Rv2988c leuC |
3-isopropylmalate dehydratase large subunit |
990 |
976 |
coexpression:696 database:900 textmining:615 |
Rv2987c leuD |
3-isopropylmalate dehydratase small subunit |
990 |
976 |
coexpression:695 database:900 textmining:616 |
Rv0189c ilvD |
dihydroxy-acid dehydratase |
988 |
965 |
coexpression:655 database:900 textmining:695 |
Rv2210c ilvE |
branched-chain amino acid aminotransferase |
987 |
965 |
coexpression:608 database:900 textmining:662 |
Rv3285 accA3 |
bifunctional protein acetyl-/propionyl-CoA carboxylase subunit alpha AccA |
945 |
943 |
coexpression:431 database:900 |
Rv2501c accA1 |
acetyl/propionyl-CoA carboxylase subuit alpha |
945 |
942 |
coexpression:428 database:900 |
Rv2247 accD6 |
acetyl-/propionyl-CoA carboxylase subunit beta |
944 |
942 |
database:900 |
Rv3002c ilvN |
acetolactate synthase small subunit |
981 |
938 |
coexpression:595 database:800 textmining:709 |
Rv1323 fadA4 |
acetyl-CoA acetyltransferase |
926 |
924 |
database:900 |
Rv0243 fadA2 |
acetyl-CoA acetyltransferase FadA |
926 |
924 |
database:900 |
Rv3523 ltp3 |
lipid carrier protein |
926 |
923 |
database:900 |
Rv3556c fadA6 |
acetyl-CoA acetyltransferase FadA |
926 |
923 |
database:900 |
Rv1867 hyp |
hypothetical protein |
925 |
923 |
database:900 |
Rv0859 fadA |
acyltransferase |
925 |
923 |
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: 2-isopropylmalate synthase
- MTBC0 PGAP product: 2-isopropylmalate synthase
- Pfam (hmmscan --cut_ga): HMGL-like PF00682.26 (E=9e-75), IPMS_D2 PF22615.2 (E=4e-35), LeuA_dimer PF08502.16 (E=2e-16)
- (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_218227.3)
- Domains: Pfam-A via hmmscan --cut_ga — HMGL-like (PF00682.26), IPMS_D2 (PF22615.2), LeuA_dimer (PF08502.16)
- 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
COG0119
- Curated reference: UniProt
P9WQB3
(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 —
152 functional partner(s)
- Primary literature: none located yet; annotation rests on the domain/homology sources above.
Ancestral MTBC0 protein sequence
>mtbc0_003933|Rv3710|leuA
MTTSESPDAYTESFGAHTIVKPAGPPRVGQPSWNPQRASSMPVNRYRPFAEEVEPIRLRNRTWPDRVIDRAPLWCAVDLRDGNQALIDPMSPARKRRMFDLLVRMGYKEIEVGFPSASQTDFDFVREIIEQGAIPDDVTIQVLTQCRPELIERTFQACSGAPRAIVHFYNSTSILQRRVVFRANRAEVQAIATDGARKCVEQAAKYPGTQWRFEYSPESYTGTELEYAKQVCDAVGEVIAPTPERPIIFNLPATVEMTTPNVYADSIEWMSRNLANRESVILSLHPHNDRGTAVAAAELGFAAGADRIEGCLFGNGERTGNVCLVTLGLNLFSRGVDPQIDFSNIDEIRRTVEYCNQLPVHERHPYGGDLVYTAFSGSHQDAINKGLDAMKLDADAADCDVDDMLWQVPYLPIDPRDVGRTYEAVIRVNSQSGKGGVAYIMKTDHGLSLPRRLQIEFSQVIQKIAEGTAGEGGEVSPKEMWDAFAEEYLAPVRPLERIRQHVDAADDDGGTTSITATVKINGVETEISGSGNGPLAAFVHALADVGFDVAVLDYYEHAMSAGDDAQAAAYVEASVTIASPAQPGEAGRHASDPVTIASPAQPGEAGRHASDPVTIASPAQPGEAGRHASDPVTIASPAQPGEAGRHASDPVTSKTVWGVGIAPSITTASLRAVVSAVNRAAR
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