folC Resolved · high auto-curated
H37Rv Rv2447c · MTBC0 mtbc0_002606 ·
487 aa · 2770383–2771846 (-) ·
RefSeq NP_216963.1
Annotation: from legacy to revised
| Legacy (H37Rv / Mycobrowser) | folylpolyglutamate synthase FolC |
|---|---|
| MTBC0 PGAP re-annotation | bifunctional tetrahydrofolate synthase/dihydrofolate synthase |
| Revised (this work) | Bifunctional tetrahydrofolate synthase/dihydrofolate synthase. Pfam: Mur_ligase_M (PF08245.19), Mur_ligase_C (PF02875.27). |
Auto-curated: this verdict and function were generated by rules from PGAP + Pfam + Foldseek and have not been hand-reviewed.
Curated reference (UniProt)
| UniProt |
I6Y0R5
SwissProt · reviewed
· Evidence at protein level
|
|---|---|
| UniProt name | Dihydrofolate synthase/folylpolyglutamate synthase |
| EC (curated) |
EC 6.3.2.12, EC 6.3.2.17
|
| Curated function | Catalyzes the addition of a glutamate residue to dihydropteroate (7,8-dihydropteroate or H2Pte) to form dihydrofolate (7,8-dihydrofolate monoglutamate or H2Pte-Glu). Also catalyzes successive additions of L-glutamate to tetrahydrofolate, leading to folylpolyglutamate derivatives (By similarity)..; FUNCTION: Is involved in the bioactivation of the antituberculous drug para-aminosalicylic acid (PAS). Is able to use hydroxy-dihydropteroate (H2PtePAS) as substrate, which is the product formed by the action of DHPS (FolP1) on PAS, leading to hydroxy-dihydrofolate (H2PtePAS-Glu). This compound inhib. |
Functional vocabulary (eggNOG-mapper, orthology transfer)
| COG category |
H Coenzyme transport and metabolism
|
|---|---|
| Preferred name | folC |
| eggNOG description | Folylpolyglutamate synthase |
| Orthologous group | COG0285 |
| EC number |
EC 6.3.2.12, EC 6.3.2.17
|
| KEGG orthology |
K11754
|
| KEGG pathways |
map00790, map01100
|
| KEGG modules |
M00126, M00841
|
| Gene Ontology (57) |
GO:0003674, GO:0003824, GO:0004326, GO:0005575, GO:0005622, GO:0005623, GO:0005737, GO:0006082, GO:0006575, GO:0006725, GO:0006732, GO:0006760 +45 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 | 3.64 · diversifying/relaxed |
|---|---|
| Polymorphic sites (≥ 0.1% of strains) | 1 synonymous, 10 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 |
|---|---|---|---|---|
Mur_ligase_M | PF08245.19 | 3.0e-10 | 158–308 | Mur ligase middle domain |
Mur_ligase_C | PF02875.27 | 1.4e-15 | 337–448 | Mur ligase, glutamate ligase domain |
Functional interaction network (STRING v12, guilt-by-association)
Closest characterised functional partner: folP1 (dihydropteroate synthase), high confidence from genomic context alone (score 994 excluding text-mining).
| Partner | Product | Score | No text-mining | Channels (≥400) |
|---|---|---|---|---|
Rv3608c folP1 |
dihydropteroate synthase | 999 | 994 ctx | fusion:840 coexpression:431 database:900 textmining:924 |
Rv1207 folP2 |
dihydropteroate synthase | 993 | 985 ctx | fusion:603 coexpression:431 database:900 textmining:603 |
Rv2448c valS |
valine--tRNA ligase | 959 | 935 ctx | neighborhood:881 coexpression:475 textmining:406 |
Rv2446c |
integral membrane protein | 967 | 909 ctx | neighborhood:882 textmining:660 |
Rv2763c dfrA |
dihydrofolate reductase | 991 | 900 | database:900 textmining:922 |
Rv2764c thyA |
thymidylate synthase ThyA | 985 | 801 | database:800 textmining:929 |
Rv2445c ndkA |
nucleoside diphosphate kinase | 810 | 751 ctx | neighborhood:708 |
Rv1093 glyA1 |
serine hydroxymethyltransferase | 658 | 609 | database:500 |
Rv0070c glyA2 |
serine hydroxymethyltransferase | 654 | 604 | database:500 |
Rv2449c |
trans-acting enoyl reductase | 603 | 603 ctx | neighborhood:599 |
Rv3607c folB |
dihydroneopterin aldolase | 919 | 487 | coexpression:445 textmining:850 |
Rv3609c folE |
GTP cyclohydrolase I | 870 | 487 | coexpression:445 textmining:757 |
Rv3606c folK |
2-amino-4-hydroxy-6-hydroxymethyldihydropteridinepyrophosphokinase | 689 | 487 | coexpression:445 textmining:419 |
Rv3396c guaA |
GMP synthase | 719 | 467 | textmining:496 |
Rv1341 rdgB |
non-canonical purine NTP pyrophosphatase | 494 | 461 |
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: folylpolyglutamate synthase FolC
- MTBC0 PGAP product: bifunctional tetrahydrofolate synthase/dihydrofolate synthase
- Pfam (hmmscan --cut_ga): Mur_ligase_M PF08245.19 (E=3e-10), Mur_ligase_C PF02875.27 (E=1e-15)
- (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_216963.1)
- Domains: Pfam-A via hmmscan --cut_ga — Mur_ligase_M (PF08245.19), Mur_ligase_C (PF02875.27)
- 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
COG0285 - Curated reference: UniProt I6Y0R5 (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 —
64 functional partner(s); context anchor
folP1 - Primary literature: none located yet; annotation rests on the domain/homology sources above.
Ancestral MTBC0 protein sequence
>mtbc0_002606|Rv2447c|folC MNSTNSGPPDSGSATGVVPTPDEIASLLQVEHLLDQRWPETRIDPSLTRISALMDLLGSPQRSYPSIHIAGTNGKTSVARMVDALVTALHRRTGRTTSPHLQSPVERISIDGKPISPAQYVATYREIEPLVALIDQQSQASAGKGGPAMSKFEVLTAMAFAAFADAPVDVAVVEVGMGGRWDATNVINAPVAVITPISIDHVDYLGADIAGIAGEKAGIITRAPDGSPDTVAVIGRQVPKVMEVLLAESVRADASVAREDSEFAVLRRQIAVGGQVLQLQGLGGVYSDIYLPLHGEHQAHNAVLALASVEAFFGAGAQRQLDGDAVRAGFAAVTSPGRLERMRSAPTVFIDAAHNPAGASALAQTLAHEFDFRFLVGVLSVLGDKDVDGILAALEPVFDSVVVTHNGSPRALDVEALALAAGERFGPDRVRTAENLRDAIDVATSLVDDAAADPDVAGDAFSRTGIVITGSVVTAGAARTLFGRDPQ