folD Resolved · high auto-curated
H37Rv Rv3356c · MTBC0 - ·
281 aa · 3769804–3770649 (-) ·
RefSeq NP_217873.1
Annotation: from legacy to revised
| Legacy (H37Rv / Mycobrowser) | bifunctional methylenetetrahydrofolate dehydrogenase/methenyltetrahydrofolate cyclohydrolase |
|---|---|
| MTBC0 PGAP re-annotation | — |
| Revised (this work) | Bifunctional methylenetetrahydrofolate dehydrogenase/methenyltetrahydrofolate cyclohydrolase. Pfam: THF_DHG_CYH (PF00763.29), THF_DHG_CYH_C (PF02882.26). |
Auto-curated: this verdict and function were generated by rules from PGAP + Pfam + Foldseek and have not been hand-reviewed.
Annotated on the H37Rv protein: this gene has no 1:1 ancestral MTBC0 anchor (PE/PPE, paralogue, IS element, or otherwise unanchored CDS).
Curated reference (UniProt)
| UniProt |
P9WG81
SwissProt · reviewed
· Evidence at protein level
|
|---|---|
| UniProt name | Bifunctional protein FolD [Includes: Methylenetetrahydrofolate dehydrogenase |
| EC (curated) |
EC 1.5.1.5, EC 3.5.4.9
|
| Curated function | Catalyzes the oxidation of 5,10-methylenetetrahydrofolate to 5,10-methenyltetrahydrofolate and then the hydrolysis of 5,10-methenyltetrahydrofolate to 10-formyltetrahydrofolate. |
Functional vocabulary (eggNOG-mapper, orthology transfer)
| COG category |
F Nucleotide transport and metabolism
|
|---|---|
| Preferred name | folD |
| eggNOG description | Catalyzes the oxidation of 5,10- methylenetetrahydrofolate to 5,10-methenyltetrahydrofolate and then the hydrolysis of 5,10-methenyltetrahydrofolate to 10- formyltetrahydrofolate |
| Orthologous group | COG0190 |
| EC number |
EC 1.5.1.5, EC 3.5.4.9
|
| KEGG orthology |
K01491
|
| KEGG pathways |
map00670, map00720, map01100, map01120, map01200
|
| KEGG modules |
M00140, M00377
|
| Gene Ontology (31) |
GO:0003674, GO:0003824, GO:0004477, GO:0004488, GO:0005575, GO:0005576, GO:0005622, GO:0005623, GO:0005737, GO:0005829, GO:0005886, GO:0006730 +19 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 | 0.563 · relaxed/neutral |
|---|---|
| Polymorphic sites (≥ 0.1% of strains) | 2 synonymous, 3 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 |
|---|---|---|---|---|
THF_DHG_CYH | PF00763.29 | 7.5e-37 | 6–120 | Tetrahydrofolate dehydrogenase/cyclohydrolase, catalytic domain |
THF_DHG_CYH_C | PF02882.26 | 1.5e-52 | 139–280 | Tetrahydrofolate dehydrogenase/cyclohydrolase, NAD(P)-binding domain |
Functional interaction network (STRING v12, guilt-by-association)
Closest characterised functional partner: Rv3355c (integral membrane protein), high confidence from genomic context alone (score 882 excluding text-mining).
| Partner | Product | Score | No text-mining | Channels (≥400) |
|---|---|---|---|---|
Rv0070c glyA2 |
serine hydroxymethyltransferase | 982 | 971 | coexpression:647 database:900 textmining:415 |
Rv1093 glyA1 |
serine hydroxymethyltransferase | 982 | 971 | coexpression:651 database:900 textmining:415 |
Rv0957 purH |
bifunctional phosphoribosylaminoimidazolecarboxamide formyltransferase/inosinemonophosphate cyclohydrolase | 994 | 969 | coexpression:648 database:900 textmining:845 |
Rv0956 purN |
phosphoribosylglycinamide formyltransferase PurN | 995 | 962 | coexpression:425 database:900 textmining:895 |
Rv2211c gcvT |
aminomethyltransferase | 960 | 948 | coexpression:460 database:900 |
Rv1406 fmt |
methionyl-tRNA formyltransferase | 961 | 947 | coexpression:461 database:900 |
Rv2964 purU |
formyltetrahydrofolate deformylase | 974 | 941 | database:900 textmining:593 |
Rv2764c thyA |
thymidylate synthase ThyA | 965 | 924 | database:900 textmining:565 |
Rv2754c thyX |
thymidylate synthase ThyX | 948 | 908 | database:900 textmining:458 |
Rv0992c |
5-formyltetrahydrofolate cyclo-ligase | 929 | 908 | database:900 |
Rv0389 purT |
phosphoribosylglycinamide formyltransferase PurT | 906 | 900 | database:900 |
Rv3355c |
integral membrane protein | 882 | 882 ctx | neighborhood:881 |
Rv1832 gcvB |
glycine dehydrogenase | 900 | 831 | coexpression:492 database:500 textmining:435 |
Rv0777 purB |
adenylosuccinate lyase PurB | 819 | 783 | coexpression:770 |
Rv3359 |
oxidoreductase | 754 | 739 ctx | neighborhood:738 |
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
- Annotation from H37Rv (no MTBC0 1:1 anchor; H37Rv protein used): bifunctional methylenetetrahydrofolate dehydrogenase/methenyltetrahydrofolate cyclohydrolase
- Pfam (hmmscan --cut_ga): THF_DHG_CYH PF00763.29 (E=8e-37), THF_DHG_CYH_C PF02882.26 (E=2e-52)
- (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_217873.1)
- Domains: Pfam-A via hmmscan --cut_ga — THF_DHG_CYH (PF00763.29), THF_DHG_CYH_C (PF02882.26)
- 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
COG0190 - Curated reference: UniProt P9WG81 (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 —
84 functional partner(s); context anchor
Rv3355c - Primary literature: none located yet; annotation rests on the domain/homology sources above.
Ancestral MTBC0 protein sequence
>H37Rv|Rv3356c|folD MGAIMLDGKATRDEIFGDLKQRVAALDAAGRTPGLGTILVGDDPGSQAYVRGKHADCAKVGITSIRRDLPADISTATLNETIDELNANPDCTGYIVQLPLPKHLDENAALERVDPAKDADGLHPTNLGRLVLGTPAPLPCTPRGIVHLLRRYDISIAGAHVVVIGRGVTVGRPLGLLLTRRSENATVTLCHTGTRDLPALTRQADIVVAAVGVAHLLTADMVRPGAAVIDVGVSRTDDGLVGDVHPDVWELAGHVSPNPGGVGPLTRAFLLTNVVELAERR