hpt Resolved · high auto-curated

H37Rv Rv3624c · MTBC0 mtbc0_003841 · 216 aa · 4086958–4087608 MTBC0 (-) · RefSeq NP_218141.1

Annotation: from legacy to revised

Legacy (H37Rv / Mycobrowser)	hypoxanthine-guanine phosphoribosyltransferase
MTBC0 PGAP re-annotation	hypoxanthine phosphoribosyltransferase
Revised (this work)	Hypoxanthine phosphoribosyltransferase. Pfam: Pribosyltran (PF00156.34).
Functional category (TubercuList)	intermediary metabolism and respiration

Auto-curated: this verdict and function were generated by rules from PGAP + Pfam + Foldseek and have not been hand-reviewed.

In the literature (TB corpus sweep) 18 publications

18 TB publications mention this gene. 18 publication(s) discuss this gene (20 in a M. tuberculosis context, 1 in other mycobacteria — M. smegmatis (1)).

Most recent 5 of 18.
Publication	Date
The association between dietary inflammatory index and latent tuberculosis infection: Confounding role of country of birth. doi:10.1016/j.clinsp.2026.100937	2026
Non-communicable diseases and resistant tuberculosis, a growing burden among people living with HIV in Eastern Kenya. doi:10.1371/journal.pgph.0004212	2025
Two-stage treatment for severe spinal kyphotic deformity secondary to tuberculosis: halo-pelvic traction followed by a posterior-only approach correction. doi:10.1186/s12891-022-05974-7	2022
Discovery of multi-target mur enzymes inhibitors with anti-mycobacterial activity through a Scaffold approach. doi:10.1080/07391102.2022.2040593	2023
Bayesian estimation of prevalence of Johne's disease in dairy herds in Southern Italy. doi:10.1016/j.prevetmed.2021.105552	2022

This layer CITES the literature and adds context; it does not change the verdict or the function stated elsewhere in this fiche. This distinguishes a gene that is dark because nobody has looked from one that is dark despite having been studied. Source: PubMed (whole): H37Rv locus tag + GENE NAME + ortholog identifiers (Mb…, MMAR_…, MSMEG_…, ML…, MAB_…), under a mycobacterial context filter; hits verified against the abstract text. Species-context counts distinguish M. tuberculosis literature from literature on other mycobacteria. phase76/phase77, 2026-07-13.

Genomic-neighbour overlap (structural caveat) co-directional · 1 % of gene

Neighbour	tilS (Rv3625c, - strand)
Overlap	4 bp, 1 % of this gene's length

co-directional overlap: ordinary (e.g. shared stop/start codons in an operon), not the Rv2438A-type artefact P20.1, derived from GFF3 gene coordinates, 2026-08-03.

CRISPRi vulnerability

Vulnerability index -8.11 (95% CI -9.47 to -6.89). A more negative index = more vulnerable to knockdown (better drug-target quality); indicative threshold VI ≤ -6 = highly vulnerable.

Quantitative CRISPRi knockdown, graded (finer than binary Tn-seq essentiality). Source: CRISPRi vulnerability index (Bosch 2021, pebble.rockefeller.edu).

Legacy record & comparison (Mycobrowser)

Mycobrowser function	Involved in purine salvage [catalytic activity: imp + pyrophosphate = hypoxanthine + 5-phospho-alpha-D-ribose 1-diphosphate (guanine can replace hypoxanthine to produce GMP)].
Mycobrowser EC	`2.4.2.8` · agrees with the atlas

The legacy Mycobrowser record is shown for verification. Mycobrowser is no longer maintained; its EC numbers predate recent nomenclature revisions, so a class change usually reflects re-numbering, not a conflict.

Orthologues (reciprocal best hits across mycobacteria)

M. bovis	`Mb3648c` · 99.5% identity
M. leprae	`ML0214` · 83.1% identity
M. marinum	`MMAR_5124` · 88.1% identity
M. smegmatis	`MSMEG_6110` · 72.9% identity
M. orygis	`RJtmp_003724` · 99.5% identity
M. abscessus	`MAB_0523` · 72.4% identity

Reciprocal-best-hit orthologues (DIAMOND) against the Mycobrowser reference proteomes. A missing species is informative: e.g. a gene absent from M. leprae was likely lost in its reductive genome evolution. Locus tags link to Mycobrowser.

Curated reference (UniProt)

UniProt	`P9WHQ9` SwissProt · reviewed · Evidence at protein level
UniProt name	Hypoxanthine-guanine phosphoribosyltransferase
EC (curated)	`EC 2.4.2.8`
Curated function	Purine salvage pathway enzyme that catalyzes the transfer of the ribosyl-5-phosphate group from 5-phospho-alpha-D-ribose 1-diphosphate (PRPP) to the N9 position of the 6-oxopurines hypoxanthine and guanine to form the corresponding ribonucleotides IMP (inosine 5'-monophosphate) and GMP (guanosine 5'-monophosphate), with the release of PPi. Thus, specifically recycles hypoxanthine and guanine imported from the external medium, and converts them to IMP and GMP, respectively. Cannot use xanthine as substrate.

Functional vocabulary (eggNOG-mapper, orthology transfer)

COG category	`F` Nucleotide transport and metabolism
Preferred name	hpt
eggNOG description	Belongs to the purine pyrimidine phosphoribosyltransferase family
Orthologous group	`COG0634`
EC number	`EC 2.4.2.8`
KEGG orthology	`K00760`
KEGG pathways	`map00230`, `map00983`, `map01100`, `map01110`
Gene Ontology (79)	`GO:0003674`, `GO:0003824`, `GO:0004422`, `GO:0006139`, `GO:0006163`, `GO:0006164`, `GO:0006177`, `GO:0006188`, `GO:0006725`, `GO:0006753`, `GO:0006793`, `GO:0006796` +67 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	0.888 · relaxed/neutral
Polymorphic sites (≥ 0.1% of strains)	2 synonymous, 5 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.

Outgroup conservation (beyond the MTBC) Bacteria

Genus-wide presence (~53 non-MTBC Mycobacterium)	present in 53/53 (100%) · mean identity 86.1% · 4/4 closest MTBAP relatives conserved across the genus (present in 53/53 non-MTBC Mycobacterium genomes, incl. distant relatives) — an ancient core gene predating the genus radiation
Phylostratum (deepest detected homolog)	MTBC-specific → Mycobacterium → Mycobacteriaceae → Corynebacteriales → Actinomycetia → Bacteria detected in 13/13 non-Mycobacterium reference genomes (down to Bacteria) · mean identity 58.7% detected down to outside the phylum (Proteobacteria/Firmicutes controls) — a universally conserved, ancient bacterial gene

Two orthogonal outgroup signals. M. canettii (the immediate outgroup) gives a deep-divergence dN/dS (a low value confirms a constrained, real gene; shown as confident only at ≥8 substitutions, else flagged low-power). Genus-wide presence/absence (tblastn vs assembled non-MTBC genomes) places the gene on the ancient-core ↔ MTBC-specific axis: a gene absent even from the closest MTBAP relatives is a candidate MTBC-specific innovation (possible host-adaptation factor, to confirm by synteny). The phylostratum extends that axis outside the genus (tblastn vs 13 reference genomes spanning Mycobacteriaceae → Corynebacteriales → Actinomycetia → outside the phylum): it is the deepest clade in which a homolog is still detected, i.e. a proxy for gene age. Read it with the null model in mind: a shallow (young) stratum can also reflect homology-detection failure for short or fast-evolving ORFs, so it is a descriptive axis, not a proof of novelty.

Essentiality (transposon mutagenesis) essential

DeJesus 2017 call	ES · essential
What the call means	essential: insertions absent across the whole ORF
TA sites (Himar1)	12 in the ORF — 10 in the essential state, 0 growth-defect, 2 non-essential, 0 growth-advantage. Saturation 0.167, mean read count 82. A region of the protein devoid of TA sites is invisible to this assay: nothing can be inferred about it, in either direction.

Genome-wide Himar1 transposon essentiality in H37Rv (DeJesus 2017). An essential call (ES/ESD/GD) is strong, independent evidence that a "hypothetical" locus encodes a functional, selectively required gene — orthogonal to intra-species conservation.

Chemical-genetic target & druggability (PROSPECT) hypomorph tool strain

This gene is part of the PROSPECT collection of TetON transcriptional-knockdown (hypomorph) strains of essential M. tuberculosis genes, built as a sensitised background for chemical-genetic mechanism-of-action deconvolution. Being in the panel means the gene is an essential / vulnerable target for which a validated knockdown tool strain exists.

Hypomorph strain	hpt (TetON promoter NA)
Baseline knockdown fitness	4.075 median doublings (across 1 screen pool(s)) — fewer doublings = stronger growth defect on knockdown
Used in target deconvolution	no (Excluded - not in all screening waves)

Panel membership reflects essentiality/vulnerability and the availability of a genetic tool, not a specific molecular function; it never changes the verdict here. Source: Bond AN et al., Nat Commun 2025;16:9673 (doi:10.1038/s41467-025-64662-x); PROSPECT chemical-genetic platform.

Proteomics (mass spectrometry) detected

MS detection	detected in 15 of 16 independent MS datasets
Integrated abundance	78.4 ppm · rank 1466/3519 (58.4th percentile)

Detection by mass spectrometry is direct, experimental evidence that the protein product exists — orthogonal to sequence conservation and to Tn-seq essentiality, and especially decisive for a "hypothetical" locus. Reproducible detection across several independent datasets (PaxDb) makes the existence claim robust; the integrated abundance places the protein in the proteome's dynamic range.

Physico-chemical properties (computed, ProtParam)

Length	216 aa
Molecular weight	23.6 kDa
Theoretical pI	4.92
GRAVY	0.059 (hydrophobic)
Aliphatic index	107.4
Aromaticity	0.074
Instability index	26.3 (stable)

Computed from the ancestral MTBC0 sequence with the ExPASy ProtParam method (Biopython). Descriptive biophysical context: a positive GRAVY flags a hydrophobic (often membrane) protein, a high instability index (>40) predicts a short in-vitro half-life, an extreme pI hints at compartment or binding partner.

Domains (Pfam, hmmscan --cut_ga)

Pfam	Accession	i-Evalue	Residues	Description
`Pribosyltran`	PF00156.34	2.7e-21	48–197	Phosphoribosyl transferase domain

Experimental structures (Protein Data Bank) 7 solved

PDB	Method	Resolution	Coverage
`4rhx`	X-ray diffraction	2.0322 Å	99%
`4rhy`	X-ray diffraction	2.3196 Å	99%
`5knp`	X-ray diffraction	2.45 Å	99%
`5knq`	X-ray diffraction	2.553 Å	99%
`4rhu`	X-ray diffraction	2.573 Å	99%
`4rht`	X-ray diffraction	2.7633 Å	99%
`5kny`	X-ray diffraction	2.91 Å	99%

Experimentally solved structures mapped from the UniProt accession via PDBe/SIFTS (7 total; up to 8 shown, ranked by sequence coverage then resolution). An experimental structure is direct proof of the folded product and the strongest structural evidence — superseding the predicted ESMFold/AlphaFold models below for any covered region.

Structural search (AlphaFold DB model, Foldseek vs PDB — genome-wide) pLDDT 89.2

PDB hit	prob	TM-score	E-value	Description
`5kny-assembly1_B`	1.00	0.97	3.7e-34 sig	5kny-assembly1_B Crystal structure of Mycobacterium tuberculosis hypoxanthine guanine phosphoribosyltransferase in complex with (3-((3R,4R)-3-(Guanin-9-yl)-4-((S)-2-hydroxy-2-phosphonoethoxy)pyrrolidin-1-yl)-3-oxopropyl)phosphonic acid
`4rhx-assembly2_A`	1.00	0.97	1.4e-33 sig	4rhx-assembly2_A Structures of Mycobacterium tuberculosis 6-oxopurine phosphoribosyltransferase which is a potential target for drug development against this disease
`5knp-assembly3_D`	1.00	0.98	5.0e-33 sig	5knp-assembly3_D Crystal structure of Mycobacterium tuberculosis hypoxanthine guanine phosphoribosyltransferase in complex with [3S,4R]-(4-(Hypoxanthin-9-yl)pyrrolidin-3-yl)-oxymethanephosphonic acid
`5knp-assembly3_C`	1.00	0.98	4.7e-33 sig	5knp-assembly3_C Crystal structure of Mycobacterium tuberculosis hypoxanthine guanine phosphoribosyltransferase in complex with [3S,4R]-(4-(Hypoxanthin-9-yl)pyrrolidin-3-yl)-oxymethanephosphonic acid
`4rhy-assembly3_D`	1.00	0.97	8.6e-33 sig	4rhy-assembly3_D Crystal structures of Mycobacterium tuberculosis 6-oxopurine phosphoribosyltransferase which is a potential target for drug development against this disease

Foldseek search of the AlphaFold DB model (mean pLDDT 89.2, gated at 70) against the PDB — a genome-wide extension of the ESMFold dark-gene search that also covers proteins beyond the single-sequence length limit. Confident structural neighbours (E < 0.01) shown.

Genomic context (neighbours & predicted operon) operon of 4

Upstream (5' on genome)	`lpqG` (+ strand, 4 bp gap)
Downstream (3' on genome)	`mesJ` (- strand, -4 bp gap)
Predicted operon	`hpt` · `mesJ` · `Rv3626c` · `Rv3627c`

Neighbours from the H37Rv annotation (- strand). The operon is predicted by co-directional intergenic distance (same strand, gaps ≤50 bp) — a transcription-unit hypothesis, not a mapped TSS. For a "hypothetical", co-transcription with a characterised operon is a concrete functional lead (complements the STRING neighborhood channel below).

Functional interaction network (STRING v12, guilt-by-association)

Explore full network →

Node colour = verdict, dashed = hypothetical; edge colour = evidence (green experimental, orange genomic-context, grey co-expression), width ∝ score. Click a partner to open its page; "Explore full network" to walk the graph.

Closest characterised functional partner: mesJ (tRNA(Ile)-lysidine synthase), high confidence from genomic context alone (score 987 excluding text-mining).

Partner	Product	Score	No text-mining	Channels (≥400)
`Rv3625c` mesJ	tRNA(Ile)-lysidine synthase	998	987 ctx	neighborhood:881 fusion:855 textmining:888
`Rv3396c` guaA exp	GMP synthase	973	940	database:900 textmining:587
`Rv3307` deoD exp	purine nucleoside phosphorylase	975	925	database:900 textmining:693
`Rv1021` mazG exp	nucleoside triphosphate pyrophosphohydrolase	923	923	database:900
`Rv0357c` purA exp	adenylosuccinate synthetase	990	921	database:900 textmining:882
`Rv2584c` apt exp	adenine phosphoribosyltransferase	993	917	database:900 textmining:922
`Rv0733` adk	adenylate kinase	940	916 ctx	fusion:887
`Rv1389` gmk exp	guanylate kinase	963	915	database:900 textmining:593
`Rv0957` purH exp	bifunctional phosphoribosylaminoimidazolecarboxamide formyltransferase/inosinemonophosphate cyclohydrolase	932	912	database:900
`Rv3411c` guaB2 exp	inosine-5'-monophosphate dehydrogenase	990	910	database:900 textmining:893
`Rv1341` rdgB exp	non-canonical purine NTP pyrophosphatase	911	905	database:900
`Rv1843c` guaB1 exp	inosine-5'-monophosphate dehydrogenase	934	904	database:900
`Rv3410c` guaB3 exp	oxidoreductase	920	904	database:900
`Rv3393` iunH exp	nucleoside hydrolase	967	901	database:900 textmining:688
`Rv3626c` hyp	hypothetical protein	982	882 ctx	neighborhood:881 textmining:860

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 exp badge marks an experimentally-supported partner (measured interaction, experimental/database channel ≥400) as opposed to a purely predicted one — but note that the M. tuberculosis experimental interactome is dominated by a noisy bacterial-two-hybrid screen, so a strong measured link that contradicts the operon/localisation context is likely a false positive. 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: hypoxanthine-guanine phosphoribosyltransferase
MTBC0 PGAP product: hypoxanthine phosphoribosyltransferase
Pfam (hmmscan --cut_ga): Pribosyltran PF00156.34 (E=3e-21)
(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_218141.1)
Domains: Pfam-A via hmmscan --cut_ga — Pribosyltran (PF00156.34)
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 COG0634
Curated reference: UniProt P9WHQ9 (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)
Genome-wide structure: AlphaFold DB model (Jumper et al. 2021, doi:10.1038/s41586-021-03819-2; Varadi et al. 2024, doi:10.1093/nar/gkad1011) searched vs PDB with Foldseek (mean pLDDT 89.2)
Interaction network: STRING v12.0 (Szklarczyk et al. 2023, doi:10.1093/nar/gkac1000), taxon 83332, CC-BY 4.0 — 38 functional partner(s); context anchor mesJ
Essentiality: genome-wide transposon mutagenesis in H37Rv — DeJesus et al. 2017 (mBio, doi:10.1128/mBio.02133-16, CC BY)
Proteomics: integrated mass-spectrometry abundance from PaxDb 5.0 (Huang et al. 2023, doi:10.1016/j.mcpro.2023.100640), taxon 83332 — weighted average of 16 datasets, incl. Schubert et al. 2013 (doi:10.1016/j.chom.2013.04.008) and Albrethsen et al. 2013 (doi:10.1074/mcp.M112.018846)
Functional category: TubercuList scheme (Cole et al. 1998, doi:10.1038/31159), via Mycobrowser (Kapopoulou et al. 2011, doi:10.1016/j.tube.2010.09.006)
Orthologues: reciprocal best hits (DIAMOND, Buchfink et al. 2021, doi:10.1038/s41592-021-01101-x) against Mycobrowser release 5 reference proteomes
Experimental structures: PDBe/SIFTS UniProt→PDB mapping (Dana et al. 2019, doi:10.1093/nar/gky1114)
Genomic context / operon: H37Rv annotation; operon predicted by co-directional intergenic distance (Salgado et al. 2000, doi:10.1073/pnas.030539397)
Physico-chemical properties: ExPASy ProtParam method via Biopython (Gasteiger et al. 2005), computed from the MTBC0 sequence
Primary literature: none located yet; annotation rests on the domain/homology sources above.

Ancestral MTBC0 protein sequence

>mtbc0_003841|Rv3624c|hpt
MTPALVVGPAAWHAVHVTQSSSAITPGQTAELYPGDIKSVLLTAEQIQARIAELGEQIGNDYRELSATTGQDLLLITVLKGAVLFVTDLARAIPVPTQFEFMAVSSYGSSTSSSGVVRILKDLDRDIHGRDVLIVEDVVDSGLTLSWLSRNLTSRNPRSLRVCTLLRKPDAVHANVEIAYVGFDIPNDFVVGYGLDYDERYRDLSYIGTLDPRVYQ

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Genomic neighbourhood (genome browser)