pks1 Resolved · high auto-curated

Annotation: from legacy to revised

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).

In the literature (TB corpus sweep) 10 publications

10 TB publications mention this gene. 10 publication(s) discuss this gene (10 in a M. tuberculosis context).

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 · 0 % of gene

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.

Post-translational modifications

1 reported modified residue(s), incl. 1 phosphosite(s): O-(pantetheine 4'-phosphoryl)serine @1549.

Experimentally reported post-translational modification(s). A phosphosite indicates the protein is expressed and is a substrate of the M. tuberculosis Ser/Thr/Tyr kinase signalling network — a regulatory context, NOT a molecular function. Source: UniProt (Modified residue features; PTM sites curated from the M. tuberculosis literature).

CRISPRi vulnerability

Vulnerability index 0.29 (95% CI -1.90 to 3.55). 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)

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 Mycobrowser is no longer maintained; its EC numbers predate recent nomenclature revisions, so a class change usually reflects re-numbering, not a conflict.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)

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 still lists this protein as Putative inactive phenolphthiocerol synthesis polyketide synthase type I Pks1; the revised annotation above is ahead of the current UniProt record.

Functional vocabulary (eggNOG-mapper, orthology transfer)

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 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) Actinomycetia

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)

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.

Proteomics (mass spectrometry) detected

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)

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)

Structural search (AlphaFold DB model, Foldseek vs PDB — genome-wide) pLDDT 87.0

Foldseek search of the AlphaFold DB model (mean pLDDT 87.0, 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 5

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).

Transcriptional regulation (signed TRN: ChIP-seq + TFOE)

Regulatory edges from the ISB signed transcriptional regulatory network (TF ChIP-seq binding, Minch 2015 + TF-overexpression response, Rustad 2014). An edge is regulatory evidence (binding and/or expression change), not necessarily direct. For a "hypothetical", membership in a known regulon (e.g. DosR dormancy, PhoP virulence) is a strong physiological-context lead.

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: fas (fatty acid synthase), high confidence from genomic context alone (score 1000 excluding text-mining).

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

• Annotation from H37Rv (no MTBC0 1:1 anchor; H37Rv protein used): polyketide synthase
• Pfam (hmmscan --cut_ga): CurL-like_PKS_C PF22621.3 (E=4e-08), Acyl_transf_1 PF00698.27 (E=2e-61), PKS_DH_N PF21089.4 (E=5e-29), PS-DH PF14765.13 (E=1e-30), SpnB_Rossmann PF22953.4 (E=1e-33), ADH_N PF08240.18 (E=1e-09), ADH_zinc_N PF00107.33 (E=4e-13), ADH_zinc_N_2 PF13602.13 (E=3e-18), KR PF08659.17 (E=2e-60), adh_short PF00106.32 (E=1e-14), Epimerase PF01370.28 (E=4e-05), adh_short_C2 PF13561.13 (E=1e-09), PP-binding PF00550.32 (E=6e-15)
• (auto-curated by rules from PGAP + Pfam + Foldseek; not hand-reviewed)

Ancestral MTBC0 protein sequence

>H37Rv|Rv2946c|pks1
MISARSAEALTAQAGRLMAHVQANPGLDPIDVGCSLASRSVFEHRAVVVGASREQLIAGLAGLAAGEPGAGVAVGQPGSVGKTVVVFPGQGAQRIGMGRELYGELPVFAQAFDAVADELDRHLRLPLRDVIWGADADLLDSTEFAQPALFAVEVASFAVLRDWGVLPDFVMGHSVGELAAAHAAGVLTLADAAMLVVARGRLMQALPAGGAMVAVAASEDEVEPLLGEGVGIAAINAPESVVISGAQAAANAIADRFAAQGRRVHQLAVSHAFHSPLMEPMLEEFARVAARVQAREPQLGLVSNVTGELAGPDFGSAQYWVDHVRRPVRFADSARHLQTLGATHFIEAGPGSGLTGSIEQSLAPAEAMVVSMLGKDRPELASALGAAGQVFTTGVPVQWSAVFAGSGGRRVQLPTYAFQRRRFWETPGADGPADAAGLGLGATEHALLGAVVERPDSDEVVLTGRLSLADQPWLADHVVNGVVLFPGAGFVELVIRAGDEVGCALIEELVLAAPLVMHPGVGVQVQVVVGAADESGHRAVSVYSRGDQSQGWLLNAEGMLGVAAAETPMDLSVWPPEGAESVDISDGYAQLAERGYAYGPAFQGLVAIWRRGSELFAEVVAPGEAGVAVDRMGMHPAVLDAVLHALGLAVEKTQASTETRLPFCWRGVSLHAGGAGRVRARFASAGADAISVDVCDATGLPVLTVRSLVTRPITAEQLRAAVTAAGGASDQGPLEVVWSPISVVSGGANGSAPPAPVSWADFCAGSDGDASVVVWELESAGGQASSVVGSVYAATHTALEVLQSWLGADRAATLVVLTHGGVGLAGEDISDLAAAAVWGMARSAQAENPGRIVLIDTDAAVDASVLAGVGEPQLLVRGGTVHAPRLSPAPALLALPAAESAWRLAAGGGGTLEDLVIQPCPEVQAPLQAGQVRVAVAAVGVNFRDVVAALGMYPGQAPPLGAEGAGVVLETGPEVTDLAVGDAVMGFLGGAGPLAVVDQQLVTRVPQGWSFAQAAAVPVVFLTAWYGLADLAEIKAGESVLIHAGTGGVGMAAVQLARQWGVEVFVTASRGKWDTLRAMGFDDDHIGDSRTCEFEEKFLAVTEGRGVDVVLDSLAGEFVDASLRLLVRGGRFLEMGKTDIRDAQEIAANYPGVQYRAFDLSEAGPARMQEMLAEVRELFDTRELHRLPVTTWDVRCAPAAFRFMSQARHIGKVVLTMPSALADRLADGTVVITGATGAVGGVLARHLVGAYGVRHLVLASRRGDRAEGAAELAADLTEAGAKVQVVACDVADRAAVAGLFAQLSREYPPVRGVIHAAGVLDDAVITSLTPDRIDTVLRAKVDAAWNLHQATSDLDLSMFALCSSIAATVGSPGQGNYSAANAFLDGLAAHRQAAGLAGISLAWGLWEQPGGMTAHLSSRDLARMSRSGLAPMSPAEAVELFDAALAIDHPLAVATLLDRAALDARAQAGALPALFSGLARRPRRRQIDDTGDATSSKSALAQRLHGLAADEQLELLVGLVCLQAAAVLGRPSAEDVDPDTEFGDLGFDSLTAVELRNRLKTATGLTLPPTVIFDHPTPTAVAEYVAQQMSGSRPTESGDPTSQVVEPAAAEVSVHA