Rv2946c (pks1)

Current annotations:
- TBCAP: (community-based annotations - see table at bottom of page)
- TBDB: polyketide synthase 1/15
- REFSEQ: polyketide synthase PKS1
- PATRIC: Malonyl CoA-acyl carrier protein transacylase (EC 2.3.1.39)
- TUBERCULIST: Probable polyketide synthase Pks1
- NCBI: Probable polyketide synthase Pks1
- updated information (H37Rv4):
  - gene name: pks1
  - function:
  - reference:
Coordinates in H37Rv: 3291503 - 3296353
Gene length: 4851 bp (with stop codon), 1616 aa (without stop codon)
Operon:

Trans-membrane region:
Role: I.I - Polyketide and non-ribosomal peptide synthesis
GO terms:
- GO:0071770 - DIM/DIP cell wall layer assembly (Uniprot)
- GO:0071766 - Actinobacterium-type cell wall biogenesis (Uniprot)
- GO:0055114 - oxidation-reduction process (Uniprot)
- GO:0031177 - phosphopantetheine binding (Uniprot)
- GO:0016746 - transferase activity, transferring acyl groups (Uniprot)
- GO:0016740 - transferase activity (Uniprot)
- GO:0016491 - oxidoreductase activity (Uniprot)
- GO:0008610 - lipid biosynthetic process (Uniprot)
- GO:0008152 - metabolic process (Uniprot)
- GO:0006633 - fatty acid biosynthetic process (Uniprot)
- GO:0006631 - fatty acid metabolic process (Uniprot)
- GO:0006629 - lipid metabolic process (Uniprot)
- GO:0005886 - plasma membrane (Uniprot)
Reaction(s) (based on iSM810 metabolic model):
Gene Expression Profile (Transcriptional Responses to Drugs; Boshoff et al, 2004)
Gene Modules extracted from cluster analysis of 249 transcriptomic datasets using ICA
Orthologs among selected mycobacteria
Protein structure:
Search for Latest Homologs in PDB

Top 10 Homologs in PDB (as of Apr 2026):

PDB	aa ident	species	PDB title
7VRS	56%	Streptomyces albus subsp. albus	The complex of Acyltransferase and Acyl Carrier Protein Domains from module 9 of Salinomycin Polyketide Synthase
6H0J	54%	Mycobacterium ulcerans (strain Agy99)	A1-type ACP domain from module 5 of MLSA1
3SLK	54%	Saccharopolyspora spinosa	Structure of ketoreductase and enoylreductase didomain from modular polyketide synthase
9IYW	53%	Streptomyces graminofaciens	Crystal structure of chimeric KSQ-AT didomain
9JJB	52%	Streptomyces graminofaciens	Class 1 state of the GfsA KSQ-ancestralAT chimeric didomain in complex with the GfsA ACP domain
9JJ9	52%	Streptomyces graminofaciens	Class 3 state of the GfsA KSQ-ancestralAT chimeric didomain in complex with the GfsA ACP domain
8IN9	52%	Streptomyces graminofaciens	The structure of the GfsA KSQ-AT didomain in complex with the GfsA ACP domain
9JJB	52%	Streptomyces graminofaciens	Class 1 state of the GfsA KSQ-ancestralAT chimeric didomain in complex with the GfsA ACP domain
9JJ9	52%	Streptomyces graminofaciens	Class 3 state of the GfsA KSQ-ancestralAT chimeric didomain in complex with the GfsA ACP domain
2Z5L	51%	Streptomyces fradiae	The first ketoreductase of the tylosin PKS

Links to additional information on pks1:
- TBDB (updated)
- Phyre2 structure prediction, model: final.casp.pdb (from Mao et al, 2013)
- UniProt
- AlphaFold model
- Vulnerability = 0.291 (from Jeremy Rock's lab)
- KEGG - nucleotide and amino acid sequences of gene
- BioCyc
- Systems Biology
- Mycobrowser
- PATRIC

Amino Acid Sequence

VISARSAEALTAQAGRLMAHVQANPGLDPIDVGCSLASRSVFEHRAVVVGASREQLIAGLAGLAAGEPGAGVAVGQPGSVGKTVVVFPGQGAQRIGMGRE
LYGELPVFAQAFDAVADELDRHLRLPLRDVIWGADADLLDSTEFAQPALFAVEVASFAVLRDWGVLPDFVMGHSVGELAAAHAAGVLTLADAAMLVVARG
RLMQALPAGGAMVAVAASEDEVEPLLGEGVGIAAINAPESVVISGAQAAANAIADRFAAQGRRVHQLAVSHAFHSPLMEPMLEEFARVAARVQAREPQLG
LVSNVTGELAGPDFGSAQYWVDHVRRPVRFADSARHLQTLGATHFIEAGPGSGLTGSIEQSLAPAEAMVVSMLGKDRPELASALGAAGQVFTTGVPVQWS
AVFAGSGGRRVQLPTYAFQRRRFWETPGADGPADAAGLGLGATEHALLGAVVERPDSDEVVLTGRLSLADQPWLADHVVNGVVLFPGAGFVELVIRAGDE
VGCALIEELVLAAPLVMHPGVGVQVQVVVGAADESGHRAVSVYSRGDQSQGWLLNAEGMLGVAAAETPMDLSVWPPEGAESVDISDGYAQLAERGYAYGP
AFQGLVAIWRRGSELFAEVVAPGEAGVAVDRMGMHPAVLDAVLHALGLAVEKTQASTETRLPFCWRGVSLHAGGAGRVRARFASAGADAISVDVCDATGL
PVLTVRSLVTRPITAEQLRAAVTAAGGASDQGPLEVVWSPISVVSGGANGSAPPAPVSWADFCAGSDGDASVVVWELESAGGQASSVVGSVYAATHTALE
VLQSWLGADRAATLVVLTHGGVGLAGEDISDLAAAAVWGMARSAQAENPGRIVLIDTDAAVDASVLAGVGEPQLLVRGGTVHAPRLSPAPALLALPAAES
AWRLAAGGGGTLEDLVIQPCPEVQAPLQAGQVRVAVAAVGVNFRDVVAALGMYPGQAPPLGAEGAGVVLETGPEVTDLAVGDAVMGFLGGAGPLAVVDQQ
LVTRVPQGWSFAQAAAVPVVFLTAWYGLADLAEIKAGESVLIHAGTGGVGMAAVQLARQWGVEVFVTASRGKWDTLRAMGFDDDHIGDSRTCEFEEKFLA
VTEGRGVDVVLDSLAGEFVDASLRLLVRGGRFLEMGKTDIRDAQEIAANYPGVQYRAFDLSEAGPARMQEMLAEVRELFDTRELHRLPVTTWDVRCAPAA
FRFMSQARHIGKVVLTMPSALADRLADGTVVITGATGAVGGVLARHLVGAYGVRHLVLASRRGDRAEGAAELAADLTEAGAKVQVVACDVADRAAVAGLF
AQLSREYPPVRGVIHAAGVLDDAVITSLTPDRIDTVLRAKVDAAWNLHQATSDLDLSMFALCSSIAATVGSPGQGNYSAANAFLDGLAAHRQAAGLAGIS
LAWGLWEQPGGMTAHLSSRDLARMSRSGLAPMSPAEAVELFDAALAIDHPLAVATLLDRAALDARAQAGALPALFSGLARRPRRRQIDDTGDATSSKSAL
AQRLHGLAADEQLELLVGLVCLQAAAVLGRPSAEDVDPDTEFGDLGFDSLTAVELRNRLKTATGLTLPPTVIFDHPTPTAVAEYVAQQMSGSRPTESGDP
TSQVVEPAAAEVSVHA

(Nucleotide sequence available on KEGG)

Additional Information

ESSENTIALITY

MtbTnDB - interactive tool for exploring a database of published TnSeq datasets for Mtb

TnSeqCorr - genes with correlated TnSeq profiles across ~100 conditions

Rv2946c/pks1, gene len: 4850 bp, num TA sites: 51

condition	dataset	call	medium	method	notes
in-vitro	DeJesus 2017 mBio	non-essential	7H9	HMM	fully saturated, 14 TnSeq libraries combined
in-vitro	Sassetti 2003 Mol Micro	non-essential	7H9	TRASH	essential if hybridization ratio<0.2
in-vivo (mice)	Sassetti 2003 PNAS	non-essential	BL6 mice	TRASH	essential if hybridization ratio<0.4, min over 4 timepoints (1-8 weeks)
in-vitro (glycerol)	Griffin 2011 PPath	non-essential	M9 minimal+glycerol	Gumbel	2 replicates; Padj<0.05
in-vitro (cholesterol)	Griffin 2011 PPath	non-essential	M9 minimal+cholesterol	Gumbel	3 replicates; Padj<0.05
differentially essential in cholesterol	Griffin 2011 PPath	NO (LFC=0.21)	cholesterol vs glycerol	resampling-SR	YES if Padj<0.05, else not significant; LFC<0 means less insertions/more essential in cholesterol
in-vitro	Smith 2022 eLife	non-essential	7H9	HMM	6 replicates (raw data in Subramaniam 2017, PMID 31752678)
in-vivo (mice)	Smith 2022 eLife	non-essential	BL6 mice	HMM	6 replicates (raw data in Subramaniam 2017, PMID 31752678)
differentially essential in mice	Smith 2022 eLife	YES (LFC=-0.422)	in-vivo vs in-vitro	ZINB	YES if Padj<0.05, else not significant; LFC<0 means less insertions/more essential in mice
in-vitro (minimal)	Minato 2019 mSys	non-essential	minimal medium	HMM
in-vitro (YM rich medium)	Minato 2019 mSys	non-essential	YM rich medium	HMM	7H9 supplemented with ~20 metabolites (amino acids, cofactors)
differentially essential in YM rich medium	Minato 2019 mSys	NO (LFC=-0.45)	YM rich vs minimal medium	resampling

Analysis of Positive Selection in Clinical Isolates new

data from Culviner et al (2025) (55,259 Mtb clinical isolates)
- overall pN/pS for Rv2946c: 0.870554091
- lineage-specific pN/pS in L1: 0.796292298
- lineage-specific pN/pS in L2: 1.295278526
- lineage-specific pN/pS in L3: 0.753015542
- lineage-specific pN/pS in L4: 0.831114678

Analysis of dN/dS (omega) in a global collection of 10k Mtb clinical isolates using GenomegaMap (Window model)
clinical isolates collection: global set of 10,626 Mtb genomes
In the omega plots, the black line shows the mean estimate of omega (dN/dS) at each codon, and the blue lines are the bounds for the 95% credible interval (95%CI, from MCMC sampling).
A gene is under significant positive selection if the lower-bound of the 95%CI of omega (lower blue line) exceeds 1.0 at any codon.

	global set of 10,626 Mtb clinical isolates
under significant positive selection?	YES
omega peak height (95%CI lower bound)	2.15 (1.15)
codons under selection	878, 879, 880, 881, 882, 884, 885, 886, 887, 888, 889, 890, 1207, 1208, 1209, 1210, 1211, 1212, 1213, 1214, 1215, 1217, 1218
omega plots
genetic variants*	link

* example format for variants: "D27 (GAC): D27H (CAC,11)" means "Asp27 (native codon GAC) mutated to His (codon CAC) in 11 isolates"

TnSeq Data No data currently available.

No TnSeq data currently available for this Target.

RNASeq Data No data currently available.

No RNA-Seq data currently available for this Target.

Metabolomic Profiles No data currently available.

No Metabolomic data currently available for this Target.

Proteomic Data No data currently available.

No Proteomic data currently available for this Target.

Regulatory Relationships from Systems Biology

BioCyc

Gene interactions based on ChIPSeq and Transcription Factor Over-Expression (TFOE) (Systems Biology)

NOTE: see table of TFOE interactions below

Interactions based on ChIPSeq data

Binds To:
- No bindings to other targets were found.
Bound By:

Interactions based on ChIPSeq data (Minch et al. 2014)

Binds To:
- No bindings to other targets were found.
Bound By:
- Rv3830c (-) (Direct binding)
- Rv0273c (-) (Upstream of operon)

Interactions based on TFOE data (Rustad et al. 2014)

TFOE = Transcription Factor Over-Expression study
significance criteria used in paper: greater than 2-fold change (|LFC|>=1.0) and Padj<0.01

gene	dysregulated by OE of	LFC
Rv2946c/pks1	Rv3223c/sigH	-1.08
Rv2946c/pks1	Rv1846c/blaI	-1.09
Rv2946c/pks1	Rv3058c/-	-1.36
Rv2946c/pks1	Rv0023/-	-1.79
Rv2946c/pks1	Rv3295/-	-1.85

Upregulates:
- Does not upregulate other genes.
Upregulated by:
- Not upregulated by other genes.
Downregulates:
- Does not downregulate other genes.
Downregulated by:

Property	Value	Creator	Evidence	PMID	Comment
Name	Together with Pks15, type I polyketide synthase involved in the elongation of p-hydroxybenzoic acid derivatives with malonyl-CoA to form p-hydroxyphenylalkanoates (precursors of phenolic glycolipids [PGL]); the pks15 and pks1 genes are fused in PGL-producing strains of M. tuberculosis but a frameshift mutation causes this polyketide synthase to be inactive in the H37Rv strain	mjackson	IMP		Phthiocerol dimycocerosates (PDIM), phenolic glycolipids (PGL) and para-hydroxybenzoic acid derivatives
Citation	Role of the pks15/1 gene in the biosynthesis of phenolglycolipids in the Mycobacterium tuberculosis complex. Evidence that all strains synthesize glycosylated p-hydroxybenzoic methyl esters and that strains devoid of phenolglycolipids harbor a frameshift mutation in the pks15/1 gene. P. Constant, E. Perez et al. J. Biol. Chem. 2002	mjackson		12138124	Together with Pks15, type I polyketide synthase involved in the elongation of p-hydroxybenzoic acid derivatives with malonyl-CoA to form p-hydroxyphenylalkanoates (precursors of phenolic glycolipids [PGL]); the pks15 and pks1 genes are fused in PGL-producing strains of M. tuberculosis but a frameshift mutation causes this polyketide synthase to be inactive in the H37Rv strain (phenotypic [mycobacterial recombinant strains])
Other	TBPWY:Phthiocerol dimycocerosates, PGL & pHBAD	mjackson			Together with Pks15, type I polyketide synthase involved in the elongation of p-hydroxybenzoic acid derivatives with malonyl-CoA to form p-hydroxyphenylalkanoates (precursors of phenolic glycolipids [PGL]); the pks15 and pks1 genes are fused in PGL-producing strains of M. tuberculosis but a frameshift mutation causes this polyketide synthase to be inactive in the H37Rv strain (phenotypic [mycobacterial recombinant strains]) P. Constant, E. Perez et al. Role of the pks15/1 gene in the biosynthesis of phenolglycolipids in the Mycobacterium tuberculosis complex. Evidence that all strains synthesize glycosylated p-hydroxybenzoic methyl esters and that strains devoid of phenolglycolipids harbor a frameshift mutation in the pks15/1 gene. J. Biol. Chem. 2002
Citation	Role of the pks15/1 gene in the biosynthesis of phenolglycolipids in the Mycobacterium tuberculosis complex. Evidence that all strains synthesize glycosylated p-hydroxybenzoic methyl esters and that strains devoid of phenolglycolipids harbor a frameshift mutation in the pks15/1 gene. P. Constant, E. Perez et al. J. Biol. Chem. 2002	jjmcfadden		12138124	Inferred from direct assay
Other	EC:	jjmcfadden			Inferred from direct assay P. Constant, E. Perez et al. Role of the pks15/1 gene in the biosynthesis of phenolglycolipids in the Mycobacterium tuberculosis complex. Evidence that all strains synthesize glycosylated p-hydroxybenzoic methyl esters and that strains devoid of phenolglycolipids harbor a frameshift mutation in the pks15/1 gene. J. Biol. Chem. 2002

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