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:
Type: Not Target
Start: 3291503
End: 3296353
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 Homologs in PDB

Top 10 Homologs in PDB (as of Nov 2020):

PDB	aa ident	species	PDB title
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
2Z5L	51%	Streptomyces fradiae	The first ketoreductase of the tylosin PKS
6IYO	50%	Streptomyces albus subsp. albus	Crystal Structure of the acyltransferase domain from the second module of the salinomycin polyketide synthase
5HVC	50%	Mycobacterium ulcerans	Solution structure of the apo state of the acyl carrier protein from the MLSA2 subunit of the mycolactone polyketide synthase
5HV8	50%	Mycobacterium ulcerans	Solution structure of an octanoyl- loaded acyl carrier protein domain from module MLSA2 of the mycolactone polyketide synthase.
6OBV	49%	Actinomadura vulgaris	Structural insights into dehydratase substrate selection for the borrelidin and fluvirucin polyketide synthases
6H0Q	49%	Mycobacterium ulcerans (strain Agy99)	B1-type ACP domain from module 7 of MLSB
2JU2	47%	Saccharopolyspora erythraea	Minimized mean solution structure of the acyl carrier protein domain from module 2 of 6-deoxyerythronolide B synthase (DEBS)
5XWV	47%	Streptomyces nodosus	Substrate-bound Structure of a Ketoreductase from the Second Module of the amphotericin Polyketide Synthases

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

Analysis of Positive Selection in Clinical Isolates new

Analysis of dN/dS (omega) in two collections of Mtb clinical isolates using GenomegaMap (Window model) (see description of methods)
- Moldova: 2,057 clinical isolates
- global set: 5,195 clinical isolates from 15 other countries
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.

	Moldova (2,057)	global set (5,195)
under significant positive selection?	NO	NO
omega peak height (95%CI lower bound)	1.93 (0.45)	1.78 (0.98)
codons under selection
omega plots
genetic variants*	link	link
statistics at each codon	link	link

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

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, vitamins)
differentially essential in YM rich medium	Minato 2019 mSys	NO (LFC=-0.45)	YM rich vs minimal medium	resampling

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: Green edges represent the connected genes being classified as differentially essential as a result of the middle gene being knocked out. These interactions are inferred based on RNASeq.

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)

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

TB Genome Annotation Portal