Rv2947c (pks15)

Current annotations:
- TBCAP: (community-based annotations - see table at bottom of page)
- TBDB: polyketide synthase 1/15
- REFSEQ: polyketide synthase PKS15
- PATRIC: (MTCY24G1.02) len: 496 aa Probable polyketide synthase almost identical to G560508 PKS002B (495 aa) fasta scores opt: 3270 E(): 0 (99.6% identity in 496 aa overlap); contains PS00606 Beta-ketoacyl synthases active site; similar to MTCY338.20 (49.9% identity in 465 aa overlap) and MTCY24G1.09 (50.2% identity in 454 aa overlap) and MTCY22H8.03 (47.6% identity in 437 aa overlap)
- TUBERCULIST: Probable polyketide synthase Pks15
- NCBI: Probable polyketide synthase Pks15
- updated information (H37Rv4):
  - gene name: pks15
  - function:
  - reference:
Type: Not Target
Start: 3296350
End: 3297840
Operon:

Trans-membrane region:
Role: I.I - Polyketide and non-ribosomal peptide synthesis
GO terms:
- GO:0048037 - cofactor binding (Uniprot)
- GO:0016740 - transferase activity (Uniprot)
- GO:0009247 - glycolipid biosynthetic process (Uniprot)
- GO:0008152 - metabolic process (Uniprot)
- GO:0005829 - cytosol (Uniprot)
- GO:0003824 - catalytic activity (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
2HG4	64%	Saccharopolyspora erythraea	Structure of the ketosynthase-acyltransferase didomain of module 5 from DEBS.
2QO3	61%	Saccharopolyspora erythraea	Crystal Structure of [KS3][AT3] didomain from module 3 of 6-deoxyerthronolide B synthase
6C9U	60%	Saccharopolyspora erythraea	Crystal structure of [KS3][AT3] didomain from module 3 of 6-deoxyerthronolide B synthase in complex with antibody fragment (Fab)
4MZ0	50%	Moorea producens 3L	Structure of a ketosynthase-acyltransferase di-domain from module CurL of the curacin A polyketide synthase
5BP1	48%	Mycobacterium smegmatis (strain ATCC 700084 / mc(2)155)	Condensing di-domain (KS-AT) of a mycocerosic acid synthase-like (MAS-like) PKS
4OQJ	43%	Streptomyces albus	Streptomcyes albus JA3453 oxazolomycin ketosynthase domain OzmQ KS1
4ZDN	42%	Streptomyces platensis subsp. rosaceus	Streptomyces platensis isomigrastatin ketosynthase domain MgsF KS4
4WKY	42%	Streptomyces albus	Streptomcyes albus JA3453 oxazolomycin ketosynthase domain OzmN KS2
4QYR	42%	Streptomyces platensis subsp. rosaceus	Streptomyces platensis isomigrastatin ketosynthase domain MgsE KS3
4NA1	41%	Bacillus subtilis subsp. subtilis	Crystal Structure of the second ketosynthase from the bacillaene polyketide synthase

Links to additional information on pks15:
- TBDB (updated)
- Phyre2 structure prediction, model: final.casp.pdb (from Mao et al, 2013)
- UniProt
- AlphaFold model
- Vulnerability = 1.134 (from Jeremy Rock's lab)
- KEGG - nucleotide and amino acid sequences of gene
- Mycobrowser
- PATRIC
- BioCyc
- Systems Biology

Amino Acid Sequence

VIEEQRTMSVEGADQQSEKLFHYLKKVAVELDETRARLREYEQRATEPVAVVGIGCRFPGGVDGPDGLWDVVSAGRDVVSEFPTDRGWDVEGLYDPDPDA
EGKTYTRWGAFLDDATGFDAGFFGIAPSEVLAMDPQQRLMLEVSWEALEHAGIDPLSLRGSATGVYTGIFAASYGNRDTGGLQGYGLTGTSISVASGRVS
YVLGLQGPAVSVDTACSSSLVAIHWAMSSLRSGECDLALAGGVTVMGLPSIFVGFSRQRGLAADGRCKAFAAAADGTGWGEGAGVVVLERLSDARRLGHS
VLAVVRGSAVNQDGASNGLTAPNGLAQQRVIQVALANAGLSAADVDVVEAHGTATTLGDPIEAQALLSTYGQGGPAEQPLWVGSIKSNMGHTQAAAGVAG
VIKMVQAMRHGVMPATLHVDEPSPRVDWTSGAVSVLTEAREWSVDGRPRRAAVSSFGISGTNAHLILEEAPVPAPAEAPVEASESTGGRGRRWCRG

(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	YES
omega peak height (95%CI lower bound)	2.7 (0.99)	1.8 (1.03)
codons under selection		422, 423, 424, 425, 426, 427, 447, 448
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

Rv2947c/pks15, gene len: 1490 bp, num TA sites: 22

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=-0.13)	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	NO (LFC=-0.039)	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=0.29)	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:
- Rv0023 (-)
- Rv3295 (-)

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

Binds To:
- No bindings to other targets were found.
Bound By:
- Rv0081 (-) (Direct binding)
- Rv0602c (tcrA) (Direct binding)
- Rv0678 (-) (Direct binding)
- Rv1985c (-) (Direct binding)
- Rv3765c (tcrX) (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:
- Rv0023 (-)
- Rv3295 (-)

Property	Value	Creator	Evidence	PMID	Comment
Citation	Identification and substrate specificity of beta -ketoacyl (acyl carrier protein) synthase III (mtFabH) from Mycobacterium tuberculosis. KH. Choi, L. Kremer et al. J. Biol. Chem. 2000	njamshidi	IDA	10840036	mtFABH (Rv0533c) - link between FAS I and FAS II - highest affinity for C12:0, see PMID: 10840036 (since FA synthesis is lumped, does not extend immediately to FAS II).
Term	EC:2.3.1.85 Fatty-acid synthase. - IDA	njamshidi	IDA	10840036	mtFABH (Rv0533c) - link between FAS I and FAS II - highest affinity for C12:0, see PMID: 10840036 (since FA synthesis is lumped, does not extend immediately to FAS II). KH. Choi, L. Kremer et al. Identification and substrate specificity of beta -ketoacyl (acyl carrier protein) synthase III (mtFabH) from Mycobacterium tuberculosis. J. Biol. Chem. 2000
Term	TBRXN:FAS140 fatty acid synthase (n-C14:0) - IDA	njamshidi	IDA	10840036	mtFABH (Rv0533c) - link between FAS I and FAS II - highest affinity for C12:0, see PMID: 10840036 (since FA synthesis is lumped, does not extend immediately to FAS II). KH. Choi, L. Kremer et al. Identification and substrate specificity of beta -ketoacyl (acyl carrier protein) synthase III (mtFabH) from Mycobacterium tuberculosis. J. Biol. Chem. 2000
Interaction	RegulatedBy Rv1221	yamir.moreno	IEP		Microarrays. mRNA levels of regulated element measured and compared between wild-type and trans-element mutation (knockout, over expression etc.) performed by using microarray (or macroarray) experiments.. R. Manganelli, MI. Voskuil et al. The Mycobacterium tuberculosis ECF sigma factor sigmaE: role in global gene expression and survival in macrophages. Mol. Microbiol. 2001
Name	Together with Pks1, type 1 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
Other	TBPWY:Phthiocerol dimycocerosates, PGL & pHBAD	mjackson			Together with Pks1, type 1 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	mjackson		12138124	Together with Pks1, type 1 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]).
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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