Rv2048c (pks12)

Current annotations:
- TBCAP: (community-based annotations - see table at bottom of page)
- TBDB: polyketide synthase 12
- REFSEQ: polyketide synthase pks12
- PATRIC: Malonyl CoA-acyl carrier protein transacylase (EC 2.3.1.39)
- TUBERCULIST: Polyketide synthase Pks12
- NCBI: Polyketide synthase Pks12
- updated information (H37Rv4):
  - gene name: pks12
  - function:
  - reference:
Type: Not Target
Start: 2294531
End: 2306986
Operon:

Trans-membrane region:
Role: I.I - Polyketide and non-ribosomal peptide synthesis
GO terms:
- GO:0055114 - oxidation-reduction process (Uniprot)
- GO:0042802 - identical protein binding (Uniprot)
- GO:0031177 - phosphopantetheine binding (Uniprot)
- GO:0016740 - transferase activity (Uniprot)
- GO:0016491 - oxidoreductase activity (Uniprot)
- GO:0008152 - metabolic process (Uniprot)
- GO:0003824 - catalytic activity (Uniprot)
Reaction(s) (based on iSM810 metabolic model):
- COA[c] + PENTA_METHYL_TRICONTANOYL[c] -> PENTA_METHYL_TRICONTANOYL_COA[c]
- 20 NADPH[c] + 5 SMMALONYLCOA[c] + 5 MALCOA[c] + HEXANOYL_COA[c] -> 20 NADP[c] + 10 CO2[c] + 11 COA[c] + PENTA_METHYL_TRICONTANO... <Preview truncated at 128 characters>
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
2QO3	56%	Saccharopolyspora erythraea	Crystal Structure of [KS3][AT3] didomain from module 3 of 6-deoxyerthronolide B synthase
2HG4	55%	Saccharopolyspora erythraea	Structure of the ketosynthase-acyltransferase didomain of module 5 from DEBS.
5HVC	55%	Mycobacterium ulcerans	Solution structure of the apo state of the acyl carrier protein from the MLSA2 subunit of the mycolactone polyketide synthase
5HV8	55%	Mycobacterium ulcerans	Solution structure of an octanoyl- loaded acyl carrier protein domain from module MLSA2 of the mycolactone polyketide synthase.
6C9U	55%	Saccharopolyspora erythraea	Crystal structure of [KS3][AT3] didomain from module 3 of 6-deoxyerthronolide B synthase in complex with antibody fragment (Fab)
3SLK	54%	Saccharopolyspora spinosa	Structure of ketoreductase and enoylreductase didomain from modular polyketide synthase
6H0Q	53%	Mycobacterium ulcerans (strain Agy99)	B1-type ACP domain from module 7 of MLSB
2JU2	53%	Saccharopolyspora erythraea	Minimized mean solution structure of the acyl carrier protein domain from module 2 of 6-deoxyerythronolide B synthase (DEBS)
2JU1	53%	Saccharopolyspora erythraea	Solution structure of acyl carrier protein domain from module 2 of 6-deoxyerythronolide B synthase (DEBS)
6IYR	53%	Streptomyces albus subsp. albus	Crystal Structure of the acyltransferase domain from module 8 of the salinomycin polyketide synthase

Links to additional information on pks12:
- KEGG - nucleotide and amino acid sequences of gene
- Mycobrowser
- PATRIC
- BioCyc
- Systems Biology
- TBDB (updated)
- Phyre2 structure prediction, model: final.casp.pdb (from Mao et al, 2013)
- UniProt
- AlphaFold model
- Vulnerability = 0.065 (from Jeremy Rock's lab)

Amino Acid Sequence

MVDQLQHATEALRKALVQVERLKRTNRALLERSSEPIAIVGMSCRFPGGVDSPEGLWQMVADARDVMSEFPTDRGWDLAGLFDPDPDVRHKSYARTGGFV
DGVADFDPAFFGISPSEALAMDPQHRMLLELSWEALERAGIDPTGLRGSATGVFAGLIVGGYGMLAEEIEGYRLTGMTSSVASGRVAYVLGLEGPAVSVD
TACSSSLVALHMAVGSLRSGECDLALAGGVTVNATPTVFVEFSRHRGLAPDGRCKPYAGRADGVGWSEGGGMLVLQRLSDARRLGHPVLAVVVGSAVNQD
GASNGLTAPNGPSQQRVVRAALANAGLSAAEVDVVEGHGTGTTLGDPIEAQALLATYGQDRGEPGEPLWLGSVKSNMGHTQAAAGVAGVIKMVLAMRHEL
LPATLHVDVPSPHVDWSAGAVELLTAPRVWPAGARTRRAGVSSFGISGTNAHVIIEAVPVVPRREAGWAGPVVPWVVSAKSESALRGQAARLAAYVRGDD
GLDVADVGWSLAGRSVFEHRAVVVGGDRDRLLAGLDELAGDQLGGSVVRGTATAAGKTVFVFPGQGSQWLGMGIELLDTAPAFAQQIDACAEAFAEFVDW
SLVDVLRGAPGAPGLDRVDVVQPVLFAVMVSLAELWKSVAVHPDAVIGHSQGEIAAAYVAGALSLRDAARVVTLRSKLLAGLAGPGGMVSIACGADQARD
LLAPFGDRVSIAVVNGPSAVVVSGEVGALEELIAVCSTKELRTRRIEVDYASHSVEVEAIRGPLAEALSGIEPRSTRTVFFSTVTGNRLDTAGLDADYWY
RNVRQTVLFDQAVRNACEQGYRTFIESSPHPALITGVEETFAACTDGDSEAIVVPTLGRGDGGLHRFLLSAASAFVAGVAVNWRGTLDGAGYVELPTYAF
DKRRFWLSAEGSGADVSGLGLGASEHPLLGAVVDLPASGGVVLTGRLSPNVQPWLADHAVSDVVLFPGTGFVELAIRAGDEVGCSVLDELTLAAPLLLPA
TGSVAVQVVVDAGRDSNSRGVSIFSRADAQAGWLLHAEGILRPGSVEPGADLSVWPPAGAVTVDVADGYERLATRGYRYGPAFRGLTAMWARGEEIFAEV
RLPEAAGGVGGFGVHPALLDAVLHAVVIAGDPDELALPFAWQGVSLHATGASAVRARIAPAGPSAVSVELADGLGLPVLSVASMVARPVTERQLLAAVSG
SGPDRLFEVIWSPASAATSPGPTPAYQIFESVAADQDPVAGSYVRSHQALAAVQSWLTDHESGVLVVATRGAMALPREDVADLAGAAVWGLVRSAQTEHP
GRIVLVDSDAATDDAAIAMALATGEPQVVLRGGQVYTARVRGSRAADAILVPPGDGPWRLGLGSAGTFENLRLEPVPNADAPLGPGQVRVAMRAIAANFR
DIMITLGMFTHDALLGGEGAGVVVEVGPGVTEFSVGDSVFGFFPDGSGTLVAGDVRLLLPMPADWSYAEAAAISAVFTTAYYAFIHLADVQPGQRVLIHA
GTGGVGMAAVQLARHLGLEVFATASKGKWDTLRAMGFDDDHISDSRSLEFEDKFRAATGGRGFDVVLDSLAGEFVDASLRLVAPGGVFLEMGKTDIRDPG
VIAQQYPGVRYRAFDLFEPGRPRMHQYMLELATLFGDGVLRPLPVTTFDVRRAPAALRYLSQARHTGKVVMLMPGSWAAGTVLITGGTGMAGSAVARHVV
ARHGVRNLVLVSRRGPDAPGAAELVAELAAAGAQVQVVACDAADRAALAKVIADIPVQHPLSGVIHTAGALDDAVVMSLTPDRVDVVLRSKVDAAWHLHE
LTRDLDVSAFVMFSSMAGLVGSSGQANYAAANSFLDALAAHRRAHGLPAISLGWGLWDQASAMTGGLDAADLARLGREGVLALSTAEALELFDTAMIVDE
PFLAPARIDLTALRAHAVAVPPMFSDLASAPTRRQVDDSVAAAKSKSALAHRLHGLPEAEQHAVLLGLVRLHIATVLGNITPEAIDPDKAFQDLGFDSLT
AVEMRNRLKSATGLSLSPTLIFDYPTPNRLASYIRTELAGLPQEIKHTPAVRTTSEDPIAIVGMACRYPGGVNSPDDMWDMLIQGRDVLSEFPADRGWDL
AGLYNPDPDAAGACYTRTGGFVDGVGDFDPAFFGVGPSEALAMDPQHRMLLELSWEALERAGIDPTGLRGSATGVFAGVMTQGYGMFAAEPVEGFRLTGQ
LSSVASGRVAYVLGLEGPAVSVDTACSSSLVALHMAVGSLRSGECDLALAGGVTVNATPDIFVEFSRWRGLSPDGRCKAFAAAADGTGFSEGGGMLVLQR
LSDARRLGHPVLAVVVGSAVNQDGASNGLTAPNGPSQQRVVRAALANAGLSAAEVDVVEGHGTGTTLGDPIEAQALLATYGQDRGEPGEPLWLGSVKSNM
GHTQAAAGVAGVIKMVLAMRHELLPATLHVDVPSPHVDWSAGAVELLTAPRVWPAGARTRRAGVSSFGISGTNAHVIIEAVPVVPRREAGWAGPVVPWVV
SAKSESALRGQAARLAAYVRGDDGLDVADVGWSLAGRSVFEHRAVVVGGDRDRLLAGLDELAGDQLGGSVVRGTATAAGKTVFVFPGQGSQWLGMGMGLH
AGYPVFAEAFNTVVGELDRHLLRPLREVMWGHDENLLNSTEFAQPALFAVEVALFRLLGSWGVRPDFVMGHSIGELSAAHVAGVLSLENAAVLVAARGRL
MQALPAGGAMVAVQAAEEEVRPLLSAEVDIAAVNGPASLVISGAQNAVAAVADQLRADGRRVHQLAVSHAFHSPLMDPMIDEFAAVAAGIAIGRPTIGVI
SNVTGQLAGDDFGSAAYWRRHIRQAVRFADSVRFAQAAGGSRFLEVGPSGGLVASIEESLPDVAVTTMSALRKDRPEPATLTNAVAQGFVTGMDLDWRAV
VGEAQFVELPTYAFQRRRFWLSGDGVAADAAGLGLAASEHALLGAVIDLPASGGVVLTGRLSPSVQGWLADHSVAGVTIFPGAGFVELAIRAGDEVGCGV
VDESTLAAPLVLPASGSVAVQVVVNGPDESGVRGVSVYSRGDVGTGWVLHAEGALRAGSAEPTADLAMWPPAGAVPVEVADGYQQLAERGYGYGPAFRGL
TAMWRRGDEVFAEVALPADAGVSVTGFGVHPVLLDAALHAVVLSAESAERGQGSVLVPFSWQGVSLHAAGASAVRARIAPVGPSAVSIELADGLGLPVLS
VASMLARPVTDQQLRAAVSSSGPDRLFEVTWSPQPSAAVEPLPVCAWGTTEDSAAVVFESVPLAGDVVAGVYAATSSVLDVLQSWLTRDGAGVLVVMTRG
AVALPGEDVTDLAGAAVWGLVRSAQTEHPGRIVLVDSDAPLDDSALAAVVTTGEPQVLWRRGEVYTARVHGSRAVGGLLVPPSDRPWRLAMSTAGTFENL
RLELIPDADAPLGPGQVRVAVSAIAANFRDVMIALGLYPDPDAVMGVEACGVVIETSLNKGSFAVGDRVMGLFPEGTGTVASTDQRLLVKVPAGWSHTAA
ATTSVVFATAHYALVDLAAARSGQRVLIHAGTGGVGMAAVQLARHLGLEVFATASKGKWDTLRAMGFDDDHISDSRSLEFEDKFRAATGGRGFDVVLDSL
AGEFVDASLRLVAPGGVFLEMGKTDIRDPGVIAQQYPGVRYRAFDLFEPGPDRIAQILAELATLFGDGVLRPLPVTTFDVRCAPAALRYLSQARHTGKVV
MLMPGSWAAGTVLITGGTGMAGSAVARHVVARHGVRNLVLVSRRGPDAPGAAELVAELAAAGAQVQVVACDAADRAALAKVIADIPVQHPLSGVIHTAGA
LDDAVVMSLTPDRVDVVLRSKVDAAWHLHELTRDLDVSAFVMFSSMAGLVGSSGQANYAAANSFLDALAAHRRAHGLPAISLGWGLWDQASAMTGGLATV
DFKRFARDGIVAMSSADALQLFDTAMIVDEPFMLPAHIDFAALKVKFDGGTLPPMFVDLINAPTRRQVDDSLAAAKSKSALLQRLEGLPEDEQHAVLLDL
VRSHIATVLGSASPEAIDPDRAFQELGFDSLTAVEMRNRLKSATGLALSPTLIFDYPNSAALAGYMRRELLGSSPQDTSAVAAGEAELQRIVASIPVKRL
RQAGVLDLLLALANETETSGQDPALAPTAEQEIADMDLDDLVNAAFRNDDE

(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?	YES	YES
omega peak height (95%CI lower bound)	4.52 (2.09)	3.6 (2.1)
codons under selection	157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172	468, 469, 470, 471, 472, 473, 474, 475, 476, 477, 478, 479, 480, 481, 482, 483, 2370, 2371, 2372, 2373, 2374, 2382, 2383, 2384, 2385, 2391, 2392, 2393, 2394, 2395, 2396, 2397, 2398, 2399, 2400, 2401, 2406, 2407, 2408, 2409, 2410, 2411, 2412, 2413, 2414, 2415, 2416, 2417, 2418, 2419, 2420, 2421, 2488, 2489, 2490, 2491, 2492, 2493, 2494, 2495, 2496, 2497, 2498, 2499, 2500, 3403, 3404, 3405, 3406, 3407, 3408, 3409, 3410, 3411, 3414, 3415, 3416, 3417, 3983, 3984, 3985, 3986, 3987, 3988
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

Rv2048c/pks12, gene len: 12455 bp, num TA sites: 149

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	no data	7H9	TRASH	essential if hybridization ratio<0.2
in-vivo (mice)	Sassetti 2003 PNAS	essential	BL6 mice	TRASH	essential if hybridization ratio<0.4, min over 4 timepoints (1-8 weeks)
in-vitro (glycerol)	Griffin 2011 PPath	essential	M9 minimal+glycerol	Gumbel	2 replicates; Padj<0.05
in-vitro (cholesterol)	Griffin 2011 PPath	essential	M9 minimal+cholesterol	Gumbel	3 replicates; Padj<0.05
differentially essential in cholesterol	Griffin 2011 PPath	YES (LFC=-1.92)	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	growth defect	7H9	HMM	6 replicates (raw data in Subramaniam 2017, PMID 31752678)
in-vivo (mice)	Smith 2022 eLife	growth defect	BL6 mice	HMM	6 replicates (raw data in Subramaniam 2017, PMID 31752678)
differentially essential in mice	Smith 2022 eLife	YES (LFC=-1.133)	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	growth defect	minimal medium	HMM
in-vitro (YM rich medium)	Minato 2019 mSys	growth defect	YM rich medium	HMM	7H9 supplemented with ~20 metabolites (amino acids, vitamins)
differentially essential in YM rich medium	Minato 2019 mSys	YES (LFC=1.54)	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 (-)
- Rv3058c (-)

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

Binds To:
- No bindings to other targets were found.
Bound By:
- Rv0678 (-) (Direct binding)
- Rv0767c (-) (Direct binding)

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 (-)
- Rv3058c (-)

Property	Value	Creator	Evidence	PMID	Comment
Interaction	ActivatedBy Rv2047c	ravirajsoni	NAS		T. Chopra, S. Banerjee et al. Novel intermolecular iterative mechanism for biosynthesis of mycoketide catalyzed by a bimodular polyketide synthase. PLoS Biol. 2008
Name	Mycoketide synthase	mjackson	IMP		Mannosyl-b-1-phosphomycoketides
Name	Mycoketide synthase	mjackson	IDA		Mannosyl-b-1-phosphomycoketides
Other	TBPWY:Mannosyl-beta-1-phosphomycoketides	mjackson			Mycoketide synthase (phenotypic [mycobacterial recombinant strains]; enzymatic) T. Chopra, S. Banerjee et al. Novel intermolecular iterative mechanism for biosynthesis of mycoketide catalyzed by a bimodular polyketide synthase. PLoS Biol. 2008
Citation	Mycobacterium tuberculosis pks12 produces a novel polyketide presented by CD1c to T cells. I. Matsunaga, A. Bhatt et al. J. Exp. Med. 2004	mjackson		15611286	Mycoketide synthase (phenotypic [mycobacterial recombinant strains]; enzymatic)
Other	TBPWY:Mannosyl-beta-1-phosphomycoketides	mjackson			Mycoketide synthase (phenotypic [mycobacterial recombinant strains]; enzymatic) I. Matsunaga, A. Bhatt et al. Mycobacterium tuberculosis pks12 produces a novel polyketide presented by CD1c to T cells. J. Exp. Med. 2004
Citation	Novel intermolecular iterative mechanism for biosynthesis of mycoketide catalyzed by a bimodular polyketide synthase. T. Chopra, S. Banerjee et al. PLoS Biol. 2008	mjackson		18613748	Mycoketide synthase (phenotypic [mycobacterial recombinant strains]; enzymatic)
Citation	Mycobacterium tuberculosis pks12 produces a novel polyketide presented by CD1c to T cells. I. Matsunaga, A. Bhatt et al. J. Exp. Med. 2004	jjmcfadden		15611286	Inferred from direct assay
Other	EC:	jjmcfadden			Inferred from direct assay I. Matsunaga, A. Bhatt et al. Mycobacterium tuberculosis pks12 produces a novel polyketide presented by CD1c to T cells. J. Exp. Med. 2004

TB Genome Annotation Portal