PHAS_MYCTU
ID PHAS_MYCTU Reviewed; 2126 AA.
AC P9WQE9; L0TDW7; O07798; Q7D4T0;
DT 16-APR-2014, integrated into UniProtKB/Swiss-Prot.
DT 16-APR-2014, sequence version 1.
DT 03-AUG-2022, entry version 49.
DE RecName: Full=Phthioceranic/hydroxyphthioceranic acid synthase {ECO:0000305};
DE EC=2.3.1.287 {ECO:0000269|PubMed:11278910};
DE AltName: Full=Polyketide synthase pks2;
GN Name=pks2 {ECO:0000303|PubMed:9634230};
GN Synonyms=msl2 {ECO:0000303|PubMed:11278910}; OrderedLocusNames=Rv3825c;
OS Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv).
OC Bacteria; Actinobacteria; Corynebacteriales; Mycobacteriaceae;
OC Mycobacterium; Mycobacterium tuberculosis complex.
OX NCBI_TaxID=83332;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=ATCC 25618 / H37Rv;
RX PubMed=9634230; DOI=10.1038/31159;
RA Cole S.T., Brosch R., Parkhill J., Garnier T., Churcher C.M., Harris D.E.,
RA Gordon S.V., Eiglmeier K., Gas S., Barry C.E. III, Tekaia F., Badcock K.,
RA Basham D., Brown D., Chillingworth T., Connor R., Davies R.M., Devlin K.,
RA Feltwell T., Gentles S., Hamlin N., Holroyd S., Hornsby T., Jagels K.,
RA Krogh A., McLean J., Moule S., Murphy L.D., Oliver S., Osborne J.,
RA Quail M.A., Rajandream M.A., Rogers J., Rutter S., Seeger K., Skelton S.,
RA Squares S., Squares R., Sulston J.E., Taylor K., Whitehead S.,
RA Barrell B.G.;
RT "Deciphering the biology of Mycobacterium tuberculosis from the complete
RT genome sequence.";
RL Nature 393:537-544(1998).
RN [2]
RP INDUCTION.
RC STRAIN=ATCC 25618 / H37Rv;
RX PubMed=10500215; DOI=10.1073/pnas.96.20.11554;
RA Graham J.E., Clark-Curtiss J.E.;
RT "Identification of Mycobacterium tuberculosis RNAs synthesized in response
RT to phagocytosis by human macrophages by selective capture of transcribed
RT sequences (SCOTS).";
RL Proc. Natl. Acad. Sci. U.S.A. 96:11554-11559(1999).
RN [3]
RP FUNCTION IN SULFOLIPID-1 BIOSYNTHESIS, CATALYTIC ACTIVITY, PATHWAY, AND
RP DISRUPTION PHENOTYPE.
RC STRAIN=ATCC 25618 / H37Rv;
RX PubMed=11278910; DOI=10.1074/jbc.m011468200;
RA Sirakova T.D., Thirumala A.K., Dubey V.S., Sprecher H., Kolattukudy P.E.;
RT "The Mycobacterium tuberculosis pks2 gene encodes the synthase for the
RT hepta- and octamethyl-branched fatty acids required for sulfolipid
RT synthesis.";
RL J. Biol. Chem. 276:16833-16839(2001).
RN [4]
RP FUNCTION IN SULFOLIPID-1 BIOSYNTHESIS, AND PATHWAY.
RC STRAIN=ATCC 35801 / TMC 107 / Erdman;
RX PubMed=12724526; DOI=10.1073/pnas.1030024100;
RA Converse S.E., Mougous J.D., Leavell M.D., Leary J.A., Bertozzi C.R.,
RA Cox J.S.;
RT "MmpL8 is required for sulfolipid-1 biosynthesis and Mycobacterium
RT tuberculosis virulence.";
RL Proc. Natl. Acad. Sci. U.S.A. 100:6121-6126(2003).
RN [5]
RP REGULATION BY PHOP/PHOR.
RC STRAIN=ATCC 25618 / H37Rv;
RX PubMed=16573683; DOI=10.1111/j.1365-2958.2006.05102.x;
RA Walters S.B., Dubnau E., Kolesnikova I., Laval F., Daffe M., Smith I.;
RT "The Mycobacterium tuberculosis PhoPR two-component system regulates genes
RT essential for virulence and complex lipid biosynthesis.";
RL Mol. Microbiol. 60:312-330(2006).
RN [6]
RP PATHWAY, AND REVIEW.
RX PubMed=17389997; DOI=10.1039/b616817p;
RA Gokhale R.S., Saxena P., Chopra T., Mohanty D.;
RT "Versatile polyketide enzymatic machinery for the biosynthesis of complex
RT mycobacterial lipids.";
RL Nat. Prod. Rep. 24:267-277(2007).
RN [7]
RP IDENTIFICATION AS A DRUG TARGET [LARGE SCALE ANALYSIS].
RX PubMed=19099550; DOI=10.1186/1752-0509-2-109;
RA Raman K., Yeturu K., Chandra N.;
RT "targetTB: a target identification pipeline for Mycobacterium tuberculosis
RT through an interactome, reactome and genome-scale structural analysis.";
RL BMC Syst. Biol. 2:109-109(2008).
RN [8]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC STRAIN=ATCC 25618 / H37Rv;
RX PubMed=21969609; DOI=10.1074/mcp.m111.011627;
RA Kelkar D.S., Kumar D., Kumar P., Balakrishnan L., Muthusamy B., Yadav A.K.,
RA Shrivastava P., Marimuthu A., Anand S., Sundaram H., Kingsbury R.,
RA Harsha H.C., Nair B., Prasad T.S., Chauhan D.S., Katoch K., Katoch V.M.,
RA Kumar P., Chaerkady R., Ramachandran S., Dash D., Pandey A.;
RT "Proteogenomic analysis of Mycobacterium tuberculosis by high resolution
RT mass spectrometry.";
RL Mol. Cell. Proteomics 10:M111.011627-M111.011627(2011).
RN [9]
RP PATHWAY, AND DISRUPTION PHENOTYPE.
RC STRAIN=H37Rv;
RX PubMed=24028583; DOI=10.1111/cmi.12214;
RA Passemar C., Arbues A., Malaga W., Mercier I., Moreau F., Lepourry L.,
RA Neyrolles O., Guilhot C., Astarie-Dequeker C.;
RT "Multiple deletions in the polyketide synthase gene repertoire of
RT Mycobacterium tuberculosis reveal functional overlap of cell envelope
RT lipids in host-pathogen interactions.";
RL Cell. Microbiol. 16:195-213(2014).
CC -!- FUNCTION: Involved in sulfolipid-1 biosynthesis (PubMed:11278910,
CC PubMed:12724526). Catalyzes the synthesis of the hepta- and octamethyl
CC phthioceranic and hydroxyphthioceranic acids, the methyl-branched acyl
CC constituents of sulfolipids (PubMed:11278910).
CC {ECO:0000269|PubMed:11278910, ECO:0000269|PubMed:12724526}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=7 (S)-methylmalonyl-CoA + 21 H(+) + hexadecanoyl-
CC [(hydroxy)phthioceranic acid synthase] + 14 NADPH = C37-
CC phthioceranyl-[(hydroxy)phthioceranic acid synthase] + 7 CO2 + 7 CoA
CC + 7 H2O + 14 NADP(+); Xref=Rhea:RHEA:58908, Rhea:RHEA-COMP:15244,
CC Rhea:RHEA-COMP:15246, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378,
CC ChEBI:CHEBI:16526, ChEBI:CHEBI:57287, ChEBI:CHEBI:57327,
CC ChEBI:CHEBI:57783, ChEBI:CHEBI:58349, ChEBI:CHEBI:78483,
CC ChEBI:CHEBI:142473; EC=2.3.1.287;
CC Evidence={ECO:0000269|PubMed:11278910};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=8 (S)-methylmalonyl-CoA + 24 H(+) + hexadecanoyl-
CC [(hydroxy)phthioceranic acid synthase] + 16 NADPH = C40-
CC phthioceranyl-[(hydroxy)phthioceranic acid synthase] + 8 CO2 + 8 CoA
CC + 8 H2O + 16 NADP(+); Xref=Rhea:RHEA:58904, Rhea:RHEA-COMP:15244,
CC Rhea:RHEA-COMP:15245, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378,
CC ChEBI:CHEBI:16526, ChEBI:CHEBI:57287, ChEBI:CHEBI:57327,
CC ChEBI:CHEBI:57783, ChEBI:CHEBI:58349, ChEBI:CHEBI:78483,
CC ChEBI:CHEBI:142472; EC=2.3.1.287;
CC Evidence={ECO:0000269|PubMed:11278910};
CC -!- COFACTOR:
CC Name=pantetheine 4'-phosphate; Xref=ChEBI:CHEBI:47942;
CC Evidence={ECO:0000250|UniProtKB:P96202};
CC Note=Binds 1 phosphopantetheine covalently.
CC {ECO:0000250|UniProtKB:P96202};
CC -!- PATHWAY: Lipid metabolism; fatty acid biosynthesis.
CC {ECO:0000269|PubMed:11278910, ECO:0000269|PubMed:12724526,
CC ECO:0000305|PubMed:17389997}.
CC -!- PATHWAY: Glycolipid metabolism; sulfolipid-1 biosynthesis.
CC {ECO:0000269|PubMed:11278910, ECO:0000269|PubMed:12724526,
CC ECO:0000269|PubMed:24028583, ECO:0000305|PubMed:17389997}.
CC -!- INDUCTION: Up-regulated by the PhoP/PhoR two-component system
CC (PubMed:16573683). Expressed in response to phagocytosis by human
CC macrophages (PubMed:10500215). {ECO:0000269|PubMed:10500215,
CC ECO:0000269|PubMed:16573683}.
CC -!- DISRUPTION PHENOTYPE: Disruption mutant does not synthesize sulfolipids
CC (PubMed:11278910, PubMed:24028583). Mutant is incapable of producing
CC hepta- and octamethyl phthioceranic acids and hydroxyphthioceranic
CC acids, which are the major acyl constituents of sulfolipids
CC (PubMed:11278910). {ECO:0000269|PubMed:11278910,
CC ECO:0000269|PubMed:24028583}.
CC -!- MISCELLANEOUS: Was identified as a high-confidence drug target.
CC {ECO:0000269|PubMed:19099550}.
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DR EMBL; AL123456; CCP46654.1; -; Genomic_DNA.
DR PIR; E70522; E70522.
DR RefSeq; NP_218342.1; NC_000962.3.
DR RefSeq; WP_003900763.1; NZ_NVQJ01000022.1.
DR AlphaFoldDB; P9WQE9; -.
DR SMR; P9WQE9; -.
DR STRING; 83332.Rv3825c; -.
DR PaxDb; P9WQE9; -.
DR GeneID; 886148; -.
DR KEGG; mtu:Rv3825c; -.
DR TubercuList; Rv3825c; -.
DR eggNOG; COG0604; Bacteria.
DR eggNOG; COG1028; Bacteria.
DR eggNOG; COG3321; Bacteria.
DR OMA; KDVQHYT; -.
DR PhylomeDB; P9WQE9; -.
DR BioCyc; MetaCyc:G185E-8121-MON; -.
DR BRENDA; 2.3.1.252; 3445.
DR UniPathway; UPA00094; -.
DR UniPathway; UPA01063; -.
DR PHI-base; PHI:7221; -.
DR Proteomes; UP000001584; Chromosome.
DR GO; GO:0005737; C:cytoplasm; IBA:GO_Central.
DR GO; GO:0005829; C:cytosol; HDA:MTBBASE.
DR GO; GO:0009274; C:peptidoglycan-based cell wall; HDA:MTBBASE.
DR GO; GO:0005886; C:plasma membrane; HDA:MTBBASE.
DR GO; GO:0004315; F:3-oxoacyl-[acyl-carrier-protein] synthase activity; IEA:InterPro.
DR GO; GO:0004312; F:fatty acid synthase activity; IBA:GO_Central.
DR GO; GO:0016491; F:oxidoreductase activity; IEA:InterPro.
DR GO; GO:0031177; F:phosphopantetheine binding; IEA:InterPro.
DR GO; GO:0010106; P:cellular response to iron ion starvation; IEP:MTBBASE.
DR GO; GO:0071770; P:DIM/DIP cell wall layer assembly; IBA:GO_Central.
DR GO; GO:0006633; P:fatty acid biosynthetic process; IDA:MTBBASE.
DR Gene3D; 1.10.1200.10; -; 1.
DR Gene3D; 3.10.129.110; -; 1.
DR Gene3D; 3.40.366.10; -; 1.
DR Gene3D; 3.40.47.10; -; 1.
DR InterPro; IPR001227; Ac_transferase_dom_sf.
DR InterPro; IPR036736; ACP-like_sf.
DR InterPro; IPR014043; Acyl_transferase.
DR InterPro; IPR016035; Acyl_Trfase/lysoPLipase.
DR InterPro; IPR013149; ADH-like_C.
DR InterPro; IPR013154; ADH_N.
DR InterPro; IPR011032; GroES-like_sf.
DR InterPro; IPR018201; Ketoacyl_synth_AS.
DR InterPro; IPR014031; Ketoacyl_synth_C.
DR InterPro; IPR014030; Ketoacyl_synth_N.
DR InterPro; IPR016036; Malonyl_transacylase_ACP-bd.
DR InterPro; IPR036291; NAD(P)-bd_dom_sf.
DR InterPro; IPR032821; PKS_assoc.
DR InterPro; IPR020841; PKS_Beta-ketoAc_synthase_dom.
DR InterPro; IPR020807; PKS_dehydratase.
DR InterPro; IPR042104; PKS_dehydratase_sf.
DR InterPro; IPR020843; PKS_ER.
DR InterPro; IPR013968; PKS_KR.
DR InterPro; IPR020806; PKS_PP-bd.
DR InterPro; IPR009081; PP-bd_ACP.
DR InterPro; IPR006162; Ppantetheine_attach_site.
DR InterPro; IPR016039; Thiolase-like.
DR Pfam; PF00698; Acyl_transf_1; 1.
DR Pfam; PF08240; ADH_N; 1.
DR Pfam; PF00107; ADH_zinc_N; 1.
DR Pfam; PF16197; KAsynt_C_assoc; 1.
DR Pfam; PF00109; ketoacyl-synt; 1.
DR Pfam; PF02801; Ketoacyl-synt_C; 1.
DR Pfam; PF08659; KR; 1.
DR Pfam; PF00550; PP-binding; 1.
DR Pfam; PF14765; PS-DH; 1.
DR SMART; SM00827; PKS_AT; 1.
DR SMART; SM00826; PKS_DH; 1.
DR SMART; SM00829; PKS_ER; 1.
DR SMART; SM00825; PKS_KS; 1.
DR SMART; SM00823; PKS_PP; 1.
DR SUPFAM; SSF47336; SSF47336; 1.
DR SUPFAM; SSF50129; SSF50129; 1.
DR SUPFAM; SSF51735; SSF51735; 3.
DR SUPFAM; SSF52151; SSF52151; 1.
DR SUPFAM; SSF53901; SSF53901; 1.
DR SUPFAM; SSF55048; SSF55048; 1.
DR PROSITE; PS00606; B_KETOACYL_SYNTHASE; 1.
DR PROSITE; PS50075; CARRIER; 1.
DR PROSITE; PS00012; PHOSPHOPANTETHEINE; 1.
PE 1: Evidence at protein level;
KW Acyltransferase; Fatty acid biosynthesis; Fatty acid metabolism;
KW Lipid biosynthesis; Lipid metabolism; Multifunctional enzyme; NADP;
KW Phosphopantetheine; Phosphoprotein; Reference proteome; Transferase.
FT CHAIN 1..2126
FT /note="Phthioceranic/hydroxyphthioceranic acid synthase"
FT /id="PRO_0000329012"
FT DOMAIN 2040..2126
FT /note="Carrier"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
FT REGION 1..449
FT /note="Beta-ketoacyl synthase (KS)"
FT /evidence="ECO:0000250|UniProtKB:A0R1E8"
FT REGION 449..549
FT /note="Linker domain (LD)"
FT /evidence="ECO:0000250|UniProtKB:A0R1E8"
FT REGION 550..849
FT /note="Acyltransferase (AT)"
FT /evidence="ECO:0000250|UniProtKB:A0R1E8"
FT REGION 909..1191
FT /note="Dehydratase (DH)"
FT /evidence="ECO:0000250|UniProtKB:A0R1E8"
FT REGION 1227..1398
FT /note="Pseudo beta-ketoacyl reductase (PsiKR)"
FT /evidence="ECO:0000250|UniProtKB:A0R1E8"
FT REGION 1426..1750
FT /note="Enoylreductase (ER)"
FT /evidence="ECO:0000250|UniProtKB:A0R1E8"
FT REGION 1772..2019
FT /note="Beta-ketoacyl reductase (KR)"
FT /evidence="ECO:0000250|UniProtKB:A0R1E8"
FT ACT_SITE 196
FT /note="Acyl-thioester intermediate; for beta-ketoacyl
FT synthase activity"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU10022"
FT ACT_SITE 641
FT /note="Acyl-ester intermediate; for acyltransferase
FT activity"
FT /evidence="ECO:0000250|UniProtKB:A0R1E8"
FT ACT_SITE 947
FT /note="Proton acceptor; for dehydratase activity"
FT /evidence="ECO:0000250|UniProtKB:Q03132"
FT ACT_SITE 1115
FT /note="Proton donor; for dehydratase activity"
FT /evidence="ECO:0000250|UniProtKB:Q03132"
FT BINDING 1780..1783
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000250|UniProtKB:Q03131"
FT BINDING 1803..1806
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000250|UniProtKB:Q03131"
FT BINDING 1831..1832
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000250|UniProtKB:Q03131"
FT BINDING 1904..1905
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000250|UniProtKB:Q03131"
FT MOD_RES 2075
FT /note="O-(pantetheine 4'-phosphoryl)serine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
SQ SEQUENCE 2126 AA; 225776 MW; 224469098DE741C6 CRC64;
MGLGSAASGT GADRGAWTLA EPRVTPVAVI GMACRLPGGI DSPELLWKAL LRGDDLITEV
PPDRWDCDEF YDPQPGVPGR TVCKWGGFLD NPADFDCEFF GIGEREAIAI DPQQRLLLET
SWEAMEHAGL TQQTLAGSAT GVFAGVTHGD YTMVAADAKQ LEEPYGYLGN SFSMASGRVA
YAMRLHGPAI TVDTACSSGL TAVHMACRSL HEGESDVALA GGVALMLEPR KAAAGSALGM
LSPTGRCRAF DVAADGFVSG EGCAVVVLKR LPDALADGDR ILAVIRGTSA NQDGHTVNIA
TPSQPAQVAA YRAALAAGGV DAATVGMVEA HGPGTPIGDP IEYASVSEVY GVDGPCALAS
VKTNFGHTQS TAGVLGLIKV VLALKHGVVP RNLHFTRLPD EIAGITTNLF VPEVTTPWPT
NGRQVPRRAA VSSYGFSGTN VHAVVEQAPQ TEAQPHAAST PPTGTPALFT LSASSADALR
QTAQRLTDWI QQHADSLVLS DLAYTLARRR THRSVRTAVI ASSVDELIAG LGEVADGDTV
YQPAVGQDDR GPVWLFSGQG SQWAAMGADL LTNESVFAAT VAELEPLIAA ESGFSVTEAM
TAPETVTGID RVQPTIFAMQ VALAATMAAY GVRPGAVIGH SMGESAAAVV AGVLSAEDGV
RVICRRSKLM ATIAGSAAMA SVELPALAVQ SELTALGIDD VVVAVVTAPQ STVIAGGTES
VRKLVDIWER RDVLARAVAV DVASHSPQVD PILDELIAAL ADLNPKAPEI PYYSATLFDP
REAPACDARY WADNLRHTVR FSAAVRSALD DGYRVFAELS PHPLLTHAVD QIAGSVGMPV
AALAGMRREQ PLPLGLRRLL TDLHNAGAAV DFSVLCPQGR LVDAPLPAWS HRFLFYDREG
VDNRSPGGST VAVHPLLGAH VRLPEEPERH AWQADVGTAT LPWLGDHRIH NVAALPGAAY
CEMALSAARA VLGEQSEVRD MRFEAMLLLD DQTPVSTVAT VTSPGVVDFA VEALQEGVGH
HLRRASAVLQ QVSGECEPPA YDMASLLEAH PCRVDGEDLR RQFDKHGVQY GPAFTGLAVA
YVAEDATATM LAEVALPGSI RSQQGLYAIH PALLDACFQS VGAHPDSQSV GSGLLVPLGV
RRVRAYAPVR TARYCYTRVT KVELVGVEAD IDVLDAHGTV LLAVCGLRIG TGVSERDKHN
RVLNERLLTI EWHQRELPEM DPSGAGKWLL ISDCAASDVT ATRLADAFRE HSAACTTMRW
PLHDDQLAAA DQLRDQVGSD EFSGVVVLTG SNTGTPHQGS ADRGAEYVRR LVGIARELSD
LPGAVPRMYV VTRGAQRVLA DDCVNLEQGG LRGLLRTIGA EHPHLRATQI DVDEQTGVEQ
LARQLLATSE EDETAWRDNE WYVARLCPTP LRPQERRTIV ADHQQSGMRL QIRTPGDMQT
IELAAFHRVP PGPGQIEVAV RASSVNFADV LIAFGRYPSF EGHLPQLGTD FAGVVTAVGP
GVTDHKVGDH VGGMSPNGCW GTFVTCDARL AATLPPGLGD AQAAAVTTAH ATAWYGLHEL
ARIRAGDTVL IHSGTGGVGQ AAIAIARAAG AEIFATAGTP QRRELLRNMG IEHVYDSRSI
EFAEQIRRDT NGRGVDVVLN SVTGAAQLAG LKLLAFRGRF VEIGKRDIYG DTKLGLFPFR
RNLSFYAVDL GLLSATHPEE LRDLLGTVYR LTAAGELPMP QSTHYPLVEA ATAIRVMGNA
EHTGKLVLHI PQTGKSLVTL PPEQAQVFRP DGSYIITGGL GGLGLFLAEK MAAAGCGRIV
LNSRTQPTQK MRETIEAIAA MGSEVVVECG DIAQPGTAER LVATAVATGL PVRGVLHAAA
VVEDATLANI TDELLARDWA PKVHGAWELH EATSGQPLDW FCLFSSAAAL TGSPGQSAYS
AANSWLDAFA HWRQAQGLPA TAIAWGAWSD IGQLGWWSAS PARASALEES NYTAITPDEG
AYAFEALLRH NRVYTGYAPV IGAPWLVAFA ERSRFFEVFS SSNGSGTSKF RVELNELPRD
EWPARLRQLV AEQVSLILRR TVDPDRPLPE YGLDSLGALE LRTRIETETG IRLAPKNVSA
TVRGLADHLY EQLAPDDAPA AALSSQ
