MLCA_PENCI
ID MLCA_PENCI Reviewed; 3032 AA.
AC Q8J0F7;
DT 11-MAY-2016, integrated into UniProtKB/Swiss-Prot.
DT 01-MAR-2003, sequence version 1.
DT 03-AUG-2022, entry version 104.
DE RecName: Full=Compactin nonaketide synthase, polyketide synthase component {ECO:0000303|PubMed:12172803};
DE EC=2.3.1.- {ECO:0000305};
DE AltName: Full=Compactin biosynthesis protein A {ECO:0000303|PubMed:12172803};
DE AltName: Full=Compactin nonaketide synthase mlcA {ECO:0000305};
GN Name=mlcA {ECO:0000303|PubMed:12172803};
GN Synonyms=pks4 {ECO:0000303|PubMed:12172803};
OS Penicillium citrinum.
OC Eukaryota; Fungi; Dikarya; Ascomycota; Pezizomycotina; Eurotiomycetes;
OC Eurotiomycetidae; Eurotiales; Aspergillaceae; Penicillium.
OX NCBI_TaxID=5077;
RN [1]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], INDUCTION, FUNCTION, AND DISRUPTION
RP PHENOTYPE.
RX PubMed=12172803; DOI=10.1007/s00438-002-0697-y;
RA Abe Y., Suzuki T., Ono C., Iwamoto K., Hosobuchi M., Yoshikawa H.;
RT "Molecular cloning and characterization of an ML-236B (compactin)
RT biosynthetic gene cluster in Penicillium citrinum.";
RL Mol. Genet. Genomics 267:636-646(2002).
RN [2]
RP FUNCTION.
RX PubMed=12242508; DOI=10.1007/s00438-002-0736-8;
RA Abe Y., Suzuki T., Mizuno T., Ono C., Iwamoto K., Hosobuchi M.,
RA Yoshikawa H.;
RT "Effect of increased dosage of the ML-236B (compactin) biosynthetic gene
RT cluster on ML-236B production in Penicillium citrinum.";
RL Mol. Genet. Genomics 268:130-137(2002).
RN [3]
RP BIOTECHNOLOGY.
RX PubMed=1010803; DOI=10.7164/antibiotics.29.1346;
RA Endo A., Kuroda M., Tsujita Y.;
RT "ML-236A, ML-236B, and ML-236C, new inhibitors of cholesterogenesis
RT produced by Penicillium citrinium.";
RL J. Antibiot. 29:1346-1348(1976).
RN [4]
RP INDUCTION.
RX PubMed=12436257; DOI=10.1007/s00438-002-0755-5;
RA Abe Y., Ono C., Hosobuchi M., Yoshikawa H.;
RT "Functional analysis of mlcR, a regulatory gene for ML-236B (compactin)
RT biosynthesis in Penicillium citrinum.";
RL Mol. Genet. Genomics 268:352-361(2002).
RN [5]
RP INDUCTION.
RX PubMed=18667169; DOI=10.1016/j.fgb.2008.07.002;
RA Baba S., Nihira T., Hosobuchi M.;
RT "Identification of the specific sequence recognized by Penicillium citrinum
RT MlcR, a GAL4-type transcriptional activator of ML-236B (compactin)
RT biosynthetic genes.";
RL Fungal Genet. Biol. 45:1277-1283(2008).
CC -!- FUNCTION: Nonaketide synthase; part of the gene cluster that mediates
CC the biosynthesis of compactin, also known as mevastatin or ML-236B, and
CC which acts as a potent competitive inhibitor of HMG-CoA reductase
CC (PubMed:12172803, PubMed:12242508). Compactin biosynthesis is performed
CC in two stages (PubMed:12172803). The first stage is catalyzed by the
CC nonaketide synthase mlcA, which belongs to type I polyketide synthases
CC and catalyzes the iterative nine-step formation of the polyketide
CC (PubMed:12172803). This PKS stage is completed by the action of
CC dehydrogenase mlcG, which catalyzes the NADPH-dependent reduction of
CC the unsaturated tetra-, penta- and heptaketide intermediates that arise
CC during the mlcA-mediated biosynthesis of the nonaketide chain and leads
CC to dihydro-ML-236C carboxylate (PubMed:12172803). Covalently bound
CC dihydro-ML-236C carboxylate is released from mlcA by the mlcF esterase
CC (PubMed:12172803). Conversion of dihydro-ML-236C carboxylate into ML-
CC 236A carboxylate is subsequently performed with the participation of
CC molecular oxygen and P450 monoogygenase mlcC (PubMed:12172803).
CC Finally, mlcH performs the conversion of ML-236A carboxylate to ML-
CC 236B/compactin carboxylate through the addition of the side-chain
CC diketide moiety produced by the diketide synthase mlcB
CC (PubMed:12172803). {ECO:0000269|PubMed:12172803,
CC ECO:0000269|PubMed:12242508}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=20 H(+) + holo-[compactin nonaketide synthase] + 9 malonyl-CoA
CC + 11 NADPH = 9 CO2 + 9 CoA + dihydro-ML-236C-[compactin nonaketide
CC synthase] + 6 H2O + 11 NADP(+); Xref=Rhea:RHEA:57612, Rhea:RHEA-
CC COMP:14940, Rhea:RHEA-COMP:14941, ChEBI:CHEBI:15377,
CC ChEBI:CHEBI:15378, ChEBI:CHEBI:16526, ChEBI:CHEBI:57287,
CC ChEBI:CHEBI:57384, ChEBI:CHEBI:57783, ChEBI:CHEBI:58349,
CC ChEBI:CHEBI:64479, ChEBI:CHEBI:142039; Evidence={ECO:0000305};
CC -!- COFACTOR:
CC Name=pantetheine 4'-phosphate; Xref=ChEBI:CHEBI:47942;
CC Evidence={ECO:0000250|UniProtKB:Q9Y8A5};
CC Note=Binds 1 phosphopantetheine covalently.
CC {ECO:0000250|UniProtKB:Q9Y8A5};
CC -!- PATHWAY: Polyketide biosynthesis. {ECO:0000305}.
CC -!- INDUCTION: Expression is induced at the beginning of the stationary
CC phase, which is consistent with the timing of compactin production
CC (PubMed:12172803). Expression is controlled by the ML-236B/compactin
CC cluster transcription regulator mlcR (PubMed:12436257,
CC PubMed:18667169). {ECO:0000269|PubMed:12172803,
CC ECO:0000269|PubMed:12436257, ECO:0000269|PubMed:18667169}.
CC -!- DISRUPTION PHENOTYPE: Impairs the production of compactin
CC (PubMed:12172803). {ECO:0000269|PubMed:12172803}.
CC -!- BIOTECHNOLOGY: Compactin (also known as mevastatin or ML-236B) and the
CC intermediary metabolites Ml-236C and ML-236A are inhibitors of HMG-CoA
CC reductase involved in cholesterogenesis (PubMed:1010803). Their
CC hypocholesterolemic activity might be useful for lowering cholesterol
CC levels in the blood and reduce artherosclerosis and coronary heart
CC disease (PubMed:1010803). {ECO:0000269|PubMed:1010803}.
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DR EMBL; AB072893; BAC20564.1; -; Genomic_DNA.
DR SMR; Q8J0F7; -.
DR GO; GO:0004315; F:3-oxoacyl-[acyl-carrier-protein] synthase activity; IEA:InterPro.
DR GO; GO:0008168; F:methyltransferase activity; IEA:UniProtKB-KW.
DR GO; GO:0016491; F:oxidoreductase activity; IEA:UniProtKB-KW.
DR GO; GO:0031177; F:phosphopantetheine binding; IEA:InterPro.
DR GO; GO:0006633; P:fatty acid biosynthetic process; IEA:InterPro.
DR GO; GO:0032259; P:methylation; IEA:UniProtKB-KW.
DR GO; GO:0044550; P:secondary metabolite biosynthetic process; IEA:UniProt.
DR Gene3D; 3.10.129.110; -; 1.
DR Gene3D; 3.30.559.10; -; 1.
DR Gene3D; 3.40.366.10; -; 1.
DR Gene3D; 3.40.47.10; -; 1.
DR Gene3D; 3.40.50.150; -; 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; IPR023213; CAT-like_dom_sf.
DR InterPro; IPR001242; Condensatn.
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; IPR013217; Methyltransf_12.
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; IPR013968; PKS_KR.
DR InterPro; IPR020806; PKS_PP-bd.
DR InterPro; IPR009081; PP-bd_ACP.
DR InterPro; IPR029063; SAM-dependent_MTases_sf.
DR InterPro; IPR016039; Thiolase-like.
DR Pfam; PF00698; Acyl_transf_1; 1.
DR Pfam; PF00668; Condensation; 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; PF08242; Methyltransf_12; 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; SM00825; PKS_KS; 1.
DR SMART; SM00823; PKS_PP; 1.
DR SUPFAM; SSF47336; SSF47336; 1.
DR SUPFAM; SSF51735; SSF51735; 2.
DR SUPFAM; SSF52151; SSF52151; 1.
DR SUPFAM; SSF53335; SSF53335; 1.
DR SUPFAM; SSF53901; SSF53901; 1.
DR SUPFAM; SSF55048; SSF55048; 1.
DR PROSITE; PS00606; B_KETOACYL_SYNTHASE; 1.
DR PROSITE; PS50075; CARRIER; 1.
PE 1: Evidence at protein level;
KW Acyltransferase; Methyltransferase; Multifunctional enzyme; NADP;
KW Oxidoreductase; Phosphopantetheine; Phosphoprotein;
KW S-adenosyl-L-methionine; Transferase.
FT CHAIN 1..3032
FT /note="Compactin nonaketide synthase, polyketide synthase
FT component"
FT /id="PRO_0000436280"
FT DOMAIN 2441..2520
FT /note="Carrier"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
FT REGION 1..449
FT /note="Beta-ketoacyl synthase"
FT /evidence="ECO:0000250|UniProtKB:Q9Y8A5"
FT REGION 560..901
FT /note="Acyl and malonyl transferase"
FT /evidence="ECO:0000250|UniProtKB:Q9Y8A5"
FT REGION 985..997
FT /note="Dehydratase-like"
FT /evidence="ECO:0000250|UniProtKB:Q9Y8A5"
FT REGION 1506..1544
FT /note="Methyltransferase"
FT /evidence="ECO:0000250|UniProtKB:Q9Y8A5"
FT REGION 2531..2580
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 2586..2946
FT /note="Peptide synthetase elongation"
FT /evidence="ECO:0000250|UniProtKB:Q9Y8A5"
FT COMPBIAS 2531..2561
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT ACT_SITE 181
FT /note="For beta-ketoacyl synthase activity"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU10022"
FT ACT_SITE 654
FT /note="For malonyltransferase activity"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU10022"
FT ACT_SITE 985
FT /note="For beta-hydroxyacyl dehydratase activity"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU10022"
FT MOD_RES 2480
FT /note="O-(pantetheine 4'-phosphoryl)serine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
SQ SEQUENCE 3032 AA; 334041 MW; 63D36DB86CE10A13 CRC64;
MDQANYPNEP IVVVGSGCRF PGGVNTPSKL WELLKEPRDV QTKIPKERFD VDTFYSPDGT
HPGRTNAPFA YLLQEDLRGF DASFFNIQAG EAETIDPQQR LLLETVYEAV SNAGLRIQGL
QGSSTAVYVG MMTHDYETIV TRELDSIPTY SATGVAVSVA SNRVSYFFDW HGPSMTIDTA
CSSSLAAVHL AVQQLRTGES TMAVAAGANL ILGPMTFVME SKLNMLSPNG RSRMWDAAAD
GYARGEGVCS IVLKTLSQAL RDGDSIECVI RETGINQDGR TTGITMPNHS AQEALIRATY
AKAGLDITNP QERCQFFEAH GTGTPAGDPQ EAEAIATAFF GHKDGTIDSD GEKDELFVGS
IKTVLGHTEG TAGIAGLMKA SFAVRNGVIP PNLLFEKISP RVAPFYTHLK IATEATEWPI
VAPGQPRRVS VNSFGFGGTN AHAIIEEYMA PPHKPTAVVT EVTSDADACS LPLVLSSKSQ
RSMKATLENM LQFLETHDDV DMHDIAYTLL EKRSILPFRR AIAAHNKEVA RAALEAAIAD
GEVVTDFRTD ANDNPRVLGV FTGQGAQWPG MLKKLMVGMP FVRGILEELD NSLQTLPEKY
RPTWTLYDQL MLEGDASNVR LASFSQPLCC AVQIVLVRLL AAAGIEFSAI VGHSSGEIAC
AFAAGFISAT QAIRIAHLRG VVSAEHASSP SGQTGAMLAA GMSYDDAKEL CELEAFEGRV
CVAASNSPDS VTFSGDMDAI QHVEGVLEDE STFARILRVD KAYHSHHMHP CAAPYVKALL
ECDCAVADGQ GNDSVAWFSA VHETSKQMTV QDVMPAYWKD NLVSPVLFSQ AVQKAVITHR
LIDVAIEIGA HPALKGPCLA TIKDALAGVE LPYTGCLARN VDDVDAFAGG LGYIWERFGV
RSIDAEGFVQ QVRPDRAVQN LSKSLPTYSW DHTRQYWAES RSTRQHLRGG APHLLLGKLS
SYSTASTFQW TNFIRPRDLE WLDGHALQGQ TVFPAAGYII MAMEAAMKVA GERAAQVQLL
EILDMSINKA IVFEDENTSV ELNLTAEVTS DNDADGQVTV KFVIDSCLAK ESELSTSAKG
QIVITLGEAS PSSQLLPPPE EEYPQMNNVN IDFFYRELDL LGYDYSKDFR RLQTMRRADS
KASGTLAFLP LKDELRNEPL LLHPAPLDIA FQTVIGAYSS PGDRRLRSLY VPTHVDRVTL
IPSLCISAGN SGETELAFDT INTHDKGDFL SGDITVYDST KTTLFQVDNI VFKPFSPPTA
STDHRIFAKW VWGPLTPEKL LEDPATLIIA RDKEDILTIE RIVYFYIKSF LAQITPDDRQ
NADLHSQKYI EWCDQVQADA RAGHHQWYQE SWEEDTSVHI EQMCESNSSH PHVRLIQRVG
KELISIVRGN GDPLDIMNRD GLFTEYYTNK LAFGSAIHVV QDLVSQIAHR YQSIDILEIG
LGTGIATKRV LASPQLGFNS YTCTDISADV IGKAREQLSE FDGLMQFEAL DINRSPAEQG
FKPHSYDLII ASDVLHASSN FEEKLAHIRS LLKPGGHLVT FGVTHREPAR LAFISGLFAD
RWTGEDETRA LSASGSVDQW EHTLKRVGFS GVDSRTLDRE DDLIPSVFST HAVDATVERL
YDPLSAPLKD SYPPLVVIGG ESTKTERILN DMKAALPHRH IHSVKRLESV LDDPALQPKS
TFVILSELDD EVFCNLEEDK FEAVKSLLFY AGRMMWLTEN AWIDHPHQAS TIGMLRTIKL
ENPDLGTHVF DVDTVENLDT KFFVEQLLRF EESDDQLLES ITWTHEPEVY WCKGRAWVPR
LKQDIARNDR MNSSRRPIFG NFNSSKTAIA LKEARGASSS MYYLESTETC DSLEDARHAG
KATVRVRYAL PQAIRVGHLG YFHVVQGSIL ENTCEVPVVA LAEKNGSILH VPRNYMHSLP
DNMAEGEDSS FLLSTAAALL AETILSSAQS FGSDASILIM EPPIFCVKAI LESAKTYGVQ
VHLATTLSDV KTIPAPWIRL HAKETDARLK HSLPTNMMAF FDLSTDRTAA GITNRLAKLL
PPSCFMYSGD YLIRSTASTY KVSHVEDIPI LEHSVAMAKN TVSASTVDDT EKVITATQIL
LPGQLSVNHN DQRFNLATVI DWKENEVSAR ICPIDSGNLF SNKKTYLLVG LTGDLGRSLC
RWMILHGARH VVLTSRNPRL DPKWIANMEA LGGDITVLSM DVANEDSVDA GLGKLVDMKL
PPVAGIAFGP LVLQDVMLKN MDHQMMDMVL KPKVQGARIL HERFSEQTGS KALDFFIMFS
SIVAVIGNPG QSNYGAANAY LQALAQQRCA RGLAGSTIDI GAVYGVGFVT RAEMEEDFDA
IRFMFDSVEE HELHTLFAEA VVSDQRARQQ PQRKTVIDMA DLELTTGIPD LDPALQDRII
YFNDPRFGNF KIPGQRGDGG DNGSGSKGSI ADQLKQATTL DQVRQIVIDG LSEKLRVTLQ
VSDGESVDPT IPLIDQGVDS LGAVTVGSWF SKQLYLDLPL LRVLGGASVA DLADDAATRL
PATSIPLLLQ IGDSTGTSDS GASPTPTDSH DEASSATSTD ASSAEEDEEQ EDDNEQGGRK
ILRRERLSLG QEYSWRQQQM VKDHTIFNNT IGMFMKGTID LDRLRRALKA SLRRHEIFRT
CFVTGDDYSS DLNGPVQVVL KNPENRVHFV QVNNAAEAEE EYRKLEKTNY SISTGDTLRL
VDFYWGTDDH LLVIGYHRLV GDGSTTENLF NEIGQIYSGV KMQRPSTQFS DLAVQQRENL
ENGRMGDDIA FWKSMHSKVS SSAPTVLPIM NLINDPAANS EQQQIQPFTW QQYEAIARLD
PMVAFRIKER SRKHKATPMQ FYLAAYHVLL ARLTGSKDIT IGLAETNRST MEEISAMGFF
ANVLPLRFDE FVGSKTFGEH LVATKDSVRE AMQHARVPYG VILDCLGLNL PTSGEEPKTQ
THAPLFQAVF DYKQGQAESG SIGNAKMTSV LASRERTPYD IVLEMWDDPT KDPLIHVKLQ
SSLYGPEHAQ AFVDHFSSIL TMFSMNPALK LA
