MOKA_MONPI
ID MOKA_MONPI Reviewed; 3075 AA.
AC Q3S2T9;
DT 11-MAY-2016, integrated into UniProtKB/Swiss-Prot.
DT 11-OCT-2005, sequence version 1.
DT 03-AUG-2022, entry version 93.
DE RecName: Full=Lovastatin nonaketide synthase mokA {ECO:0000303|PubMed:18578535};
DE EC=2.3.1.161 {ECO:0000250|UniProtKB:Q9Y8A5};
DE AltName: Full=Monacolin K biosynthesis protein A {ECO:0000303|PubMed:18578535};
GN Name=mokA {ECO:0000303|PubMed:18578535};
OS Monascus pilosus (Red mold).
OC Eukaryota; Fungi; Dikarya; Ascomycota; Pezizomycotina; Eurotiomycetes;
OC Eurotiomycetidae; Eurotiales; Aspergillaceae; Monascus.
OX NCBI_TaxID=89488;
RN [1]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], FUNCTION, AND DISRUPTION PHENOTYPE.
RX PubMed=18578535; DOI=10.1021/jf800595k;
RA Chen Y.P., Tseng C.P., Liaw L.L., Wang C.L., Chen I.C., Wu W.J., Wu M.D.,
RA Yuan G.F.;
RT "Cloning and characterization of monacolin K biosynthetic gene cluster from
RT Monascus pilosus.";
RL J. Agric. Food Chem. 56:5639-5646(2008).
RN [2]
RP FUNCTION.
RX PubMed=19693441; DOI=10.1007/s10529-009-0093-3;
RA Sakai K., Kinoshita H., Nihira T.;
RT "Identification of mokB involved in monacolin K biosynthesis in Monascus
RT pilosus.";
RL Biotechnol. Lett. 31:1911-1916(2009).
RN [3]
RP INDUCTION.
RX PubMed=19968298; DOI=10.1021/jf903139x;
RA Chen Y.-P., Yuan G.-F., Hsieh S.-Y., Lin Y.-S., Wang W.-Y., Liaw L.-L.,
RA Tseng C.-P.;
RT "Identification of the mokH gene encoding transcription factor for the
RT upregulation of monacolin K biosynthesis in Monascus pilosus.";
RL J. Agric. Food Chem. 58:287-293(2010).
RN [4]
RP BIOTECHNOLOGY.
RX PubMed=21821946; DOI=10.1271/bbb.110195;
RA Hong S.Y., Oh J.H., Lee I.;
RT "Simultaneous enrichment of deglycosylated ginsenosides and monacolin K in
RT red ginseng by fermentation with Monascus pilosus.";
RL Biosci. Biotechnol. Biochem. 75:1490-1495(2011).
CC -!- FUNCTION: Nonaketide synthase; part of the gene cluster that mediates
CC the biosynthesis of monakolin K, also known as lovastatin, and which
CC acts as a potent competitive inhibitor of HMG-CoA reductase
CC (PubMed:18578535). Monakolin K biosynthesis is performed in two stages
CC (PubMed:19693441). The first stage is catalyzed by the nonaketide
CC synthase mokA, which belongs to type I polyketide synthases and
CC catalyzes the iterative nine-step formation of the polyketide
CC (PubMed:18578535, PubMed:19693441). This PKS stage is completed by the
CC action of dehydrogenase mokE, which catalyzes the NADPH-dependent
CC reduction of the unsaturated tetra-, penta- and heptaketide
CC intermediates that arise during the mokA-mediated biosynthesis of the
CC nonaketide chain and leads to dihydromonacolin L (PubMed:19693441).
CC Covalently bound dihydromonacolin L is released from mokA by the mokD
CC esterase (By similarity). Conversion of dihydromonacolin L into
CC monacolin L and then monacolin J is subsequently performed with the
CC participation of molecular oxygen and P450 monoogygenase mokC
CC (PubMed:19693441). Finally, mokF performs the conversion of monacoline
CC J to monacoline K through the addition of the side-chain diketide
CC moiety (2R)-2-methylbutanoate produced by the diketide synthase mokB
CC (PubMed:19693441). {ECO:0000250|UniProtKB:Q0C8M2,
CC ECO:0000250|UniProtKB:Q9Y8A5, ECO:0000269|PubMed:18578535,
CC ECO:0000303|PubMed:19693441}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=19 H(+) + holo-[lovastatin nonaketide synthase] + 9 malonyl-
CC CoA + 11 NADPH + S-adenosyl-L-methionine = 9 CO2 + 9 CoA +
CC dihydromonacolin L-[lovastatin nonaketide synthase] + 6 H2O + 11
CC NADP(+) + S-adenosyl-L-homocysteine; Xref=Rhea:RHEA:18565, Rhea:RHEA-
CC COMP:10042, Rhea:RHEA-COMP:10043, ChEBI:CHEBI:15377,
CC ChEBI:CHEBI:15378, ChEBI:CHEBI:16526, ChEBI:CHEBI:57287,
CC ChEBI:CHEBI:57384, ChEBI:CHEBI:57783, ChEBI:CHEBI:57856,
CC ChEBI:CHEBI:58349, ChEBI:CHEBI:59789, ChEBI:CHEBI:64479,
CC ChEBI:CHEBI:79032; EC=2.3.1.161;
CC Evidence={ECO:0000250|UniProtKB:Q9Y8A5};
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; lovastatin biosynthesis.
CC {ECO:0000269|PubMed:18578535}.
CC -!- INDUCTION: Expression is controlled by the monacolin K cluster
CC transcription regulator mokH (PubMed:19968298).
CC {ECO:0000269|PubMed:19968298}.
CC -!- DISRUPTION PHENOTYPE: Impairs the production of monacoline K
CC (PubMed:18578535). {ECO:0000269|PubMed:18578535}.
CC -!- BIOTECHNOLOGY: Monacoline K acts as an inhibitor of HMG-CoA reductase
CC involved in cholesterogenesis (PubMed:21821946). Its
CC hypocholesterolemic activity might be useful for lowering cholesterol
CC levels in the blood and reduce artherosclerosis and coronary heart
CC disease (PubMed:21821946). {ECO:0000269|PubMed:21821946}.
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DR EMBL; DQ176595; ABA02239.1; -; Genomic_DNA.
DR PDB; 6AD3; X-ray; 1.79 A; A=2578-3075.
DR PDBsum; 6AD3; -.
DR SMR; Q3S2T9; -.
DR PRIDE; Q3S2T9; -.
DR UniPathway; UPA00875; -.
DR GO; GO:0004315; F:3-oxoacyl-[acyl-carrier-protein] synthase activity; IEA:InterPro.
DR GO; GO:0050637; F:lovastatin nonaketide synthase activity; IEA:UniProtKB-EC.
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 3D-structure; Acyltransferase; Methyltransferase; Multifunctional enzyme;
KW NADP; Oxidoreductase; Phosphopantetheine; Phosphoprotein;
KW S-adenosyl-L-methionine; Transferase.
FT CHAIN 1..3075
FT /note="Lovastatin nonaketide synthase mokA"
FT /id="PRO_0000436279"
FT DOMAIN 2492..2571
FT /note="Carrier"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
FT REGION 42..490
FT /note="Beta-ketoacyl synthase"
FT /evidence="ECO:0000250|UniProtKB:Q9Y8A5"
FT REGION 603..945
FT /note="Acyl and malonyl transferase"
FT /evidence="ECO:0000250|UniProtKB:Q9Y8A5"
FT REGION 1029..1041
FT /note="Dehydratase-like"
FT /evidence="ECO:0000250|UniProtKB:Q9Y8A5"
FT REGION 1556..1594
FT /note="Methyltransferase"
FT /evidence="ECO:0000250|UniProtKB:Q9Y8A5"
FT REGION 2176..2470
FT /note="Beta-ketoacyl reductase"
FT /evidence="ECO:0000250|UniProtKB:Q9Y8A5"
FT REGION 2582..2624
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 2633..2989
FT /note="Peptide synthetase elongation"
FT /evidence="ECO:0000250|UniProtKB:Q9Y8A5"
FT COMPBIAS 2586..2610
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT ACT_SITE 222
FT /note="For beta-ketoacyl synthase activity"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU10022"
FT ACT_SITE 697
FT /note="For malonyltransferase activity"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU10022"
FT ACT_SITE 1029
FT /note="For beta-hydroxyacyl dehydratase activity"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU10022"
FT MOD_RES 2531
FT /note="O-(pantetheine 4'-phosphoryl)serine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
FT STRAND 2628..2633
FT /evidence="ECO:0007829|PDB:6AD3"
FT HELIX 2636..2647
FT /evidence="ECO:0007829|PDB:6AD3"
FT HELIX 2651..2654
FT /evidence="ECO:0007829|PDB:6AD3"
FT STRAND 2656..2664
FT /evidence="ECO:0007829|PDB:6AD3"
FT HELIX 2668..2681
FT /evidence="ECO:0007829|PDB:6AD3"
FT HELIX 2683..2686
FT /evidence="ECO:0007829|PDB:6AD3"
FT STRAND 2687..2696
FT /evidence="ECO:0007829|PDB:6AD3"
FT STRAND 2701..2708
FT /evidence="ECO:0007829|PDB:6AD3"
FT STRAND 2713..2717
FT /evidence="ECO:0007829|PDB:6AD3"
FT HELIX 2721..2732
FT /evidence="ECO:0007829|PDB:6AD3"
FT HELIX 2738..2740
FT /evidence="ECO:0007829|PDB:6AD3"
FT STRAND 2744..2751
FT /evidence="ECO:0007829|PDB:6AD3"
FT TURN 2752..2754
FT /evidence="ECO:0007829|PDB:6AD3"
FT STRAND 2755..2762
FT /evidence="ECO:0007829|PDB:6AD3"
FT HELIX 2764..2766
FT /evidence="ECO:0007829|PDB:6AD3"
FT HELIX 2769..2783
FT /evidence="ECO:0007829|PDB:6AD3"
FT HELIX 2795..2807
FT /evidence="ECO:0007829|PDB:6AD3"
FT TURN 2808..2811
FT /evidence="ECO:0007829|PDB:6AD3"
FT HELIX 2812..2822
FT /evidence="ECO:0007829|PDB:6AD3"
FT STRAND 2857..2863
FT /evidence="ECO:0007829|PDB:6AD3"
FT HELIX 2866..2878
FT /evidence="ECO:0007829|PDB:6AD3"
FT HELIX 2883..2899
FT /evidence="ECO:0007829|PDB:6AD3"
FT STRAND 2902..2910
FT /evidence="ECO:0007829|PDB:6AD3"
FT HELIX 2916..2920
FT /evidence="ECO:0007829|PDB:6AD3"
FT STRAND 2927..2933
FT /evidence="ECO:0007829|PDB:6AD3"
FT HELIX 2942..2957
FT /evidence="ECO:0007829|PDB:6AD3"
FT TURN 2958..2961
FT /evidence="ECO:0007829|PDB:6AD3"
FT HELIX 2964..2970
FT /evidence="ECO:0007829|PDB:6AD3"
FT STRAND 2979..2981
FT /evidence="ECO:0007829|PDB:6AD3"
FT STRAND 2990..2996
FT /evidence="ECO:0007829|PDB:6AD3"
FT HELIX 3000..3003
FT /evidence="ECO:0007829|PDB:6AD3"
FT STRAND 3008..3016
FT /evidence="ECO:0007829|PDB:6AD3"
FT STRAND 3023..3029
FT /evidence="ECO:0007829|PDB:6AD3"
FT STRAND 3037..3043
FT /evidence="ECO:0007829|PDB:6AD3"
FT TURN 3044..3046
FT /evidence="ECO:0007829|PDB:6AD3"
FT HELIX 3051..3068
FT /evidence="ECO:0007829|PDB:6AD3"
SQ SEQUENCE 3075 AA; 338037 MW; 6BDE751D492E9813 CRC64;
MYVGRIGATT YISRPADSRA TPKVIKTQGS ITTSNLTSLT TMAQSTYPNE PIVVVGSGCR
FPGGANTPSK LWELLREPRD VRSKIPKERF DVDAFYHPDG KHHGRTNAPY AYMLQEDLRA
FDGPFFNIQA GEAESMDPQQ RLLLETVYEA VSDAGMRIQD LQGSSTAVYV GMMTHDYETV
STRDLESIPT YSATGVAVSV ASNRISYFFD WHGPSMTIDT ACSSSLVAVH LAVQQLRSGQ
SSMAIAAGAN MILGPMTFVL ESKLNMLSPS GRSRMWDAGA DGYARGEAVC SVVLKTLSQA
LRDGDSIECV IRETGVNQDG RTTGITMPNH SAQEALIRAT YSKAGLDITN PEDRCQFFEA
HGTGTPAGDP QEAEAIATAF FGHKKEASDA ENAETPLFVG SVKTVVGHTE GTAGLAGLMK
ASFAVQHGVI PPNLLFENIS PRVAPFYSNL KIATETTPWP TIKPGQPRRV SVNSFGFGGT
NAHAIIEEYI KSDQKVPASR QPVEYSDSPS TLNLPLVLSA KSQRSMKTTL ESMVQFLQSN
PEVNLRDLSW TLLRKRSILP FRRAIVGHSH EAIRAALEAA IEDGIVVSDF SADVKGKPSV
LGVFTGQGAQ WPGMLKELIV GSSYVRSIAE ELDHSLQTLP EKYRPSWTIL EQLMLEDEAS
NVRHASFSQP LCCAVQIVLV RLLKAAGIQF AAVVGHSSGE IACAFATGLI SASLAIRIAH
LRGVVSAEHA ASASGGRGSM LAAGMSYEEA KELCELDAFE SRICVAASNS PDSVTFSGDA
DAIEHLQGVL EDEATFARLL RVDTAYHSHH MLPCAAPYMQ ALEECGCAVA DGDGQVEEGS
WYSSVKDSNE PMGLADVTAE YWKDNLVSPV LFSQAVQRAA IMHRPLDVGI EVGCHPALKG
PCLATIKDAL SDVDLAYTGC LERGKNDMNA FSQALAYLWE QFGIPSLDAD RFISTIAPER
SCVSLSKQLP TYSWDHSRSY WTESRATRQH LRGPKPHLLL GKLSEYSTPL TFQWLNFVRP
RDIEWLDGHA LQGQVVFPAA GYIVMAMEAA MEIANSHQVQ VQLLEILDMS IDKAVVFDDE
DSLVELNLTA EVTSGIGKGD RMILSFIIDS CLSREGDLST SAKGQLVVTL DEGHLQVTPD
NEKQLLPPPE EEHPHMNRVN INSFYHELDL MGYDYSKDFR RLHSMRRADA RASGILEFIP
LNDEVHGRPL LLHPAPLDIA FQTVIGAYSS PGDRRLRCLY VPTHIDRIAL VPSLCLATAA
SGCDKIAFNT INTYDKGDFL SGDIVAFDAE QTSLFHVENI VFKPFSPPTA STDHPIFAKW
SWGPLTPETL LDNPNHWATA QDKEAIPIIE RIVYFYIKLF LQQLTREDRE QAAFHLQRQI
VWCEQVVADA HEGRHQWYDA AWENDTEAQI EQLCARSSYH PHVRLVQRVG QNLLATIRSN
GNPFDLMDHD GLLTEFYTNT LSFGPALHYA QDLVGQIAHR YQSMDILEIG AGTGGATKYV
LATPQLGFNS YTYTDISTGF FEKAREQFAA FEDRMEFEPL DIRRSPAEQG FTEHVYDLII
ASNVLHATPD LEKTMAHARS LLKPGGQMVI LEITHRNHTR LGFIFGLFAD WWAGIDDGRT
MEPFVSFDRW DEILKHVGFS GIDSRTKDRD ADLFPTSVFS THAVNSTIDY LHKPLDAPVK
DSYPPLVVVG GQTPKTQRIL DEIKAVMPNR QIQLHQRLVD LLDAEDMQAK FTFVVLTELD
EELFAGLTED SFEAVKLLLM YAGNMLWLTE NAWVKRPHQA STIGMLRSIR REHPDIGVHI
MDVDSAENLD AHFLVEQVLR LEEDIDELAA TTTWTQEPEV FWCNGRAWIP RLKHDKSRNN
RMNSSRRQIF ETLNPSKIPV ALKKAAASSS YYLESAETWP VPGAVTAGDR KTVHVRLSHP
HALRVGHLGF FYLVQGHVLK GDQALPVVAL AERNASIVHV RSDYVHVLED TAVSANNGSF
ILAAAAAVLA ETVIHSAKSL GADASVLVLN APGFCAQTLL RAARDSGLRV HLATTSSSTD
PSPGADRCVR LHPRDTDRRL KQLLPRGTQA FFDLSTDPSS EGLTQRLPNV LIPSCVRHST
EYLLRDTASA GGKATLPAAY WERVASLANH SLSTHFKEND NASNGCQVLS CTDIVARNNK
SRLNASTVIS WPDDAALPAR IRPIDTETLF AAEKTYLLVG LTGDLGRSLG RWMVLHGARR
IVLTSRNPQV SPNWVAHVEE LGGQVTVLSM DVTSEDSVDS GLAKLQDLKL PPIGGIAFGP
LVLQDVMLKN MDLQMMEMVL KPKVEGARIL HEKFSDPASS NPLDFFVMFS SIVAVMGNPG
QANYSAANCY LQALAQRRCA SGLAASTIDI GAVYGVGFVT RAELEEDFNA IRFMFDSVEE
HELHSLFAEA VVSGRRAMHQ QQQFKTVLDM ADIELTTGIP PLDPTLKDRI TFFDDARVGN
FKIPERRGKA GDNAAGSKGS VKEQLLQATS LDQVRQIVID GLSEKLRVTL QIPDGESVHP
TIPLIDQGVD SLGAVTVGTW FSKQLYLDLP LLRVLGGASV ADLADDAAAR LPPSSIPLVA
ASEGGAETSD NDTSGPEGTD LSASTTITEP SSADEEDEKQ EDDNDNSVLA LHPLSLGQEY
AWRLQKAADD STIFNNTIGM FMTGSIDAKR LSKALRAVLR RHEIFRTGFA AVGNNADATS
LAQIVFGRTK NKVQVIQVAD RAGAEEGYRQ LVQTQYDITA GDTLRLVDFF WGKDEHLFVV
AYHRFVGDGS TTENIFVEAS QLYGGVTLDK HVPQFADLAT RQREALESGQ MDADLAYWES
MHHQPTGVVS PVLPRMLLGE DGLNSPNHAR QPNSWKQHEA IARLDPMVAF RIRERSRKHK
ATPMQFYLAA YHVLLARLTG SSDFSIGLAD TNRTNVDELA GMGFFANLLP LRFRNFVPHI
TFGEHLVATK DKVREAMQHA RVPYGVLLER LGFEVPGATA ETAEPAPLFQ AVFDYKQGQA
ESGSIGSAKM TEVIATRERT PYDVVLEMSD DPTKDPLLTV KLQSSVYEVH HPRAFLESYI
SILSMFSMNP ALKLA
