MLCB_PENCI
ID MLCB_PENCI Reviewed; 2563 AA.
AC Q8J0F5;
DT 11-MAY-2016, integrated into UniProtKB/Swiss-Prot.
DT 01-MAR-2003, sequence version 1.
DT 03-AUG-2022, entry version 109.
DE RecName: Full=Compactin diketide synthase mlcB {ECO:0000303|PubMed:12172803};
DE EC=2.3.1.244 {ECO:0000269|PubMed:12172803};
DE AltName: Full=Compactin biosynthesis protein B {ECO:0000303|PubMed:12172803};
GN Name=mlcB;
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, CATALYTIC ACTIVITY,
RP AND DISRUPTION 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).
CC -!- FUNCTION: Diketide synthase; part of the gene cluster that mediates the
CC 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=3 H(+) + holo-[2-methylbutanoate polyketide synthase] + 2
CC malonyl-CoA + 2 NADPH + S-adenosyl-L-methionine = (S)-2-
CC methylbutanoyl-[2-methylbutanoate polyketide synthase] + 2 CO2 + 2
CC CoA + H2O + 2 NADP(+) + S-adenosyl-L-homocysteine;
CC Xref=Rhea:RHEA:42852, Rhea:RHEA-COMP:10260, Rhea:RHEA-COMP:10261,
CC ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:16526,
CC ChEBI:CHEBI:57287, ChEBI:CHEBI:57384, ChEBI:CHEBI:57783,
CC ChEBI:CHEBI:57856, ChEBI:CHEBI:58349, ChEBI:CHEBI:59789,
CC ChEBI:CHEBI:64479, ChEBI:CHEBI:82764; EC=2.3.1.244;
CC Evidence={ECO:0000269|PubMed:12172803};
CC -!- COFACTOR:
CC Name=pantetheine 4'-phosphate; Xref=ChEBI:CHEBI:47942;
CC Evidence={ECO:0000250|UniProtKB:Q9Y7D5};
CC Note=Binds 1 phosphopantetheine covalently.
CC {ECO:0000250|UniProtKB:Q9Y7D5};
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 {ECO:0000269|PubMed:12172803, ECO:0000269|PubMed:12436257}.
CC -!- DISRUPTION PHENOTYPE: Impairs the production of compactin and leads to
CC the accumulation of the ML-236A intermediate (PubMed:12172803).
CC {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}.
CC ---------------------------------------------------------------------------
CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms
CC Distributed under the Creative Commons Attribution (CC BY 4.0) License
CC ---------------------------------------------------------------------------
DR EMBL; AB072893; BAC20566.1; -; Genomic_DNA.
DR AlphaFoldDB; Q8J0F5; -.
DR SMR; Q8J0F5; -.
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; 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 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; IPR013149; ADH-like_C.
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; 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; 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; IPR029063; SAM-dependent_MTases_sf.
DR InterPro; IPR016039; Thiolase-like.
DR Pfam; PF00698; Acyl_transf_1; 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; 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; 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; 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.
DR PROSITE; PS00012; PHOSPHOPANTETHEINE; 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..2563
FT /note="Compactin diketide synthase mlcB"
FT /id="PRO_0000436282"
FT DOMAIN 2485..2562
FT /note="Carrier"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
FT REGION 22..452
FT /note="Beta-ketoacyl synthase"
FT /evidence="ECO:0000250|UniProtKB:Q9Y8A5"
FT REGION 568..915
FT /note="Acyl and malonyl transferase"
FT /evidence="ECO:0000250|UniProtKB:Q9Y8A5"
FT REGION 951..971
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 998..1010
FT /note="Dehydratase-like"
FT /evidence="ECO:0000250|UniProtKB:Q9Y8A5"
FT REGION 1542..1579
FT /note="Methyltransferase"
FT /evidence="ECO:0000250|UniProtKB:Q9Y8A5"
FT ACT_SITE 202
FT /note="For beta-ketoacyl synthase activity"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU10022"
FT ACT_SITE 658
FT /note="For malonyltransferase activity"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU10022"
FT ACT_SITE 998
FT /note="For beta-hydroxyacyl dehydratase activity"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU10022"
FT MOD_RES 2522
FT /note="O-(pantetheine 4'-phosphoryl)serine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
SQ SEQUENCE 2563 AA; 280159 MW; 304BFF399BFBFEFC CRC64;
MNNTPAVTAT ATATATATAM AGSACSNTST PIAIVGMGCR FAGDATSPQK LWEMVERGGS
AWSKVPSSRF NVRGVYHPNG ERVGSTHVKG GHFIDEDPAL FDAAFFNMTT EVASCMDPQY
RLMLEVVYES LESAGITIDG MAGSNTSVFG GVMYHDYQDS LNRDPETVPR YFITGNSGTM
LSNRISHFYD LRGPSVTVDT ACSTTLTALH LACQSLRTGE SDTAIVIGAN LLLNPDVFVT
MSNLGFLSPD GISYSFDPRA NGYGRGEGIA ALVIKALPNA LRDQDPIRAV IRETALNQDG
KTPAITAPSD VAQKSLIQEC YDKAGLDMSL TSYVEAHGTG TPTGDPLEIS AISAAFKGHP
LHLGSVKANI GHTEAASGLA SIIKVALALE KGLIPPNARF LQKNSKLMLD QKNIKIPMSA
QDWPVKDGTR RASVNNFGFG GSNAHVILES YDRASLALPE DQVHVNGNSE HGRVEDGSKQ
SRIYVVRAKD EQACRRTIAS LRDYIKSVAD IDGEPFLASL AYTLGSRRSI LPWTSVYVAD
SLGGLVSALS DESNQPKRAN EKVRLGFVFT GQGAQWHAMG RELVNTFPVF KQAILECDGY
IKQLGASWNF MEELHRDELT TRVNDAEYSL PLSTAIQIAL VRLLWSWGIR PTGITSHSSG
EAAAAYAAGA LSARSAIGIT YIRGVLTTKP KPALAAKGGM MAVGLGRSET NVYISRLNQE
DGCVVVGCIN SQCSVTVSGD LGAIEKLEKL LHADGIFTRK LKVTEAFHSS HMRPMADAFG
ASLRDLFNSD NNNDNPNADT SKGVLYSSPK TGSRMTDLKL LLDPTHWMDS MLQPVEFESS
LREMCFDPNT KEKAVDVIIE IGPHGALGGP INQVMQDLGL KGTDINYLSC LSRGRSSLET
MYRAATELIS KGYGLKMDAI NFPHGRKEPR VKVLSDLPAY PWNHQTRYWR EPRGSRESKQ
RTHPPHTLIG SRESLSPQFA PKWKHVLRLS DIPWIRDHVV GSSIIFPGAG FISMAIEGFS
QVCPPVAGAS INYNLRDVEL AQALIIPADA EAEVDLRLTI RSCEERSLGT KNWHQFSVHS
ISGENNTWTE HCTGLIRSES ERSHLDCSTV EASRRLNLGS DNRSIDPNDL WESLHANGIC
HGPIFQNIQR IQNNGQGSFC RFSIADTASA MPHSYENRHI VHPTTLDSVI QAAYTVLPYA
GTRMKTAMVP RRLRNVKISS SLADLEAGDA LDAQASIKDR NSQSFSTDLA VFDDYDSGSS
PSDGIPVIEI EGLVFQSVGS SFSDQKSDSN DTENACSSWV WAPDISLGDS TWLKEKLSTE
AETKETELMM DLRRCTINFI QEAVTDLTNS DIQHLDGHLQ KYFDWMNVQL DLARQNKLSP
ASCDWLSDDA EQKKCLQARV AGESVNGEMI SRLGPQLIAM LRRETEPLEL MMQDQLLSRY
YVNAIKWSRS NAQASELIRL CAHKNPRSRI LEIGGGTGGC TKLIVNALGN TKPIDRYDFT
DVSAGFFESA REQFADWQDV MTFKKLDIES DPEQQGFECA TYDVVVACQV LHATRCMKRT
LSNVRKLLKP GGNLILVETT RDQLDLFFTF GLLPGWWLSE EPERKSTPSL TTDLWNTMLD
TSGFNGVELE VRDCEDDEFY MISTMLSTAR KENTTPDTVA ESEVLLLHGA LRPPSSWLES
LQAAICEKTS SSPSINALGE VDTTGRTCIF LGEMESSLLG EVGSETFKSI TAMLNNCNAL
LWVSRGAAMS SEDPWKALHI GLLRTIRNEN NGKEYVSLDL DPSRNAYTHE SLYAICNIFN
GRLGDLSEDK EFEFAERNGV IHVPRLFNDP HWKDQEAVEV TLQPFEQPGR RLRMEVETPG
LLDSLQFRDD EGREGKDLPD DWVEIEPKAF GLNFRDVMVA MGQLEANRVM GFECAGVITK
LGGAAAASQG LRLGDRVCAL LKGHWATRTQ TPYTNVVRIP DEMGFPEAAS VPLAFTTAYI
ALYTTAKLRR GERVLIHSGA GGVGQAAIIL SQLAGAEVFV TAGTQAKRDF VGDKFGINPD
HIFSSRNDLF VDGIKAYTGG LGVHVVLNSL AGQLLQASFD CMAEFGRFVE IGKKDLEQNS
RLDMLPFTRD VSFTSIDLLS WQRAKSEEVS EALNHVTKLL ETKAIGLIGP IQQHSLSNIE
KAFRTMQSGQ HVGKVVVNVS GDELVPVGDG GFSLKLKPDS SYLVAGGLGG IGKQICQWLV
DHGAKHLIIL SRSAKASPFI TSLQNQQCAV YLHACDISDQ DQVTKVLRLC EEAHAPPIRG
IIQGAMVLKD ALLSRMTLDE FNAATRPKVQ GSWYLHKIAQ DVDFFVMLSS LVGVMGGAGQ
ANYAAAGAFQ DALAHHRRAH GMPAVTIDLG MVKSVGYVAE TGRGVADRLA RIGYKPMHEK
DVMDVLEKAI LCSSPQFPSP PAAVVTGINT SPGAHWTEAN WIQEQRFVGL KYRQVLHADQ
SFVSSHKKGP DGVRAQLSRV TSHDEAISIV LKAMTEKLMR MFGLAEDDMS SSKNLAGVGV
DSLVAIELRN WITSEIHVDV SIFELMNGNT IAGLVELVVA KCS
