MLCC_PENCI
ID MLCC_PENCI Reviewed; 518 AA.
AC Q8J0F6;
DT 11-MAY-2016, integrated into UniProtKB/Swiss-Prot.
DT 01-MAR-2003, sequence version 1.
DT 03-AUG-2022, entry version 72.
DE RecName: Full=Dihydro-ML-236C monooxygenase mlcC {ECO:0000305};
DE EC=1.14.14.- {ECO:0000305};
DE AltName: Full=Compactin biosynthesis protein C {ECO:0000303|PubMed:12172803};
DE AltName: Full=DihydroML-236B hydroxylase {ECO:0000250|UniProtKB:Q9Y7C8};
GN Name=mlcC {ECO:0000303|PubMed:12172803};
OS Penicillium citrinum.
OC Eukaryota; Fungi; Dikarya; Ascomycota; Pezizomycotina; Eurotiomycetes;
OC Eurotiomycetidae; Eurotiales; Aspergillaceae; Penicillium.
OX NCBI_TaxID=5077 {ECO:0000312|EMBL:BAC20565.1};
RN [1]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], INDUCTION, AND FUNCTION.
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: Dihydro-ML-236C carboxylate monooxygenase; part of the gene
CC cluster that mediates the biosynthesis of compactin, also known as
CC mevastatin or ML-236B, and which acts as a potent competitive inhibitor
CC of HMG-CoA reductase (PubMed:12172803, PubMed:12242508). Compactin
CC biosynthesis is performed in two stages (PubMed:12172803). The first
CC stage is catalyzed by the nonaketide synthase mlcA, which belongs to
CC type I polyketide synthases and catalyzes the iterative nine-step
CC formation of the polyketide (PubMed:12172803). This PKS stage is
CC completed by the action of dehydrogenase mlcG, which catalyzes the
CC NADPH-dependent reduction of the unsaturated tetra-, penta- and
CC heptaketide intermediates that arise during the mlcA-mediated
CC biosynthesis of the nonaketide chain and leads to dihydro-ML-236C
CC carboxylate (PubMed:12172803). Covalently bound dihydro-ML-236C
CC 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=dihydro-ML-236C carboxylate + O2 + reduced [NADPH--hemoprotein
CC reductase] = H(+) + 2 H2O + ML-236C carboxylate + oxidized [NADPH--
CC hemoprotein reductase]; Xref=Rhea:RHEA:57620, Rhea:RHEA-COMP:11964,
CC Rhea:RHEA-COMP:11965, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378,
CC ChEBI:CHEBI:15379, ChEBI:CHEBI:57618, ChEBI:CHEBI:58210,
CC ChEBI:CHEBI:142045, ChEBI:CHEBI:142047; Evidence={ECO:0000305};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=ML-236C carboxylate + O2 + reduced [NADPH--hemoprotein
CC reductase] = H(+) + H2O + ML-236A carboxylate + oxidized [NADPH--
CC hemoprotein reductase]; Xref=Rhea:RHEA:57632, Rhea:RHEA-COMP:11964,
CC Rhea:RHEA-COMP:11965, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378,
CC ChEBI:CHEBI:15379, ChEBI:CHEBI:57618, ChEBI:CHEBI:58210,
CC ChEBI:CHEBI:142047, ChEBI:CHEBI:142048; Evidence={ECO:0000305};
CC -!- COFACTOR:
CC Name=heme; Xref=ChEBI:CHEBI:30413;
CC Evidence={ECO:0000250|UniProtKB:Q02928};
CC Note=Binds 1 heme group per subunit. {ECO:0000250|UniProtKB:Q02928};
CC -!- PATHWAY: Polyketide biosynthesis. {ECO:0000305}.
CC -!- SUBCELLULAR LOCATION: Endoplasmic reticulum membrane
CC {ECO:0000250|UniProtKB:Q9Y7C8}; Single-pass type II membrane protein
CC {ECO:0000250|UniProtKB:Q9Y7C8}.
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 -!- 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 -!- SIMILARITY: Belongs to the cytochrome P450 family. {ECO:0000305}.
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DR EMBL; AB072893; BAC20565.1; -; Genomic_DNA.
DR AlphaFoldDB; Q8J0F6; -.
DR SMR; Q8J0F6; -.
DR GO; GO:0005789; C:endoplasmic reticulum membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0016021; C:integral component of membrane; IEA:UniProtKB-KW.
DR GO; GO:0020037; F:heme binding; IEA:InterPro.
DR GO; GO:0005506; F:iron ion binding; IEA:InterPro.
DR GO; GO:0004497; F:monooxygenase activity; IEA:UniProtKB-KW.
DR GO; GO:0016705; F:oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen; IEA:InterPro.
DR Gene3D; 1.10.630.10; -; 1.
DR InterPro; IPR001128; Cyt_P450.
DR InterPro; IPR002401; Cyt_P450_E_grp-I.
DR InterPro; IPR036396; Cyt_P450_sf.
DR Pfam; PF00067; p450; 1.
DR PRINTS; PR00463; EP450I.
DR PRINTS; PR00385; P450.
DR SUPFAM; SSF48264; SSF48264; 1.
PE 1: Evidence at protein level;
KW Endoplasmic reticulum; Heme; Iron; Membrane; Metal-binding; Monooxygenase;
KW Oxidoreductase; Signal-anchor; Transmembrane; Transmembrane helix.
FT CHAIN 1..518
FT /note="Dihydro-ML-236C monooxygenase mlcC"
FT /id="PRO_0000436284"
FT TOPO_DOM 1..31
FT /note="Cytoplasmic"
FT /evidence="ECO:0000305"
FT TRANSMEM 32..48
FT /note="Helical; Signal-anchor for type II membrane protein"
FT /evidence="ECO:0000255"
FT TOPO_DOM 49..518
FT /note="Lumenal"
FT /evidence="ECO:0000305"
FT BINDING 454
FT /ligand="heme"
FT /ligand_id="ChEBI:CHEBI:30413"
FT /ligand_part="Fe"
FT /ligand_part_id="ChEBI:CHEBI:18248"
FT /note="axial binding residue"
FT /evidence="ECO:0000250|UniProtKB:Q02928"
SQ SEQUENCE 518 AA; 59444 MW; EAD23DEA087AC3CA CRC64;
MLGQVLLTVE SYQWVSTPQA LVAVAVLLSL IAYRLRGRQS ELQVYNPKKW WELTTMRARQ
DFDTYGPSWI EAWFSKNDKP LRFIVDSGYC TILPSSMADE FRKIKDMCMY KFLADDFHSH
LPGFDGFKEI CQDAHLVNKV VLNQLQTQAP KYTKPLATLA DATIAKLFGK SEEWQTAPVY
SNGLDLVTRT VTLIMVGDKI CHNEEWLDIA KNHAVSVAVQ ARQLRVWPML LRPLAHWFQP
QGRKLRDQVR RARKIIDPEI QRRRAEKAAC VAKGVQPPQY VDTMQWFEDT ADGRWYDVAG
AQLAMDFAGI YASTDLFVGA LVDIARHPDL IQPLRQEIRT VIGEGGWTPA SLFKLKLLDS
CMKETQRIKP VECATMRSTA LRDITLSNGL FIPKGELAAV AADRMNNPDV WENPENYDPY
RFMRMREDPD KAFTAQLENT NGDHIGFGWN PRACPGRFFA SKEIKILLAH ILIQYDVKPV
PGDDDKYYRH AFSVRMHPTT KLMVRRRNED IPLPHDRC