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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
 
 
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