MLCD_PENCI
ID MLCD_PENCI Reviewed; 1173 AA.
AC Q8J0F4;
DT 11-MAY-2016, integrated into UniProtKB/Swiss-Prot.
DT 01-MAR-2003, sequence version 1.
DT 25-MAY-2022, entry version 95.
DE RecName: Full=3-hydroxy-3-methylglutaryl coenzyme A reductase mlcD {ECO:0000305};
DE Short=HMG-CoA reductase {ECO:0000303|PubMed:12172803};
DE EC=1.1.1.34 {ECO:0000305};
DE AltName: Full=Compactin biosynthesis protein G {ECO:0000303|PubMed:12172803};
GN Name=mlcD {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:BAC20567.1};
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).
CC -!- FUNCTION: HMG-CoA reductase; 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). HMG-CoA reductase mlcD may act as a down-regulator
CC of compactin production and is involved in conferring resistance to ML-
CC 236B/compactin (PubMed:12242508). {ECO:0000269|PubMed:12172803,
CC ECO:0000269|PubMed:12242508}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=(R)-mevalonate + CoA + 2 NADP(+) = (3S)-hydroxy-3-
CC methylglutaryl-CoA + 2 H(+) + 2 NADPH; Xref=Rhea:RHEA:15989,
CC ChEBI:CHEBI:15378, ChEBI:CHEBI:36464, ChEBI:CHEBI:43074,
CC ChEBI:CHEBI:57287, ChEBI:CHEBI:57783, ChEBI:CHEBI:58349; EC=1.1.1.34;
CC -!- PATHWAY: Polyketide biosynthesis. {ECO:0000305}.
CC -!- SUBCELLULAR LOCATION: Endoplasmic reticulum membrane
CC {ECO:0000250|UniProtKB:P04035}; Multi-pass membrane protein
CC {ECO:0000255}.
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 -!- 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 HMG-CoA reductase family. {ECO:0000305}.
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DR EMBL; AB072893; BAC20567.1; -; Genomic_DNA.
DR AlphaFoldDB; Q8J0F4; -.
DR SMR; Q8J0F4; -.
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:0004420; F:hydroxymethylglutaryl-CoA reductase (NADPH) activity; IEA:UniProtKB-EC.
DR GO; GO:0015936; P:coenzyme A metabolic process; IEA:InterPro.
DR GO; GO:0008299; P:isoprenoid biosynthetic process; IEA:InterPro.
DR CDD; cd00643; HMG-CoA_reductase_classI; 1.
DR Gene3D; 1.10.3270.10; -; 1.
DR Gene3D; 3.30.70.420; -; 1.
DR Gene3D; 3.90.770.10; -; 1.
DR InterPro; IPR025583; HMG-CoA_N_dom.
DR InterPro; IPR002202; HMG_CoA_Rdtase.
DR InterPro; IPR023074; HMG_CoA_Rdtase_cat_sf.
DR InterPro; IPR023076; HMG_CoA_Rdtase_CS.
DR InterPro; IPR004554; HMG_CoA_Rdtase_eu_arc.
DR InterPro; IPR023282; HMG_CoA_Rdtase_N.
DR InterPro; IPR009023; HMG_CoA_Rdtase_NAD(P)-bd_sf.
DR InterPro; IPR009029; HMG_CoA_Rdtase_sub-bd_dom_sf.
DR InterPro; IPR000731; SSD.
DR PANTHER; PTHR10572; PTHR10572; 1.
DR Pfam; PF00368; HMG-CoA_red; 1.
DR Pfam; PF13323; HPIH; 1.
DR Pfam; PF12349; Sterol-sensing; 1.
DR PRINTS; PR00071; HMGCOARDTASE.
DR SUPFAM; SSF55035; SSF55035; 1.
DR SUPFAM; SSF56542; SSF56542; 1.
DR TIGRFAMs; TIGR00533; HMG_CoA_R_NADP; 1.
DR PROSITE; PS00066; HMG_COA_REDUCTASE_1; 1.
DR PROSITE; PS00318; HMG_COA_REDUCTASE_2; 1.
DR PROSITE; PS01192; HMG_COA_REDUCTASE_3; 1.
DR PROSITE; PS50065; HMG_COA_REDUCTASE_4; 1.
DR PROSITE; PS50156; SSD; 1.
PE 1: Evidence at protein level;
KW Endoplasmic reticulum; Glycoprotein; Membrane; NADP; Oxidoreductase;
KW Transmembrane; Transmembrane helix.
FT CHAIN 1..1173
FT /note="3-hydroxy-3-methylglutaryl coenzyme A reductase
FT mlcD"
FT /id="PRO_0000436290"
FT TRANSMEM 242..262
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 272..292
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 302..322
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 368..388
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 397..417
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 479..499
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 594..614
FT /note="Helical"
FT /evidence="ECO:0000255"
FT DOMAIN 241..420
FT /note="SSD"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00199"
FT REGION 498..673
FT /note="Linker"
FT /evidence="ECO:0000250|UniProtKB:P04035"
FT REGION 647..669
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 674..1133
FT /note="Catalytic"
FT /evidence="ECO:0000250|UniProtKB:P04035"
FT REGION 1132..1173
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 1135..1158
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT ACT_SITE 822
FT /note="Charge relay system"
FT /evidence="ECO:0000250|UniProtKB:P04035"
FT ACT_SITE 956
FT /note="Charge relay system"
FT /evidence="ECO:0000250|UniProtKB:P04035"
FT ACT_SITE 1032
FT /note="Charge relay system"
FT /evidence="ECO:0000250|UniProtKB:P04035"
FT ACT_SITE 1128
FT /note="Proton donor"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU10003"
FT CARBOHYD 143
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
FT CARBOHYD 186
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
FT CARBOHYD 886
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
FT CARBOHYD 997
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
FT CARBOHYD 1132
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
SQ SEQUENCE 1173 AA; 125847 MW; 53BCFA1CE5DAF31B CRC64;
MVASLLPSRF RGRESMNQQH PLRSGNRALT STLQFLSKTA CLHPIHTVCT IAILASTTYV
GLLKDSFFHG PANVDKAEWG SLVEGSRSLI TGPQNGWKWQ SFDGDADVLG DFNHQALMTL
VFPGSYGVAS QAASPFLAPL PVNLSVIDLP STSSPLTAYS KDKVFAFSVE YSSAPELVAA
VQEIPNNSAD LKLQETQLIE MERQMWIMKA ARAHTKRSLA QWVHDTWTES LDLIKSAQTL
DVVVMVLGYI SMHLTFVSLF LSMKKLGSKV WLATSVLLSS TFAFLLGLDV AIRLGVPMSM
RLLSEGLPFL VVIVGFEKSI TLTRAVLSYA VQHRKPQKIQ SDQGSVTAIA ESTINYAVRS
AIREKGYNIV CHYVVEILLL VIGAVLGIQG GLQHFCVLAA LILFFDCLLL FTFYTAILSI
KLEVNRLKRH INMRYALEDE GLSQRTAESV ATSNDAQDSA RTYLFGNDMK GSSVPKFKFW
MVVGFLIVNL VNIGSTLFQA SSSGSLSSIS SWTESLSGSA IKPPLEPFKV AGSGLDELLF
QARGRGQSTM VTVLAPIKYE LEYPSIHRGT SQLHEYGVGG KMVGSLLTSL EDPVLSKWVF
VALALSVALN SYLFKAARLG IKDPNLPSHP VDPVELDQAE SFNAAQNQTP QIQSSLQAPQ
TRVFTPTTTD SDSDASLVLI KASLKVTKRA EGKTATSELP VSRTQIELDN LLKQNTISEL
NDEDVVALSL RGKVPGYALE KSLKDCTRAV KVRRSIISRT PATAELTSML EHSKLPYENY
AWERVLGACC ENVIGYMPVP VGVAGPIVID GKSYFIPMAT TEGVLVASAS RGSKAINLGG
GAVTVLTGDG MTRGPCVKFD VLERAGAAKI WLDSDVGQTV MKEAFNSTSR FARLQSMRTT
IAGTHLYIRF KTTTGDAMGM NMISKGVEHA LNVMATEAGF SDMNIITLSG NYCTDKKPSA
LNWIDGRGKG IVAEAIIPAN VVRDVLKSDV DSMVQLNISK NLIGSAMAGS VGGFNAQAAN
LAAAIFIATG QDPAQVVESA NCITLMNNLR GSLQISVSMP SIEVGTLGGG TILEPQGAML
DMLGVRGSHP TTPGENARQL ARIIGSAVLA GELSLCAALA AGHLVKAHMA HNRSAPASSA
PSRSVSPSGG TRTVPVPNNA LRPSAAATDR ARR
