ID   MLCH_PENCI              Reviewed;         418 AA.
AC   Q8J0G0;
DT   11-MAY-2016, integrated into UniProtKB/Swiss-Prot.
DT   01-MAR-2003, sequence version 1.
DT   03-AUG-2022, entry version 54.
DE   RecName: Full=ML-236A carboxylate methylbutanoyltransferase mlcH {ECO:0000305};
DE            EC=2.3.1.- {ECO:0000305};
DE   AltName: Full=Compactin biosynthesis protein H {ECO:0000303|PubMed:12172803};
GN   Name=mlcH {ECO:0000303|PubMed:12172803};
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], AND INDUCTION.
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   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   [3]
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: Compactin diketide synthase; part of the gene cluster that
CC       mediates the biosynthesis of compactin, also known as mevastatin or ML-
CC       236B, and which acts as a potent competitive inhibitor of HMG-CoA
CC       reductase (PubMed:12172803). Compactin biosynthesis is performed in two
CC       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   -!- CATALYTIC ACTIVITY:
CC       Reaction=(S)-2-methylbutanoyl-[2-methylbutanoate polyketide synthase] +
CC         ML-236A carboxylate = holo-[2-methylbutanoate polyketide synthase] +
CC         mevinic carboxylate; Xref=Rhea:RHEA:57636, Rhea:RHEA-COMP:10260,
CC         Rhea:RHEA-COMP:10261, ChEBI:CHEBI:64479, ChEBI:CHEBI:82764,
CC         ChEBI:CHEBI:142048, ChEBI:CHEBI:142050; Evidence={ECO:0000305};
CC   -!- PATHWAY: Polyketide biosynthesis. {ECO:0000303|PubMed:12172803}.
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 class-A beta-lactamase family.
CC       {ECO:0000305}.
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DR   EMBL; AB072893; BAC20561.1; -; Genomic_DNA.
DR   AlphaFoldDB; Q8J0G0; -.
DR   SMR; Q8J0G0; -.
DR   GO; GO:0016746; F:acyltransferase activity; IEA:UniProtKB-KW.
DR   GO; GO:0016787; F:hydrolase activity; IEA:UniProtKB-KW.
DR   Gene3D; 3.40.710.10; -; 1.
DR   InterPro; IPR001466; Beta-lactam-related.
DR   InterPro; IPR012338; Beta-lactam/transpept-like.
DR   Pfam; PF00144; Beta-lactamase; 1.
DR   SUPFAM; SSF56601; SSF56601; 1.
PE   1: Evidence at protein level;
KW   Acyltransferase; Hydrolase; Transferase.
FT   CHAIN           1..418
FT                   /note="ML-236A carboxylate methylbutanoyltransferase mlcH"
FT                   /id="PRO_0000436288"
FT   ACT_SITE        81
FT                   /note="Acyl-ester intermediate"
FT                   /evidence="ECO:0000250|UniProtKB:Q9Y7D1"
FT   BINDING         78
FT                   /ligand="monacolin J"
FT                   /ligand_id="ChEBI:CHEBI:79034"
FT                   /evidence="ECO:0000250|UniProtKB:Q9Y7D1"
FT   BINDING         178
FT                   /ligand="monacolin J"
FT                   /ligand_id="ChEBI:CHEBI:79034"
FT                   /evidence="ECO:0000250|UniProtKB:Q9Y7D1"
FT   BINDING         193
FT                   /ligand="monacolin J"
FT                   /ligand_id="ChEBI:CHEBI:79034"
FT                   /evidence="ECO:0000250|UniProtKB:Q9Y7D1"
FT   BINDING         262
FT                   /ligand="monacolin J"
FT                   /ligand_id="ChEBI:CHEBI:79034"
FT                   /evidence="ECO:0000250|UniProtKB:Q9Y7D1"
FT   BINDING         370
FT                   /ligand="2-methylbutanoate"
FT                   /ligand_id="ChEBI:CHEBI:48946"
FT                   /evidence="ECO:0000250|UniProtKB:Q9Y7D1"
SQ   SEQUENCE   418 AA;  46688 MW;  871E472845BB90C6 CRC64;
     MAPSIDVIPT AASTAAGMIS DMEAAFKSAV KLKQIPGAVV MARSMNGDID YTRCFGARTV
     ERDECQRLPP MEIDTPLRLA SATKLLTTIM ALQCMEQGLV DLDENVNRLL PDLSDMQVLT
     GFDAAGNAIM RDREGIIKLR HLLTHTSGLS YAFLHPLLQE YMAKGYLKTA EKFGIQSRLA
     PPAINDPGVE WIYGANLDWA GKLIERATGV DLEEFMQKNI CEPLGITDMT FKLQQRPDML
     ARRSDQTRRN ENGSLRYDDS VYFRHDGEEC FGGQGVFCGP ESYMKVLNSL MKHDGLLLKK
     DTIELMFQPA LDAELEKKMN DHMDTTPHIN YGAALPPVMR RNFGLGGIIA MGDLDGHNWR
     REGSLTFGGG PNIVWQIDPT VGLCTLVVFQ LEPWNDPICK DLTRKFEKAM YSQVKCRN