UniProt functional annotation for Q9Y7D1



	UniProt functional annotation for Q9Y7D1

UniProt code: Q9Y7D1.

Organism: Aspergillus terreus.

Taxonomy: Eukaryota; Fungi; Dikarya; Ascomycota; Pezizomycotina; Eurotiomycetes; Eurotiomycetidae; Eurotiales; Aspergillaceae; Aspergillus; Aspergillus subgen. Circumdati.

Function: Monacolin J acid methylbutanoyltransferase; part of the gene cluster that mediates the biosynthesis of lovastatin (also known as mevinolin, mevacor or monacolin K), a hypolipidemic inhibitor of (3S)- hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase (HMGR) (PubMed:10334994, PubMed:12929390, PubMed:21495633). The first step in the biosynthesis of lovastatin is the production of dihydromonacolin L acid by the lovastatin nonaketide synthase lovB and the trans-acting enoyl reductase lovC via condensation of one acetyl-CoA unit and 8 malonyl-CoA units (PubMed:10334994, PubMed:10381407, PubMed:19900898, PubMed:22733743). Dihydromonacolin L acid is released from lovB by the thioesterase lovG (PubMed:23653178). Next, dihydromonacolin L acid is oxidized by the dihydromonacolin L monooxygenase lovA twice to form monacolin J acid (PubMed:12929390, PubMed:21495633). The 2- methylbutyrate moiety of lovastatin is synthesized by the lovastatin diketide synthase lovF via condensation of one acetyl-CoA unit and one malonyl-CoA unit (PubMed:19530726, PubMed:21069965). Finally, the covalent attachment of this moiety to monacolin J acid is catalyzed by the transesterase lovD to yield lovastatin (PubMed:10334994, PubMed:17113998, PubMed:18988191, PubMed:19875080, PubMed:24727900). LovD has broad substrate specificity and can also convert monacolin J to simvastatin using alpha-dimethylbutanoyl-S-methyl-3- mercaptopropionate (DMB-S-MMP) as the thioester acyl donor, and can also catalyze the reverse reaction and function as hydrolase in vitro (PubMed:19875080). LovD has much higher activity with LovF-bound 2- methylbutanoate than with free diketide substrates (PubMed:21069965). {ECO:0000269|PubMed:10334994, ECO:0000269|PubMed:10381407, ECO:0000269|PubMed:12929390, ECO:0000269|PubMed:17113998, ECO:0000269|PubMed:18988191, ECO:0000269|PubMed:19530726, ECO:0000269|PubMed:19875080, ECO:0000269|PubMed:19900898, ECO:0000269|PubMed:21069965, ECO:0000269|PubMed:21495633, ECO:0000269|PubMed:22733743, ECO:0000269|PubMed:23653178, ECO:0000269|PubMed:24727900}.

Catalytic activity: Reaction=(S)-2-methylbutanoyl-[2-methylbutanoate polyketide synthase] + monacolin J carboxylate = holo-[2-methylbutanoate polyketide synthase] + lovastatin carboxylate; Xref=Rhea:RHEA:43064, Rhea:RHEA- COMP:10260, Rhea:RHEA-COMP:10261, ChEBI:CHEBI:64479, ChEBI:CHEBI:79035, ChEBI:CHEBI:79038, ChEBI:CHEBI:82764; EC=2.3.1.238; Evidence={ECO:0000269|PubMed:18988191, ECO:0000269|PubMed:19530726, ECO:0000269|PubMed:19875080};

Biophysicochemical properties: Kinetic parameters: KM=0.78 mM for monacolin J {ECO:0000269|PubMed:18988191, ECO:0000269|PubMed:19875080}; KM=0.67 mM for alpha-dimethylbutanoyl-S-methyl-3-mercaptopropionate {ECO:0000269|PubMed:18988191, ECO:0000269|PubMed:19875080}; Note=Kcat is 0.62 min(-1) for simvastatin synthesis.;

Pathway: Polyketide biosynthesis; lovastatin biosynthesis. {ECO:0000269|PubMed:10334994, ECO:0000269|PubMed:24727900}.

Subunit: Interacts with LovF. {ECO:0000269|PubMed:10334994, ECO:0000269|PubMed:19530726}.

Disruption phenotype: Loss of lovastatin biosynthesis. {ECO:0000269|PubMed:10334994}.

Biotechnology: Lovastatin acts as a hypolipidemic agent that works as inhibitor of (3S)-hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase (HMGR) which reduces HMG-CoA to mevalonate and is the key step in cholesterol biosynthesis (PubMed:6933445). Lovastatin, simvastatin and related compounds are widely used to treat hypercholesteremia and reduce the risk of cardiovascular disease (PubMed:6933445). Furthermore, statins such as lovastatin were found to be anticancer agents (PubMed:29236027, PubMed:29932104). {ECO:0000269|PubMed:29236027, ECO:0000269|PubMed:29932104, ECO:0000269|PubMed:6933445}.

Miscellaneous: Directed evolution toward higher catalytic activity with free diketides led to an enzyme with 1000-fold higher activity in simvastatin synthesis, due to numerous mutations that affect protein folding and promote optimal alignment of the residues that are important for substrate binding and catalysis. {ECO:0000305|PubMed:24727900}.

Similarity: Belongs to the class-A beta-lactamase family. {ECO:0000305}.

Annotations taken from UniProtKB at the EBI.


Organism:		Aspergillus terreus.
Taxonomy:		Eukaryota; Fungi; Dikarya; Ascomycota; Pezizomycotina; Eurotiomycetes; Eurotiomycetidae; Eurotiales; Aspergillaceae; Aspergillus; Aspergillus subgen. Circumdati.



Function:		Monacolin J acid methylbutanoyltransferase; part of the gene cluster that mediates the biosynthesis of lovastatin (also known as mevinolin, mevacor or monacolin K), a hypolipidemic inhibitor of (3S)- hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase (HMGR) (PubMed:10334994, PubMed:12929390, PubMed:21495633). The first step in the biosynthesis of lovastatin is the production of dihydromonacolin L acid by the lovastatin nonaketide synthase lovB and the trans-acting enoyl reductase lovC via condensation of one acetyl-CoA unit and 8 malonyl-CoA units (PubMed:10334994, PubMed:10381407, PubMed:19900898, PubMed:22733743). Dihydromonacolin L acid is released from lovB by the thioesterase lovG (PubMed:23653178). Next, dihydromonacolin L acid is oxidized by the dihydromonacolin L monooxygenase lovA twice to form monacolin J acid (PubMed:12929390, PubMed:21495633). The 2- methylbutyrate moiety of lovastatin is synthesized by the lovastatin diketide synthase lovF via condensation of one acetyl-CoA unit and one malonyl-CoA unit (PubMed:19530726, PubMed:21069965). Finally, the covalent attachment of this moiety to monacolin J acid is catalyzed by the transesterase lovD to yield lovastatin (PubMed:10334994, PubMed:17113998, PubMed:18988191, PubMed:19875080, PubMed:24727900). LovD has broad substrate specificity and can also convert monacolin J to simvastatin using alpha-dimethylbutanoyl-S-methyl-3- mercaptopropionate (DMB-S-MMP) as the thioester acyl donor, and can also catalyze the reverse reaction and function as hydrolase in vitro (PubMed:19875080). LovD has much higher activity with LovF-bound 2- methylbutanoate than with free diketide substrates (PubMed:21069965). {ECO:0000269\|PubMed:10334994, ECO:0000269\|PubMed:10381407, ECO:0000269\|PubMed:12929390, ECO:0000269\|PubMed:17113998, ECO:0000269\|PubMed:18988191, ECO:0000269\|PubMed:19530726, ECO:0000269\|PubMed:19875080, ECO:0000269\|PubMed:19900898, ECO:0000269\|PubMed:21069965, ECO:0000269\|PubMed:21495633, ECO:0000269\|PubMed:22733743, ECO:0000269\|PubMed:23653178, ECO:0000269\|PubMed:24727900}.


Catalytic activity:		Reaction=(S)-2-methylbutanoyl-[2-methylbutanoate polyketide synthase] + monacolin J carboxylate = holo-[2-methylbutanoate polyketide synthase] + lovastatin carboxylate; Xref=Rhea:RHEA:43064, Rhea:RHEA- COMP:10260, Rhea:RHEA-COMP:10261, ChEBI:CHEBI:64479, ChEBI:CHEBI:79035, ChEBI:CHEBI:79038, ChEBI:CHEBI:82764; EC=2.3.1.238; Evidence={ECO:0000269\|PubMed:18988191, ECO:0000269\|PubMed:19530726, ECO:0000269\|PubMed:19875080};
Biophysicochemical properties:		Kinetic parameters: KM=0.78 mM for monacolin J {ECO:0000269\|PubMed:18988191, ECO:0000269\|PubMed:19875080}; KM=0.67 mM for alpha-dimethylbutanoyl-S-methyl-3-mercaptopropionate {ECO:0000269\|PubMed:18988191, ECO:0000269\|PubMed:19875080}; Note=Kcat is 0.62 min(-1) for simvastatin synthesis.;
Pathway:		Polyketide biosynthesis; lovastatin biosynthesis. {ECO:0000269\|PubMed:10334994, ECO:0000269\|PubMed:24727900}.
Subunit:		Interacts with LovF. {ECO:0000269\|PubMed:10334994, ECO:0000269\|PubMed:19530726}.
Disruption phenotype:		Loss of lovastatin biosynthesis. {ECO:0000269\|PubMed:10334994}.
Biotechnology:		Lovastatin acts as a hypolipidemic agent that works as inhibitor of (3S)-hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase (HMGR) which reduces HMG-CoA to mevalonate and is the key step in cholesterol biosynthesis (PubMed:6933445). Lovastatin, simvastatin and related compounds are widely used to treat hypercholesteremia and reduce the risk of cardiovascular disease (PubMed:6933445). Furthermore, statins such as lovastatin were found to be anticancer agents (PubMed:29236027, PubMed:29932104). {ECO:0000269\|PubMed:29236027, ECO:0000269\|PubMed:29932104, ECO:0000269\|PubMed:6933445}.
Miscellaneous:		Directed evolution toward higher catalytic activity with free diketides led to an enzyme with 1000-fold higher activity in simvastatin synthesis, due to numerous mutations that affect protein folding and promote optimal alignment of the residues that are important for substrate binding and catalysis. {ECO:0000305\|PubMed:24727900}.
Similarity:		Belongs to the class-A beta-lactamase family. {ECO:0000305}.