Q9Y7D1 · LOVD_ASPTE

  • Protein
    Monacolin J acid methylbutanoyltransferase
  • Gene
    lovD
  • Status
    UniProtKB reviewed (Swiss-Prot)
  • Amino acids
  • Protein existence
    Evidence at protein level
  • Annotation score
    5/5

Function

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).

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.

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).

Kinetics

KM SUBSTRATE pH TEMPERATURE[C] NOTES EVIDENCE
0.78 mMmonacolin J
0.67 mMalpha-dimethylbutanoyl-S-methyl-3-mercaptopropionate
kcat is 0.62 min-1 for simvastatin synthesis.

Pathway

Polyketide biosynthesis; lovastatin biosynthesis.

Features

Showing features for binding site, active site.

TypeIDPosition(s)Description
Binding site73monacolin J (UniProtKB | ChEBI)
Active site76Acyl-ester intermediate
Binding site173monacolin J (UniProtKB | ChEBI)
Binding site188monacolin J (UniProtKB | ChEBI)
Binding site258monacolin J (UniProtKB | ChEBI)
Binding site3662-methylbutanoate (UniProtKB | ChEBI)
Binding site388monacolin J (UniProtKB | ChEBI)
Binding site390monacolin J (UniProtKB | ChEBI)

GO annotations

AspectTerm
Molecular Functionacyltransferase activity
Molecular Functionhydrolase activity
Molecular Functionpolyketide synthase activity
Biological Processantibiotic biosynthetic process
Biological Processdefense response to fungus
Biological Processlovastatin biosynthetic process
Biological Processpolyketide biosynthetic process

Keywords

Enzyme and pathway databases

Names & Taxonomy

Protein names

  • Recommended name
    Monacolin J acid methylbutanoyltransferase
  • EC number
  • Alternative names
    • Lovastatin biosynthesis cluster protein D
    • Lovastatin hydrolase
    • Simvastatin synthase LovD
      (SV synthase
      )

Gene names

    • Name
      lovD

Organism names

  • Taxonomic identifier
  • Strain
    • ATCC 20542 / MF4845
  • Taxonomic lineage
    Eukaryota > Fungi > Dikarya > Ascomycota > Pezizomycotina > Eurotiomycetes > Eurotiomycetidae > Eurotiales > Aspergillaceae > Aspergillus > Aspergillus subgen. Circumdati

Accessions

  • Primary accession
    Q9Y7D1

Organism-specific databases

Phenotypes & Variants

Disruption phenotype

Loss of lovastatin biosynthesis.

Features

Showing features for mutagenesis.

TypeIDPosition(s)Description
Mutagenesis4Strongly increases simvastatin synthase activity upon overexpression in E.coli and abolishes activity with LovD-bound alpha-methylbutanoate; when associated with V-9; E-26; S-28; L-35; R-43; R-96; C-109; P-123; V-157; G-164; N-172; F-174; L-178; G-191; I-192; M-241; S-247; K-250; T-256; H-261; S-275; G-297; M-355; L-361; I-370; V-383; S-391 and K-404.
Mutagenesis9Strongly increases simvastatin synthase activity upon overexpression in E.coli and abolishes activity with LovD-bound alpha-methylbutanoate; when associated with N-4; E-26; S-28; L-35; R-43; R-96; C-109; P-123; V-157; G-164; N-172; F-174; L-178; G-191; I-192; M-241; S-247; K-250; T-256; H-261; S-275; G-297; M-355; L-361; I-370; V-383; S-391 and K-404.
Mutagenesis12Strongly increases simvastatin synthase activity upon overexpression in E.coli; when associated with E-26; A-40; N-60; V-86; Y-161; T-190; S-275 and F-334.
Mutagenesis26Strongly increases simvastatin synthase activity upon overexpression in E.coli and abolishes activity with LovD-bound alpha-methylbutanoate; when associated with N-4; V-9; S-28; L-35; R-43; R-96; C-109; P-123; V-157; G-164; N-172; F-174; L-178; G-191; I-192; M-241; S-247; K-250; T-256; H-261; S-275; G-297; M-355; L-361; I-370; V-383; S-391 and K-404.
Mutagenesis26Strongly increases simvastatin synthase activity upon overexpression in E.coli; when associated with G-12; A-40; N-60; V-86; Y-161; T-190; S-275 and F-334.
Mutagenesis28Strongly increases simvastatin synthase activity upon overexpression in E.coli and abolishes activity with LovD-bound alpha-methylbutanoate; when associated with N-4; V-9; E-26; L-35; R-43; R-96; C-109; P-123; V-157; G-164; N-172; F-174; L-178; G-191; I-192; M-241; S-247; K-250; T-256; H-261; S-275; G-297; M-355; L-361; I-370; V-383; S-391 and K-404.
Mutagenesis35Strongly increases simvastatin synthase activity upon overexpression in E.coli and abolishes activity with LovD-bound alpha-methylbutanoate; when associated with N-4; V-9; E-26; S-28; R-43; R-96; C-109; P-123; V-157; G-164; N-172; F-174; L-178; G-191; I-192; M-241; S-247; K-250; T-256; H-261; S-275; G-297; M-355; L-361; I-370; V-383; S-391 and K-404.
Mutagenesis40Improves protein solubility upon overexpression in E.coli. Strongly improves protein solubility; when associated with N-60. Strongly increases simvastatin synthase activity upon overexpression in E.coli; when associated with G-12; E-26; N-60; V-86; Y-161; T-190; S-275 and F-334.
Mutagenesis43Strongly increases simvastatin synthase activity upon overexpression in E.coli and abolishes activity with LovD-bound alpha-methylbutanoate; when associated with N-4; V-9; E-26; S-28; L-35; R-96; C-109; P-123; V-157; G-164; N-172; F-174; L-178; G-191; I-192; M-241; S-247; K-250; T-256; H-261; S-275; G-297; M-355; L-361; I-370; V-383; S-391 and K-404.
Mutagenesis60Minor effect on protein solubility upon overexpression in E.coli. Strongly improves protein solubility; when associated with A-40. Strongly increases simvastatin synthase activity upon overexpression in E.coli; when associated with G-12; E-26; A-40; V-86; Y-161; T-190; S-275 and F-334.
Mutagenesis76Abolishes enzyme activity.
Mutagenesis86Strongly increases simvastatin synthase activity upon overexpression in E.coli; when associated with G-12; E-26; A-40; N-60; Y-161; T-190; S-275 and F-334.
Mutagenesis96Strongly increases simvastatin synthase activity upon overexpression in E.coli and abolishes activity with LovD-bound alpha-methylbutanoate; when associated with N-4; V-9; E-26; S-28; L-35; R-43; C-109; P-123; V-157; G-164; N-172; F-174; L-178; G-191; I-192; M-241; S-247; K-250; T-256; H-261; S-275; G-297; M-355; L-361; I-370; V-383; S-391 and K-404.
Mutagenesis109Strongly increases simvastatin synthase activity upon overexpression in E.coli and abolishes activity with LovD-bound alpha-methylbutanoate; when associated with N-4; V-9; E-26; S-28; L-35; R-43; R-96;.
Mutagenesis123Strongly increases simvastatin synthase activity upon overexpression in E.coli and abolishes activity with LovD-bound alpha-methylbutanoate; when associated with N-4; V-9; E-26; S-28; L-35; R-43; R-96; C-109; V-157; G-164; N-172; F-174; L-178; G-191; I-192; M-241; S-247; K-250; T-256; H-261; S-275; G-297; M-355; L-361; I-370; V-383; S-391 and K-404.
Mutagenesis157Strongly increases simvastatin synthase activity upon overexpression in E.coli and abolishes activity with LovD-bound alpha-methylbutanoate; when associated with N-4; V-9; E-26; S-28; L-35; R-43; R-96; C-109; P-123; G-164; N-172; F-174; L-178; G-191; I-192; M-241; S-247; K-250; T-256; H-261; S-275; G-297; M-355; L-361; I-370; V-383; S-391 and K-404.
Mutagenesis161Strongly increases simvastatin synthase activity upon overexpression in E.coli; when associated with G-12; E-26; A-40; N-60; V-86; T-190; S-275 and F-334.
Mutagenesis164Strongly increases simvastatin synthase activity upon overexpression in E.coli and abolishes activity with LovD-bound alpha-methylbutanoate; when associated with N-4; V-9; E-26; S-28; L-35; R-43; R-96; C-109; P-123; V-157; N-172; F-174; L-178; G-191; I-192; M-241; S-247; K-250; T-256; H-261; S-275; G-297; M-355; L-361; I-370; V-383; S-391 and K-404.
Mutagenesis172Strongly increases simvastatin synthase activity upon overexpression in E.coli and abolishes activity with LovD-bound alpha-methylbutanoate; when associated with N-4; V-9; E-26; S-28; L-35; R-43; R-96; C-109; P-123; V-157; G-164; F-174; L-178; G-191; I-192; M-241; S-247; K-250; T-256; H-261; S-275; G-297; V-383; M-355; L-361; I-370; S-391 and K-404.
Mutagenesis174Strongly increases simvastatin synthase activity upon overexpression in E.coli and abolishes activity with LovD-bound alpha-methylbutanoate; when associated with N-4; V-9; E-26; S-28; L-35; R-43; R-96; C-109; P-123; V-157; G-164; N-172; L-178; G-191; I-192; M-241; S-247; K-250; T-256; H-261; S-275; G-297; M-355; L-361; I-370; V-383; S-391 and K-404.
Mutagenesis178Strongly increases simvastatin synthase activity upon overexpression in E.coli and abolishes activity with LovD-bound alpha-methylbutanoate; when associated with N-4; V-9; E-26; S-28; L-35; R-43; R-96; C-109; P-123; V-157; G-164; N-172; F-174; G-191; I-192; M-241; S-247; K-250; T-256; H-261; S-275; G-297; M-355; L-361; I-370; V-383; S-391 and K-404.
Mutagenesis190Strongly increases simvastatin synthase activity upon overexpression in E.coli; when associated with G-12; E-26; A-40; N-60; V-86; Y-161; S-275 and F-334.
Mutagenesis191Strongly increases simvastatin synthase activity upon overexpression in E.coli and abolishes activity with LovD-bound alpha-methylbutanoate; when associated with N-4; V-9; E-26; S-28; L-35; R-43; R-96; C-109; P-123; V-157; G-164; N-172; F-174; L-178; I-192; M-241; S-247; K-250; T-256; H-261; S-275; G-297; M-355; L-361; I-370; V-383; S-391 and K-404.
Mutagenesis192Strongly increases simvastatin synthase activity upon overexpression in E.coli and abolishes activity with LovD-bound alpha-methylbutanoate; when associated with N-4; V-9; E-26; S-28; L-35; R-43; R-96; C-109; P-123; V-157; G-164; N-172; F-174; L-178; G-191; M-241; S-247; K-250; T-256; H-261; S-275; G-297; V-383; M-355; L-361; I-370; S-391 and K-404.
Mutagenesis241Strongly increases simvastatin synthase activity upon overexpression in E.coli and abolishes activity with LovD-bound alpha-methylbutanoate; when associated with N-4; V-9; E-26; S-28; L-35; R-43; R-96; C-109; P-123; V-157; G-164; N-172; F-174; L-178; G-191; I-192; S-247; K-250; T-256; H-261; S-275; G-297; M-355; L-361; I-370; V-383; S-391 and K-404.
Mutagenesis247Strongly increases simvastatin synthase activity upon overexpression in E.coli and abolishes activity with LovD-bound alpha-methylbutanoate; when associated with N-4; V-9; E-26; S-28; L-35; R-43; R-96; C-109; P-123; V-157; G-164; N-172; F-174; L-178; G-191; I-192; M-241; K-250; T-256; H-261; S-275; G-297; M-355; L-361; I-370; V-383; S-391 and K-404.
Mutagenesis250Strongly increases simvastatin synthase activity upon overexpression in E.coli and abolishes activity with LovD-bound alpha-methylbutanoate; when associated with N-4; V-9; E-26; S-28; L-35; R-43; R-96; C-109; P-123; V-157; G-164; N-172; F-174; L-178; G-191; I-192; M-241; S-247; T-256; H-261; S-275; G-297; M-355; L-361; I-370; V-383; S-391 and K-404.
Mutagenesis256Strongly increases simvastatin synthase activity upon overexpression in E.coli and abolishes activity with LovD-bound alpha-methylbutanoate; when associated with N-4; V-9; E-26; S-28; L-35; R-43; R-96; C-109; P-123; V-157; G-164; N-172; F-174; L-178; G-191; I-192; M-241; S-247; K-250; H-261; S-275; G-297; M-355; L-361; I-370; V-383; S-391 and K-404.
Mutagenesis261Strongly increases simvastatin synthase activity upon overexpression in E.coli and abolishes activity with LovD-bound alpha-methylbutanoate; when associated with N-4; V-9; E-26; S-28; L-35; R-43; R-96; C-109; P-123; V-157; G-164; N-172; F-174; L-178; G-191; I-192; M-241; S-247; K-250; T-256; S-275; G-297; V-383; M-355; L-361; I-370; S-391 and K-404.
Mutagenesis275Strongly increases simvastatin synthase activity upon overexpression in E.coli and abolishes activity with LovD-bound alpha-methylbutanoate; when associated with N-4; V-9; E-26; S-28; L-35; R-43; R-96; C-109; P-123; V-157; G-164; N-172; F-174; L-178; G-191; I-192; M-241; S-247; K-250; T-256; H-261; G-297; M-355; L-361; I-370; V-383; S-391 and K-404.
Mutagenesis275Strongly increases simvastatin synthase activity upon overexpression in E.coli; when associated with G-12; E-26; A-40; N-60; V-86; Y-161; T-190 and F-334.
Mutagenesis297Strongly increases simvastatin synthase activity upon overexpression in E.coli and abolishes activity with LovD-bound alpha-methylbutanoate; when associated with N-4; V-9; E-26; S-28; L-35; R-43; R-96; C-109; P-123; V-157; G-164; N-172; F-174; L-178; G-191; I-192; M-241; S-247; K-250; T-256; H-261; S-275; M-355; L-361; I-370; V-383; S-391 and K-404.
Mutagenesis334Strongly increases simvastatin synthase activity upon overexpression in E.coli; when associated with G-12; E-26; A-40; N-60; V-86; Y-161; T-190 and S-275.
Mutagenesis355Strongly increases simvastatin synthase activity upon overexpression in E.coli and abolishes activity with LovD-bound alpha-methylbutanoate; when associated with N-4; V-9; E-26; S-28; L-35; R-43; R-96; C-109; P-123; V-157; G-164; N-172; F-174; L-178; G-191; I-192; M-241; S-247; K-250; T-256; H-261; S-275; G-297; M-361; I-370; V-383; S-391 and K-404.
Mutagenesis361Strongly increases simvastatin synthase activity upon overexpression in E.coli and abolishes activity with LovD-bound alpha-methylbutanoate; when associated with N-4; V-9; E-26; S-28; L-35; R-43; R-96; C-109; P-123; V-157; G-164; N-172; F-174; L-178; G-191; I-192; M-241; S-247; K-250; T-256; H-261; S-275; V-383; G-297; M-355; I-370; S-391 and K-404.
Mutagenesis370Strongly increases simvastatin synthase activity upon overexpression in E.coli and abolishes activity with LovD-bound alpha-methylbutanoate; when associated with N-4; V-9; E-26; S-28; L-35; R-43; R-96; C-109; P-123; V-157; G-164; N-172; F-174; L-178; G-191; I-192; M-241; S-247; K-250; T-256; H-261; S-275; G-297; M-355; M-361; V-383; S-391 and K-404.
Mutagenesis383Strongly increases simvastatin synthase activity upon overexpression in E.coli and abolishes activity with LovD-bound alpha-methylbutanoate; when associated with N-4; V-9; E-26; S-28; L-35; R-43; R-96; C-109; P-123; V-157; G-164; N-172; F-174; L-178; G-191; I-192; M-241; S-247; K-250; T-256; H-261; S-275; G-297; M-355; L-361; I-370; S-391 and K-404.
Mutagenesis391Strongly increases simvastatin synthase activity upon overexpression in E.coli and abolishes activity with LovD-bound alpha-methylbutanoate; when associated with N-4; V-9; E-26; S-28; L-35; R-43; R-96; C-109; P-123; V-157; G-164; N-172; F-174; L-178; G-191; I-192; M-241; S-247; K-250; T-256; H-261; S-275; G-297; M-355; M-361; I-370; V-383 and K-404.
Mutagenesis404Strongly increases simvastatin synthase activity upon overexpression in E.coli and abolishes activity with LovD-bound alpha-methylbutanoate; when associated with N-4; V-9; E-26; S-28; L-35; R-43; R-96; C-109; P-123; V-157; G-164; N-172; F-174; L-178; G-191; I-192; M-241; S-247; K-250; T-256; H-261; S-275; V-383; G-297; M-355; M-361; I-370; V-383 and S-391.

PTM/Processing

Features

Showing features for chain.

TypeIDPosition(s)Description
ChainPRO_00004301001-413Monacolin J acid methylbutanoyltransferase

Interaction

Subunit

Interacts with LovF.

Family & Domains

Sequence similarities

Belongs to the class-A beta-lactamase family.

Family and domain databases

Sequence

  • Sequence status
    Complete
  • Length
    413
  • Mass (Da)
    46,037
  • Last updated
    1999-11-01 v1
  • Checksum
    731A140B6E609A24
MGSIIDAAAAADPVVLMETAFRKAVKSRQIPGAVIMARDCSGNLNYTRCFGARTVRRDECNQLPPLQVDTPCRLASATKLLTTIMALQCMERGLVDLDETVDRLLPDLSAMPVLEGFDDAGNARLRERRGKITLRHLLTHTSGLSYVFLHPLLREYMAQGHLQSAEKFGIQSRLAPPAVNDPGAEWIYGANLDWAGKLVERATGLDLEQYLQENICAPLGITDMTFKLQQRPDMLARRADQTHRNSADGRLRYDDSVYFRADGEECFGGQGVFSGPGSYMKVLHSLLKRDGLLLQPQTVDLMFQPALEPRLEEQMNQHMDASPHINYGGPMPMVLRRSFGLGGIIALEDLDGENWRRKGSLTFGGGPNIVWQIDPKAGLCTLAFFQLEPWNDPVCRDLTRTFEHAIYAQYQQG

Keywords

Sequence databases

Nucleotide SequenceProtein SequenceMolecule TypeStatus
AH007774
EMBL· GenBank· DDBJ
AAD34555.1
EMBL· GenBank· DDBJ
Genomic DNA

Genome annotation databases

Similar Proteins

Disclaimer

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