| Double Oxidation of the Cyclic Nonaketide Dihydromonacolin L to Monacolin J by a Single Cytochrome P450 Monooxygenase, LovA. | |
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MedLine Citation:
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PMID: 21495633 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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Lovastatin, a cyclic nonaketide from Aspergillus terreus, is a hypercholesterolemic agent and a precursor to simvastatin, a semi-synthetic cholesterol-lowering drug. The biosynthesis of the lovastatin backbone (dihydromonacolin L) and the final 2-methylbutyryl decoration have been fully characterized. However, it remains unclear how two central reactions are catalyzed, namely, introduction of the 4a,5-double bond and hydroxylation at C-8. A cytochrome P450 gene, lovA, clustered with polyketide synthase lovB, has been a prime candidate for these reactions, but inability to obtain LovA recombinant enzyme has impeded detailed biochemical analyses. The synthetic codon optimization and/or N-terminal peptide replacement of lovA allowed the lovA expression in yeast (Saccharomyces cerevisiae). Both in vivo feeding and in vitro enzyme assays showed that LovA catalyzed the conversion of dihydromonacolin L acid to monacolin L acid and monacolin J acid, two proposed pathway intermediates in the biosynthesis of lovastatin. LovA was demonstrated to catalyze the regio- and stereo-specific hydroxylation of monacolin L acid to yield monacolin J acid. These results demonstrate that LovA is the single enzyme that performs both of the two elusive oxidative reactions in the lovastatin biosynthesis. |
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Authors:
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Jorge Barriuso; Don T Nguyen; Jesse W-H Li; Joseph N Roberts; Gillian Macnevin; Jennifer L Chaytor; Sandra L Marcus; John C Vederas; Dae-Kyun Ro |
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Publication Detail:
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Type: JOURNAL ARTICLE Date: 2011-4-15 |
Journal Detail:
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Title: Journal of the American Chemical Society Volume: - ISSN: 1520-5126 ISO Abbreviation: - Publication Date: 2011 Apr |
Date Detail:
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Created Date: 2011-4-18 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 7503056 Medline TA: J Am Chem Soc Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Affiliation:
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Department of Biological Sciences, University of Calgary , 2500 University Drive NW, Calgary T2N 1N4, Canada. |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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