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Double Oxidation of the Cyclic Nonaketide Dihydromonacolin L to Monacolin J by a Single Cytochrome P450 Monooxygenase, LovA

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 characterize...

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Bibliographic Details
Published in:Journal of the American Chemical Society 2011-06, Vol.133 (21), p.8078-8081
Main Authors: Barriuso, Jorge, Nguyen, Don T, Li, Jesse W.-H, Roberts, Joseph N, MacNevin, Gillian, Chaytor, Jennifer L, Marcus, Sandra L, Vederas, John C, Ro, Dae-Kyun
Format: Article
Language:English
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Summary: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.
ISSN:0002-7863
1520-5126
DOI:10.1021/ja201138v