Production of a Human Metabolite of Atorvastatin by Bacterial CYP102A1 Peroxygenase

Atorvastatin is a widely used statin drug that prevents cardiovascular disease and treats hyperlipidemia. The major metabolites in humans are 2-OH and 4-OH atorvastatin, which are active metabolites known to show highly inhibiting effects on 3-hydroxy-3-methylglutaryl-CoA reductase activity. Produci...

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Bibliographic Details
Published in:Applied sciences 2021-01, Vol.11 (2), p.603
Main Authors: Nguyen, Thi, Yeom, Soo-Jin, Yun, Chul-Ho
Format: Article
Language:English
Subjects:
4-hydroxy atorvastatin
Acids
Atorvastatin
Biocatalysts
Biosynthesis
Biotransformation
Cardiovascular diseases
Catalytic activity
Chemicals
Cholesterol
CYP102A1
Enzymes
Glucose
High-throughput screening
Hydrogen peroxide
Hydroxylation
Hyperlipidemia
Metabolites
Monooxygenase
Mutagenesis
Mutants
NADPH
Oxidation
P450 peroxygenase
Potassium
Reductases
Statins
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Summary:Atorvastatin is a widely used statin drug that prevents cardiovascular disease and treats hyperlipidemia. The major metabolites in humans are 2-OH and 4-OH atorvastatin, which are active metabolites known to show highly inhibiting effects on 3-hydroxy-3-methylglutaryl-CoA reductase activity. Producing the hydroxylated metabolites by biocatalysts using enzymes and whole-cell biotransformation is more desirable than chemical synthesis. It is more eco-friendly and can increase the yield of desired products. In this study, we have found an enzymatic strategy of P450 enzymes for highly efficient synthesis of the 4-OH atorvastatin, which is an expensive commercial product, by using bacterial CYP102A1 peroxygenase activity with hydrogen peroxide without NADPH. We obtained a set of CYP102A1 mutants with high catalytic activity toward atorvastatin using enzyme library generation, high-throughput screening of highly active mutants, and enzymatic characterization of the mutants. In the hydrogen peroxide supported reactions, a mutant, with nine changed amino acid residues compared to a wild-type among tested mutants, showed the highest catalytic activity of atorvastatin 4-hydroxylation (1.8 min−1). This result shows that CYP102A1 can catalyze atorvastatin 4-hydroxylation by peroxide-dependent oxidation with high catalytic activity. The advantages of CYP102A1 peroxygenase activity over NADPH-supported monooxygenase activity are discussed. Taken together, we suggest that the P450 peroxygenase activity can be used to produce drugs’ metabolites for further studies of their efficacy and safety.
ISSN:2076-3417
2076-3417
DOI:10.3390/app11020603