Regioselective hydroxylation pathway of tenatoprazole to produce human metabolites by Bacillus megaterium CYP102A1. (December 2019)

• Record Type: Journal Article
• Authors: Le, Thien-Kim; Cha, Gun-Su; Jang, Hyun-Hee; Nguyen, Thi Huong Ha; Doan, Tiep Thi My; Lee, Young Ju; Park, Ki Deok; Shin, Yumi; Kim, Dong-Hyun; Yun, Chul-Ho
• Is Part Of: Process biochemistry. Volume 87(2019)
• Page Start: 95
• Page End: 104
• Publication Date: 2019-12
• Subjects: C-hydroxylation -- CYP102A1 -- Human metabolite -- Metabolic pathway -- Tenatoprazole -- Tenatoprazole sulfide; Biochemical engineering -- Periodicals; Biotechnology -- Periodicals; Biochemistry -- periodicals; Biotechnology -- periodicals; Chemical Engineering -- periodicals; Génie biochimique -- Périodiques; Biotechnologie -- Périodiques; Biochemical engineering; Biotechnology; Periodicals; 660.63
• DOI: 10.1016/j.procbio.2019.09.014
• Languages: English
• ISSNs: 1359-5113

Abstract

Graphical abstract: Highlights: CYP102A1 is a cytochrome P450 monooxygenase from Bacillus megaterium . A major hydroxylation product of tenatoprazole by CYP102A1 is 5'-OH tenatoprazole. Tenatoprazole sulfide is spontaneously formed as a major metabolite at neutral pH. 5'-OH tenatoprazole sulfide is produced as a minor metabolite by CYP102A1 reaction. Abstract: Tenatoprazole, a proton pump inhibitor drug candidate, is developed as an acid inhibitor to treat gastric acid hypersecretion disorders, such as gastric ulcer and reflux esophagitis. Tenatoprazole is known to be metabolized to three major metabolites—tenatoprazole sulfone, 5'-hydroxylated metabolite, and tenatoprazole sulfide—in human livers mainly by CYP2C19 and CYP3A4. In this study, an enzymatic strategy for the production of human metabolites of tenatoprazole was developed using bacterial P450 enzymes. A set of CYP102A1 mutants catalyzed the regioselective hydroxylation reactions of tenatoprazole. The major product of tenatoprazole by CYP102A1 is 5'-OH tenatoprazole, a major human metabolite produced by human CYP2C19 and CYP3A4. As another major metabolite of tenatoprazole, tenatoprazole sulfide is formed via a non-enzymatic conversion without a P450 system. In addition, 5'-OH tenatoprazole sulfide was found as a minor metabolite, which can be formed via a 5'-hydroxylation reaction of tenatoprazole sulfide by CYP102A1 and/or a non-enzymatic reduction of 5'-OH tenatoprazole to a sulfide form. Chemical synthesis of the 5'-OH tenatoprazole is not currently possible. In conclusion, an enzymatic synthesis of 5'-OH tenatoprazole, a major human metabolite of tenatoprazole, was developed by using mutants of CYP102A1 from Bacillus megaterium as a biocatalyst and tenatoprazole as a substrate.