Authors
Sachiyo Yoneda, Kaori Yasuda, Bunzo Mikami, Teisuke Takita, Kiyoshi Yasukawa, Masahiro Hamada, Hiromasa Imaishi, Toshiyuki Sakaki, Shinichi Ikushiro
Published in
Drug metabolism and pharmacokinetics. Volume 65. Pages 101506. Oct 24, 2025. Epub Oct 24, 2025.
Abstract
Streptomyces griseolus CYP105A1 showed hydroxylation activity at 25- and 1α-positions of vitamin D3 to produce an active form of vitamin D3. We have succeeded in dramatically increasing its activity by site-directed mutagenesis. We also found that CYP105A1 and its mutants metabolize various non-steroidal anti-inflammatory drugs. In this study, we attempted to metabolize simvastatin (SV), an HMG-CoA reductase inhibitor, by CYP105A1 mutants, and compared their metabolism with that by human CYP3A4. The SV was converted into multiple metabolites by the CYP105A1 variants CYP105A1-R84A and CYP105A1-R84A/M239A, with the latter exhibiting significantly higher activity than the former. The metabolites were estimated to be 6'-hydroxy-SV, 3'-hydroxy-SV, 3″-hydroxy SV, 3',5'-dihydrodiol SV, and 6'-exomethylene SV. In addition, 6'-hydroxy-SV was non-enzymatically converted to 3'-hydroxy-SV under acidic conditions. The X-ray crystal structure of SV-bound CYP105A1-R84A suggested the formation of a 3',4'-epoxide intermediate, from which 3'-hydroxy and 3',5'-dihydrodiol SV were presumed to be generated non-enzymatically. It is noted that all of these metabolites have either been reported as SV metabolites formed by human CYP3A4 or were detected in the present study. Thus, CYP105A1-R84A/M239A appears to be highly useful for the production of human metabolites of SV.
PMID:
41241974
Bibliographic data and abstract were imported from PubMed on 17 Nov 2025.
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