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KMID : 0545120170270050956
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Journal of Microbiology and Biotechnology
2017 Volume.27 No. 5 p.956 ~ p.964
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Hydroxylation of Compactin (ML-236B) by CYP105D7 (SAV_7469)
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Yao Qiuping
Ma Li
Liu Ling
Ikeda Haruo
Fushinobu Shinya
Li Shengying
Xu Lian-Hua
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Abstract
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Compactin and pravastatin are competitive cholesterol biosynthesis inhibitors of 3-hydroxy-3- methylglutaryl-CoA reductase and belong to the statin drugs; however, the latter shows superior pharmacokinetic characteristics. Previously, we reported that the bacterial P450, CYP105D7, from Streptomyces avermitilis can catalyze the hydroxylation of 1-deoxypentalenic acid, diclofenac, and naringenin. Here, we demonstrate that CYP105D7 could also catalyze compactin hydroxylation in vitro. In the presence of both bacterial and cyanobacterial redox partner systems with an NADPH regeneration system, the reaction produced two hydroxylated products, including pravastatin (hydroxylated at the C6 position). The steadystate kinetic parameters were measured using the redox partners of putidaredoxin and its reductase. The Km and kcat values for compactin were 39.1 ± 8.8 μM and 1.12 ± 0.09 min-1, respectively. The kcat/Km value for compactin (0.029 min-1·μM-1) was lower than that for diclofenac (0.114 min-1·μM-1). Spectroscopic analysis showed that CYP105D7 binds to compactin with a Kd value of 17.5 ± 3.6 μM. Molecular docking analysis was performed to build a possible binding model of compactin. Comparisons of different substrates with CYP105D7 were conclusively illustrated for the first time.
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KEYWORD
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Compactin, CYP105D7, pravastatin, Streptomyces avermitilis, hydroxylation
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