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Hydrogen-Bond-Assisted Catalysis: Hydroxylation of Paclitaxel by Human CYP2C8
Dongxiao Yue1, Elvis Wang Hei Ng2, Hajime Hirao1
1Warshel Institute for Computational Biology, School of Medicine, The Chinese University of Hong Kong, Shenzhen, Guangdong 518172, P. R. China.
Paclitaxel metabolism by CYP2C8 involves an atypical rebound mechanism. The C7 hydroxyl group aids catalysis, and the enzyme
Area of Science:
- Biochemistry
- Medicinal Chemistry
- Computational Chemistry
Background:
- Paclitaxel (PTX) is a vital chemotherapy drug.
- PTX metabolism by CYP3A4 and CYP2C8 impacts efficacy.
- The precise mechanisms of PTX metabolism are not fully understood.
Purpose of the Study:
- To elucidate the mechanism of PTX metabolism by human CYP2C8.
- To investigate the role of substrate positioning and specific functional groups in PTX hydroxylation.
Main Methods:
- Hybrid quantum mechanics/molecular mechanics (QM/MM) calculations were employed.
- Analysis of hydrogen abstraction, radical intermediate formation, and rebound steps.
- Investigation of transition state stability and spin states.
Main Results:
- CYP2C8-mediated PTX hydroxylation follows an atypical rebound mechanism.
- The C7 hydroxyl group of PTX plays a catalytic role in hydrogen abstraction and rebound.
- Product selectivity is governed by the rebound step, favoring 6α-hydroxylation.
- A stable transition state in the high-spin sextet state was observed due to enzyme-substrate interactions.
Conclusions:
- The study reveals a novel mechanism for PTX metabolism by CYP2C8.
- Enzyme-specific interactions dictate the stereoselective formation of 6α-hydroxypaclitaxel.
- Understanding this mechanism could inform strategies to optimize PTX therapy.
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