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The Structure-Function Relationship of Human Bleomycin Hydrolase: Mutation of a Cysteine Protease into a Serine
Yi-Zhen Zheng1, Jingxuan Cui2, Yung-Lin Wang3
1Department of Biological Science and Technology, National Yang Ming Chiao Tung University, Hsinchu, 30010, Taiwan.
Abstract:
Human bleomycin hydrolase (hBH) catalyzes deamidation of the anticancer drug bleomycins (BLM). This enzyme is involved in BLM detoxification and drug resistance. Herein, we report the putative BLM-binding site and catalytic mechanism of hBH. The crystal structures and biochemical studies suggest that hBH cleaves its C-terminal residue without significant preference for the type of amino acid, and therefore can accordingly accommodate the β-aminoalanine amide moiety of BLM for deamidation. Interestingly, hBH is capable of switching from a cysteine protease to a serine protease that is unable to cleave the secondary amide of hBH C-terminus but reacts with the primary amide of BLMs.
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