The Structure-Function Relationship of Human Bleomycin Hydrolase: Mutation of a Cysteine Protease into a Serine Protease

Yi Zhen Zheng, Jingxuan Cui, Yung Lin Wang, Szu Jo Huang, En Chi Lin, Sheng Cih Huang, Jeffrey D. Rudolf, Xiaohui Yan, Chin Yuan Chang*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Article numbere202200186
JournalChemBioChem
Volume23
Issue number12
DOIs
StatePublished - 20 Jun 2022

Keywords

  • bleomycin
  • crystal structures
  • cysteine proteases
  • hBH
  • serine proteases

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