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

3 Scopus citations

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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