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

doi:10.1002/cbic.202200186

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 journal › Article › peer-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 language	English
Article number	e202200186
Journal	ChemBioChem
Volume	23
Issue number	12
DOIs	https://doi.org/10.1002/cbic.202200186
State	Published - 20 Jun 2022

Keywords

bleomycin
crystal structures
cysteine proteases
hBH
serine proteases

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10.1002/cbic.202200186

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

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.",

keywords = "bleomycin, crystal structures, cysteine proteases, hBH, serine proteases",

author = "Zheng, {Yi Zhen} and Jingxuan Cui and Wang, {Yung Lin} and Huang, {Szu Jo} and Lin, {En Chi} and Huang, {Sheng Cih} and Rudolf, {Jeffrey D.} and Xiaohui Yan and Chang, {Chin Yuan}",

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doi = "10.1002/cbic.202200186",

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T1 - The Structure-Function Relationship of Human Bleomycin Hydrolase

T2 - Mutation of a Cysteine Protease into a Serine Protease

AU - Zheng, Yi Zhen

AU - Cui, Jingxuan

AU - Wang, Yung Lin

AU - Huang, Szu Jo

AU - Lin, En Chi

AU - Huang, Sheng Cih

AU - Rudolf, Jeffrey D.

AU - Yan, Xiaohui

AU - Chang, Chin Yuan

PY - 2022/6/20

Y1 - 2022/6/20

N2 - 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.

AB - 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.

KW - bleomycin

KW - crystal structures

KW - cysteine proteases

KW - hBH

KW - serine proteases

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U2 - 10.1002/cbic.202200186

DO - 10.1002/cbic.202200186

M3 - Article

C2 - 35467071

AN - SCOPUS:85129260264

SN - 1439-4227

VL - 23

JO - ChemBioChem

JF - ChemBioChem

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M1 - e202200186

ER -

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

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Keywords

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