Structural Basis for Inhibitor-Induced Hydrogen Peroxide Production by Kynurenine 3-Monooxygenase

Hyun Tae Kim, Byeong Kwan Na, Jiwoung Chung, Sulhee Kim, Sool Ki Kwon, Hyunju Cha, Jonghyeon Son, Joong Myung Cho, Kwang Yeon Hwang

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

Kynurenine 3-monooxygenase (KMO) inhibitors have been developed for the treatment of neurodegenerative disorders. The mechanisms of flavin reduction and hydrogen peroxide production by KMO inhibitors are unknown. Herein, we report the structure of human KMO and crystal structures of Saccharomyces cerevisiae (sc) and Pseudomonas fluorescens (pf) KMO with Ro 61-8048. Proton transfer in the hydrogen bond network triggers flavin reduction in p-hydroxybenzoate hydroxylase, but the mechanism triggering flavin reduction in KMO is different. Conformational changes via π-π interactions between the loop above the flavin and substrate or non-substrate effectors lead to disorder of the C-terminal α helix in scKMO and shifts of domain III in pfKMO, stimulating flavin reduction. Interestingly, Ro 61-8048 has two different binding modes. It acts as a competitive inhibitor in scKMO and as a non-substrate effector in pfKMO. These findings provide understanding of the catalytic cycle of KMO and insight for structure-based drug design of KMO inhibitors. KMO inhibitors have been developed for the treatment of neurodegenerative disorders, but the mechanisms of flavin reduction and H2O2 production by KMO inhibitors are unknown. Kim et al. propose the triggering mechanism of flavin reduction and reveal the cause of H2O2 production by the inhibitors in KMO.

Original languageEnglish
JournalCell Chemical Biology
DOIs
Publication statusAccepted/In press - 2018 Jan 1

Keywords

  • Drug design
  • Flavin reduction
  • Hydrogen peroxide
  • KMO inhibitor
  • Kynurenine 3-monooxygenase

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmacology
  • Drug Discovery
  • Clinical Biochemistry

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