Structural Basis for Inhibitor-Induced Hydrogen Peroxide Production by Kynurenine 3-Monooxygenase. Issue 4 (19th April 2018)

• Record Type: Journal Article
• Authors: Kim, Hyun Tae; Na, Byeong Kwan; Chung, Jiwoung; Kim, Sulhee; Kwon, Sool Ki; Cha, Hyunju; Son, Jonghyeon; Cho, Joong Myung; Hwang, Kwang Yeon
• Is Part Of: Cell chemical biology. Volume 25:Issue 4(2018)
• Page Start: 426
• Page End: 438.e4
• Publication Date: 2018-04-19
• Subjects: kynurenine 3-monooxygenase -- hydrogen peroxide -- flavin reduction -- KMO inhibitor -- drug design; Biochemistry -- Periodicals; 572.05
• DOI: 10.1016/j.chembiol.2018.01.008
• Languages: English
• ISSNs: 2451-9456

Abstract

Summary: 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 sc KMO and shifts of domain III in pf KMO, stimulating flavin reduction. Interestingly, Ro 61-8048 has two different binding modes. It acts as a competitive inhibitor in sc KMO and as a non-substrate effector in pf KMO. These findings provide understanding of the catalytic cycle of KMO and insight for structure-based drug design of KMO inhibitors. Graphical Abstract: Highlights: We report the structures of human KMO and Ro 61-8048-complexed sc KMO and pf KMO We propose the triggering mechanism of flavin reduction in KMO Ro 61-8048 adopts distinct binding modes in S . cerevisiae and P . fluorescens KMOs Our findings provide insight for structure-based drug design of KMO inhibitors Abstract : KMO inhibitors have been developed for the treatment of neurodegenerative disorders, but the mechanisms of flavin reduction and H2 O2 production by KMO inhibitors are unknown. Kim et al. propose the triggering mechanism of flavin reduction and reveal the cause of H2 O2 production by the inhibitors in KMO.