2. Academic Validation
  3. Structural Basis for Inhibitor-Induced Hydrogen Peroxide Production by Kynurenine 3-Monooxygenase

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

  • Cell Chem Biol. 2018 Apr 19;25(4):426-438.e4. doi: 10.1016/j.chembiol.2018.01.008.
Hyun Tae Kim 1,  Byeong Kwan Na 2,  Jiwoung Chung 2,  Sulhee Kim 3,  Sool Ki Kwon 2,  Hyunju Cha 2,  Jonghyeon Son 3,  Joong Myung Cho 4,  Kwang Yeon Hwang 5
Affiliations

Affiliations

  • 1 Crystalgenomics, Inc., 5F, Tower A, Korea Bio Park 700, Daewangpangyo-ro, Bundang-gu, Seongnam-si, Gyeonggi-do 13524, Korea; Division of Biotechnology, College of Life Sciences and Biotechnology, Korea University, 145 Anam-ro, Seongbuk-gu, Seoul 02841, Korea.
  • 2 Crystalgenomics, Inc., 5F, Tower A, Korea Bio Park 700, Daewangpangyo-ro, Bundang-gu, Seongnam-si, Gyeonggi-do 13524, Korea.
  • 3 Division of Biotechnology, College of Life Sciences and Biotechnology, Korea University, 145 Anam-ro, Seongbuk-gu, Seoul 02841, Korea.
  • 4 Crystalgenomics, Inc., 5F, Tower A, Korea Bio Park 700, Daewangpangyo-ro, Bundang-gu, Seongnam-si, Gyeonggi-do 13524, Korea. Electronic address: [email protected].
  • 5 Division of Biotechnology, College of Life Sciences and Biotechnology, Korea University, 145 Anam-ro, Seongbuk-gu, Seoul 02841, Korea. Electronic address: [email protected].
PMID: 29429898 DOI: 10.1016/j.chembiol.2018.01.008
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.

Keywords

KMO inhibitor; drug design; flavin reduction; hydrogen peroxide; kynurenine 3-monooxygenase.

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