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