PMID: 29429898

 

    Legend: Sugar

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

Abstract :
  1. Kynurenine 3-monooxygenase ( KMO ) inhibitors have been developed for the treatment of neurodegenerative disorders
  2. The mechanisms of flavin reduction and hydrogen peroxide production by KMO inhibitors are unknown
  3. Herein, we report the structure of human KMO and crystal structures of Saccharomyces cerevisiae (sc) and Pseudomonas fluorescens (pf) KMO with Ro 61-8048
  4. Proton transfer in the hydrogen bond network triggers flavin reduction in p-hydroxybenzoate hydroxylase , but the mechanism triggering flavin reduction in KMO is different
  5. 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
  6. Interestingly, Ro 61-8048 has two different binding modes
  7. It acts as a competitive inhibitor in sc KMO and as a non-substrate effector in pf KMO
  8. These findings provide understanding of the catalytic cycle of KMO and insight for structure-based drug design of KMO inhibitors