Insight into Ligand Binding and Conformational Dynamics of Kynurenine 3-Monooxygenase

Abstract

Cellular and developmental pathogenesis is the result of complicated cellular processes involving molecular interactions among cells and their intra- and inter-cellular milieus. The characterization of molecular interactions in different steps of disease-related metabolic pathways is necessary to understand how abnormalities in these interactions relate to disease and disorders, and how to develop therapeutic strategies to overcome these abnormalities. We focus on kynurenine 3-monooxygenase (KMO) of the kynurenine pathway, which is a metabolic pathway leading to the production of nicotinamide adenine dinucleotide from the degradation of tryptophan. KMO inhibition is neuroprotective in studies on animal models, by balancing the neurotoxic and neuroprotective metabolites of the kynurenine pathway. KMO is a flavin adenine dinucleotide-dependent enzyme, that catalyzes the insertion of molecular oxygen into the aromatic ring of L-kynurenine to produce 3-hydroxy-L-kynurenine. Several kinetic and structural studies have been performed on KMO as an attractive target for neurodegenerative, neuroinflammatory and immunological diseases. Atomistic-level understanding of KMO's catalytic and inhibition mechanism is still lacking but will be crucial for further advances. Herein, we performed molecular dynamics simulations to gain insight into the conformational changes and molecular interactions in KMO as a free enzyme and in complex with substrate, product, and inhibitor. We integrate simulation data with experimental findings to interpret the totality of our results and arrive at a framework to gain insight into the conformational dynamics and plasticity of KMO as a free-form enzyme or a ligand binding complex. The outcome leads to an atomistic insight into the enzyme conformational dynamics and ligand-binding interactions which will be crucial in designing novel and more effective therapeutic strategies.