Quantum mechanics/molecular mechanics (QM/MM) modeling of the irreversible transamination of l-kynurenine to kynurenic acid: The round dance of kynurenine aminotransferase II

Kynurenine aminotransferase (KAT) is a key enzyme of the kynurenine pathway along the route of tryptophan catabolism. It catalyzes the irreversible transamination reaction of l-kynurenine (l-Kyn) to kynurenic acid (KYNA), an important neuroactive metabolite that plays a role in protecting neurons from excitatory neurotransmission. Although four isoforms (KAT-I to -IV) of this enzyme have been hitherto identified, KAT-II is the enzymatic isoform that mainly accounts for the synthesis of cerebral KYNA. In this study, the transamination mechanism of l-Kyn catalyzed by KAT-II is theoretically determined by performing combined quantum mechanical and molecular mechanical (QM/MM) simulations. The results are instrumental to explore the catalytic properties of the enzyme and to provide theoretical details on the mechanism of the intramolecular condensation of the ketoacid intermediate, leading to the final product KYNA. Ultimately, they will also be of value in the future design of new KAT-II selective inhibitors.