Abstract
Under normal physiological conditions, the kynurenine pathway (KP) plays a critical role in generating cellular energy and catabolizing tryptophan. Under inflammatory conditions, however, there is an upregulation of the KP enzymes, particularly kynurenine 3-monooxygenase (KMO). KMO has garnered much attention due to its production of toxic metabolites that have been implicated in many diseases and disorders. With many of these illnesses having an inadequate or modest treatment, there exists a need to develop KMO inhibitors that reduce the production of these toxic metabolites. Though prior efforts to find an appropriate KMO inhibitor were unpromising, the development of a KMO crystal structure has provided the opportunity for a rational structure-based design in the development of inhibitors. Therefore, the purpose of this review is to describe the kynurenine pathway, the kynurenine 3-monooxygenase enzyme, and KMO inhibitors and their potential candidacy for clinical use.
Highlights
kynurenic acid (KynA) is a known neuroprotective agent which has been attributed to nicotinic acetylcholine receptor binding as well as antagonistic effects through N-methyl D-aspartate (NMDA), amino-3-hydroxy-5- methyl-4-isoxazole propionic acid (AMPA), and kainite receptor binding [2,3,4]
Their findings may be summarized as: the crystal structure was solved to a resolution of 2.1 Å after engineering the deletion mutant hKMO-374, in which the transmembrane domains or TMDs were deleted in order to obtain a human kynurenine 3-monooxygenase (KMO) protein suitable for crystallization
Of major interest are the metabolites stemming for KMO, the pivotal enzyme of the kynurenine pathway
Summary
One research stratagem has focused on the inhibition of key enzymes in the KP to shunt it towards a neuroprotective state This idea is based on the assumption that kynurenic acid (KYNA) has neuroprotective abilities. Though effects mediated by this process remain to be investigated, studies have shown that KYNA selectively binds to a G-protein-coupled receptor, GPR35, leading to its activation. It was shown that patients with schizophrenia presented with elevated kynurenic acid levels in the cerebral spinal fluid [15]. This discovery provided new insights in that KYNA has possible effects on the glutamatergic and dopaminergic systems and could play a potential role in the pathogenesis of schizophrenia. Kynurenic acid appears to be a metabolite of the kynurenine pathway that warrants further investigation in disease prevention
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