Kynurenine 3-Monooxygenase: An Influential Mediator of Neuropathology.
Mounting evidence demonstrates that kynurenine metabolism may play an important pathogenic role in the development of multiple neurological and neuropsychiatric disorders. The kynurenine pathway consists of two functionally distinct branches that generate both neuroactive and oxidatively reactive metabolites. In the brain, the rate-limiting enzyme for one of these branches, kynurenine 3-monooxygenase (KMO), is predominantly expressed in microglia and has emerged as a pivotal point of metabolic regulation. KMO substrate and expression levels are upregulated by pro-inflammatory cytokines and altered by functional genetic mutations. Increased KMO metabolism results in the formation of metabolites that activate glutamate receptors and elevate oxidative stress, while recent evidence has revealed neurodevelopmental consequences of reduced KMO activity. Together, the evidence suggests that KMO is positioned at a critical metabolic junction to influence the development or trajectory of a myriad of neurological diseases. Understanding the mechanism(s) by which alterations in KMO activity are able to impair neuronal function, and viability will enhance our knowledge of related disease pathology and provide insight into novel therapeutic opportunities. This review will discuss the influence of KMO on brain kynurenine metabolism and the current understanding of molecular mechanisms by which altered KMO activity may contribute to neurodevelopment, neurodegenerative, and neuropsychiatric diseases.
Department of Pharmacology, School of Medicine, University of Texas Health Science Center at San Antonio , San Antonio, TX , USA ; Center for Biomedical Neuroscience, University of Texas Health Science Center at San Antonio , San Antonio, TX , USA.
Jennifer M
JM
Parrott
Department of Pharmacology, School of Medicine, University of Texas Health Science Center at San Antonio , San Antonio, TX , USA ; Center for Biomedical Neuroscience, University of Texas Health Science Center at San Antonio , San Antonio, TX , USA ; Mood Disorders Translational Research Core, University of Texas Health Science Center at San Antonio , San Antonio, TX , USA ; Audie L. Murphy Memorial VA Hospital, South Texas Veterans Health System , San Antonio, TX , USA.
Jason C
JC
O'Connor
kynurenine 3-monooxygenase; kynurenine pathway; microglia; neurodegenerative diseases; neurodevelopmental disorders; neuroinflammation; neuropsychiatric disorders