TY - JOUR
T1 - Kynurenine 3-monooxygenase
T2 - An influential mediator of neuropathology
AU - Parrott, Jennifer M.
AU - O'Connor, Jason C.
N1 - Publisher Copyright:
© 2015 Parrott and O'Connor.
PY - 2015
Y1 - 2015
N2 - 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.
AB - 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.
KW - Kynurenine 3-monooxygenase
KW - Kynurenine pathway
KW - Microglia
KW - Neurodegenerative diseases
KW - Neurodevelopmental disorders
KW - Neuroinflammation
KW - Neuropsychiatric disorders
UR - http://www.scopus.com/inward/record.url?scp=84940498145&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84940498145&partnerID=8YFLogxK
U2 - 10.3389/fpsyt.2015.00116
DO - 10.3389/fpsyt.2015.00116
M3 - Review article
C2 - 26347662
AN - SCOPUS:84940498145
SN - 1664-0640
VL - 6
JO - Frontiers in Psychiatry
JF - Frontiers in Psychiatry
IS - AUG
M1 - 116
ER -