Genetic alterations affecting the kynurenine pathway and their association with diseases

Publication date: Available online 14 March 2018
Source:Mutation Research/Reviews in Mutation Research
Author(s): Fanni Boros, Zsuzsanna Bohár, László Vécsei
Tryptophan is metabolized primarily via the kynurenine pathway (KP). The KP involves several enzymes, including indoleamine 2,3-dioxygenase, tryptophan 2,3 dioxygenase (TDO2), kynurenine aminotransferases (KATs), kynurenine monooxigenase (KMO) etc. The majority of metabolites are neuroactive, some of them such as kynurenic acid show neuroprotective effects, while others, for example 3-hydroxy-L-kynurenine and quinolinic acid contribute to free radical production, leading to neurodegeneration. Impaired balance of the pathway is assumed to participate in the development of several diseases such as Parkinson's disease, Huntington's disease, Alzheimer's disease, psychiatric disorders, migraine and multiple sclerosis.The aim of this review is to summarize available literature data on genetic alterations of the KP, leading to disturbances of the pathway that can be related to different diseases.To achieve this goal, literature search was executed regarding the genetic alterations of enzymes related to the KP until April 2017 based on PubMed.Several genetic alterations of the KP were found, and suggested to be associated with diseases. Polymorphisms of the TDO2 gene can be associated with autism; KATII polymorphisms affect the immune response of patients with bacterial meningitis, mutations of the KMO gene can be associated with multiple sclerosis and cognitive functions in schizophrenia, just to mention a few.To our knowledge, this is the first comprehensive review of the genetic alterations of the KP enzymes. This work can promote the understanding of the mechanisms underlying the connected diseases, and might facilitate medicinal chemistry approaches to substitute missing components or correct the disturbed metabolite balance of KP.



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