%0 Journal Article
%T Quinolinic Acid: An Endogenous Neurotoxin with Multiple Targets
%A Rafael Lugo-Huitr¨®n
%A Perla Ugalde Mu£¿iz
%A Benjamin Pineda
%A Jos¨¦ Pedraza-Chaverr¨ª
%A Camilo R¨ªos
%A Ver¨®nica P¨¦rez-de la Cruz
%J Oxidative Medicine and Cellular Longevity
%D 2013
%I Hindawi Publishing Corporation
%R 10.1155/2013/104024
%X Quinolinic acid (QUIN), a neuroactive metabolite of the kynurenine pathway, is normally presented in nanomolar concentrations in human brain and cerebrospinal fluid (CSF) and is often implicated in the pathogenesis of a variety of human neurological diseases. QUIN is an agonist of N-methyl-D-aspartate (NMDA) receptor, and it has a high in vivo potency as an excitotoxin. In fact, although QUIN has an uptake system, its neuronal degradation enzyme is rapidly saturated, and the rest of extracellular QUIN can continue stimulating the NMDA receptor. However, its toxicity cannot be fully explained by its activation of NMDA receptors it is likely that additional mechanisms may also be involved. In this review we describe some of the most relevant targets of QUIN neurotoxicity which involves presynaptic receptors, energetic dysfunction, oxidative stress, transcription factors, cytoskeletal disruption, behavior alterations, and cell death. 1. Biosynthesis of Quinolinic Acid (QUIN) Tryptophan (TRP) is an essential amino acid that has various important biological functions. In mammals, about 90% of dietary TRP is metabolized along the kynurenine pathway (KP) (Figure 1) [1, 2], which represents the major catabolic route of TRP and a source of nicotinamide adenine nucleotide (NAD+), a cofactor in cellular respiration and energy production that plays an important role in the DNA repair and transcriptional regulation [3, 4]. In recent years, the KP has been studied given that it contains metabolites with neuroactive and redox properties. An imbalance in the levels of some metabolites of this pathway has been involved in different pathologies. Figure 1: Kynurenine pathway. NAD += nicotinamide adenine dinucleotide. The first regulatory step of the KP is the oxidative cleavage of the TRP by tryptophan 2,3-dioxygenase and indolamine 2,3-dioxygenases 1 and 2 (IDO-1 and IDO-2). The product of this cleavage is formylkynurenine, which is hydrolyzed by a formamidase enzyme to give kynurenine (KYN). This metabolite is at a branch point in the pathway and can be further metabolized by three different enzymes: (1) kynureninase, which catalyzes the conversion of KYN to anthranilic acid (AA), (2) kynurenine aminotransferases I, II and III, which catalyze the transamination of KYN to form kynurenic acid (KYNA), and (3) kynurenine 3-hydroxylase, which produces 3-hydroxykynurenine (3-HK) from L-KYN. This branch is the most important route for QUIN synthesis, and it is known that this enzyme has the highest affinity for L-KYN, suggesting that under normal conditions, it metabolizes
%U http://www.hindawi.com/journals/omcl/2013/104024/