Premium
Enzymatic transamination of d ‐kynurenine generates kynurenic acid in rat and human brain
Author(s) -
Pérezde la Cruz Veronica,
Amori Laura,
Sathyasaikumar Korrapati V.,
Wang XiaoDan,
Notarangelo Francesca M.,
Wu HuiQiu,
Schwarcz Robert
Publication year - 2012
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2012.07653.x
Subject(s) - kynurenic acid , kynurenine , transamination , quinolinic acid , kynurenine pathway , biochemistry , metabolite , microdialysis , indoleamine 2,3 dioxygenase , chemistry , biology , amino acid , extracellular , tryptophan
J. Neurochem. (2012) 120 , 1026–1035. Abstract In the mammalian brain, the α7 nicotinic and NMDA receptor antagonist kynurenic acid is synthesized by irreversible enzymatic transamination of the tryptophan metabolite l ‐kynurenine. d ‐kynurenine, too, serves as a bioprecursor of kynurenic acid in several organs including the brain, but the conversion is reportedly catalyzed through oxidative deamination by d ‐aminoacid oxidase. Using brain and liver tissue homogenates from rats and humans, and conventional incubation conditions for kynurenine aminotransferases, we show here that kynurenic acid production from d ‐kynurenine, like the more efficient kynurenic acid synthesis from l ‐kynurenine, is blocked by the aminotransferase inhibitor amino‐oxyacetic acid. In vivo, focal application of 100 μM d ‐kynurenine by reverse microdialysis led to a steady rise in extracellular kynurenic acid in the rat striatum, causing a 4‐fold elevation after 2 h. Attesting to functional significance, this increase was accompanied by a 36% reduction in extracellular dopamine. Both of these effects were duplicated by perfusion of 2 μM l ‐kynurenine. Co‐infusion of amino‐oxyacetic acid (2 mM) significantly attenuated the in vivo effects of d ‐kynurenine and essentially eliminated the effects of l ‐kynurenine. Thus, enzymatic transamination accounts in part for kynurenic acid synthesis from d ‐kynurenine in the brain. These results are discussed with regard to implications for brain physiology and pathology.