Role of d-amino acid oxidase in the production of kynurenine pathway metabolites from d-tryptophan in mice.

ABSTRACT

The kynurenine pathway (KP), the major catabolic route of the essential amino acid l-tryptophan (l-TRP), contains several neuroactive compounds, including kynurenic acid, 3-hydroxykynurenine (3-HK), and quinolinic acid (QUIN). The role of the d-enantiomer (d-TRP) in KP metabolism has received little attention so far. d-TRP can be converted to l-TRP by d-amino acid oxidase, and the same enzyme can produce d-kynurenine, a known bioprecursor of KYNA. To analyze these complex metabolic events systematically in vivo, we injected mice with d-TRP (300 mg/kg, i.p.) and examined KP metabolism in the absence or presence of the d-amino acid oxidase inhibitor 3-methylpyrazole-5-carboxylic acid (MPC; 100 mg/kg, i.p.,). After 90 min, newly formed l-TRP was recovered in plasma, liver, forebrain, and cerebellum, and MPC prevented its neosynthesis in all tissues. In the same animals, de novo production of d-kynurenine from d-TRP was also observed, but was much higher in the periphery than in the brain. d-TRP administration raised KYNA, 3-HK, and QUIN levels in all tissues examined, and KYNA production from d-TRP was significantly reduced after pre-treatment with MPC. These results indicate that catabolic routes other than those classically ascribed to l-TRP and l-kynurenine can account for the synthesis of KYNA, 3-HK and QUINin vivo. The essential amino acid l-tryptophan is catabolized via the kynurenine pathway (KP). We explored the role of the d-enantiomer in KP metabolism in mice in vivo. We report that d-tryptophan is metabolized in both brain and periphery and converted to KP metabolites, including d-kynurenine and l-kynurenine, kynurenic acid, 3-hydroxykynurenine, and quinolinic acid. Pharmacological experiments confirm the involvement of d-amino acid oxidase in these processes. Our results indicate that this enzyme participates in the synthesis of KP metabolites from d-tryptophan.