Organ Correlation with Tryptophan Metabolism Obtained by Analyses of TDO-KO and QPRT-KO Mice

Abstract

The aim of this article is to report the organ-specific correlation with tryptophan (Trp) metabolism obtained by analyses of tryptophan 2,3-dioxygenase knockout (TDO-KO) and quinolinic acid phosphoribosyltransferase knockout (QPRT-KO) mice models. We found that TDO-KO mice could biosynthesize the necessary amount of nicotinamide (Nam) from Trp, resulting in the production of key intermediate, 3-hydroxyanthranilic acid. Upstream metabolites, such as kynurenic acid and xanthurenic acid, in the urine were originated from nonhepatic tissues, and not from the liver. In QPRT-KO mice, the Trp to quinolinic acid conversion ratio was 6%; this value was higher than expected. Furthermore, we found that QPRT activity in hetero mice was half of that in wild-type (WT) mice. Urine quinolinic acid levels remain unchanged in both hetero and WT mice, and the conversion ratio of Trp to Nam was also unaffected. Collectively, these findings show that QPRT was not the rate-limiting enzyme in the conversion. In conclusion, the limiting factors in the conversion of Trp to Nam are the substrate amounts of 3-hydroxyanthranilic acid and activity of 3-hydroxyanthranilic acid 3,4-dioxygenase in the liver.

Simultaneous determination of tryptophan and its 31 catabolites in mouse tissues by polarity switching UHPLC-SRM-MS

“…We observed that the catabolites in indole pathway such as IND, 3MI, 3IS were highly produced in ileal contents, whereas those were rarely expressed in other tissues. The end-product of KP such as NA, QA, NAm and PA were highly accumulated in liver which is consistent with previous findings [49, 50]. The high production of the early catabolites of TRP such as TRM and KYN in ileum tissue could be due to rapid digestion of dietary TRP by IDO and AADC.…”

Anti-apoptotic quinolinate phosphoribosyltransferase ( QPRT ) is a target gene of Wilms' tumor gene 1 (WT1) protein in leukemic cells

“…Perhaps surprisingly therefore, we found no indication that the resistance to imatinib correlated to NAD+ levels. The lack of effect on NAD+ levels is, however, consistent with a recent report with heterozygous and homozygous QPRT knock-out mice, indicating that QPRT may not be rate-limiting for NAD-synthesis (45). Quite apart from its enzymatic effect on NAD+ production, QPRT may have additional pro-survival mechanisms.…”

Organ Co-Relationship in Tryptophan Metabolism and Factors That Govern the Biosynthesis of Nicotinamide from Tryptophan

“…We investigated the distribution of enzymes involved in the Trp-Nam metabolism. As a result, 3-HADO was found only in the liver and in small amounts in the kidneys, but was not detected in nonhepatic tissues (23). Therefore, 3-HA is an end product of the Trp degradation pathway in non-hepatic tissues.…”

“…These findings also indicate that QPRT was not the rate-limiting enzyme in the Trp→Nam conversion. Figure 2 shows the organ correlation of Trp-Nam metabolism in wild mice (23). The fi rst enzyme in Trp degradation by the liver is TDO.…”