Developmental Changes in the Enzymatic Capacity for Reduction and Oxidation of α-Ketoadipate in Rat Liver, Heart, Kidney, and Brain

Abstract

Summary a-Ketoadipate, an intermediate common to lysine and tryptophan metabolism, is a substrate for both a-ketoadipate reductase (a-KAR) and a-ketoadipate dehydrogenase (a-KADH). A comparison was made of the activities of these two enzymes in liver, heart, kidney, and brain of rats during the period from 5 days before birth to 56 days after birth. In general, both enzymes increased in activity during development in all tissues tested; however, different patterns of increase were observed ( Figs. 1 and 2).The ratio of a-KADH to a-KAR (on the basis of activitylg tissue) did not change significantly in liver until day 10 and then increased 6.6-fold (from 0.08 to 0.53) in the period from day 1 0 to day 28. For other tissues the ratios increased 5.5-fold in hearts (from 0.2 to 1.1), 12-fold in kidney (from 0.2 to 2.4), and 5.3-fold in brain (from 0.3 to 1.6) during the period from day -5 to day 56.These results suggest that a-KAR has a major role in the metabolism of lysine and tryptophan during development. SpeculationIn the late fetal stage, the metabolism of a-ketoadipate depends more on reduction to a-hydroxyadipate than on oxidation to glutaryl-CoA; as development progresses there is a shift to a greater dependence on the oxidative reaction. If an analogouspattern isiresent in human development, then a-ketoadii ate metabolism in the developing individual with a-ketoadipic iciduria would remain simila; to-that of the fetal period, i n d this might explain the abnormal accumulation not only of aketoadipate but also of a-hydroxyadipate found in these individuals.The degradative route for lysine in mammals has been shown to join that of tryptophan at a-ketoadipate. a-Ketoadipate is believed then to undergo an oxidative decarboxylation to yield glutaryl-CoA and CO, (2,13,14). The enzyme catalyzing this decarboxylation is only tentatively referred to as a-ketoadipate dehydrogenase (a-KADH) because a highly purified a-ketoglutarate dehydrogenase complex has also been reported to catalyze this reaction (7,9,14). We have recently described the purification and characterization (23), as well as the subcellular localization and tissue distribution (24), of an enzyme designated a-ketoadipate reductase (a-KAR), which specifically mediates the NADH-dependent reduction of a-ketoadipate to ahydroxyadipate.Recent papers have described several human metabolic defects that involve the degradation of a-ketoadipate: a-ketoadipic aciduria (18,25,26), glutaric aciduria (5, 6, 22), and glutaric aciduria type I1 (19). An individual with a-ketoadipic aciduria, apparently resulting from a defect in the decarboxylation of aketoadipate, was reported to have increased urinary excretion not only of a-ketoadipate but also of a-hydroxyadipate (17, 25); these findings suggest the r~ssibility of an alternate route of a-ketoadipate degradation (Scrieme 1).We reported previously that a-KAR has a dominant metabolic role in tissues that have a relatively low density of mitochondria and that a-KADH has a dominant metabolic role in tissues that have ...

Large-Scale Modeling Approach Reveals Functional Metabolic Shifts during Hepatic Differentiation

“…The essential amino acid tryptophan is mainly metabolized in the liver through the kynurenine pathway, which accounts for about 95% of its degradation in normal physiological conditions . The prediction of the activation of this pathway in mature hepatocytes is consistent with the observation of the increased activity of enzymes involved in this pathway during the development in rat liver . Conversely, the activity of the extracellular transport pathway and of the FA synthesis pathway was predicted to be lower in 30-day HepaRG cells (Table ).…”

“…41 The prediction of the activation of this pathway in mature hepatocytes is consistent with the observation of the increased activity of enzymes involved in this pathway during the development in rat liver. 42 Conversely, the activity of the extracellular transport pathway and of the FA synthesis pathway was predicted to be lower in 30-day HepaRG cells (Table 1). Our results therefore suggest a shift in the metabolism of FAs with a decrease in the FA synthesis and a concomitant increase in FA oxidation in differentiated cells.…”