Abstract
Summary: α-Ketoadipate, an intermediate common to lysine and tryptophan metabolism, is a substrate for both α-ketoadipate reductase (α-KAR) and α-ketoadipate dehydrogenase (α-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 α-KADH to α-KAR (on the basis of activity/g 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 10 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 α-KAR has a major role in the metabolism of lysine and tryptophan during development.
Speculation: In the late fetal stage, the metabolism of α-ketoadipate depends more on reduction to α-hydroxyadipate than on oxidation to glutaryl-CoA; as development progresses there is a shift to a greater dependence on the oxidative reaction. If an analogous pattern is present in human development, then a-ketoadipate metabolism in the developing individual with α-ketoadipic aciduria would remain similar to that of the fetal period, and this might explain the abnormal accumulation not only of α-ketoadipate but also of α-hydroxyadipate found in these individuals.
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Suda, T., Robinson, J. & Fjellstedt, T. Developmental Changes in the Enzymatic Capacity for Reduction and Oxidation of α-Ketoadipate in Rat Liver, Heart, Kidney, and Brain. Pediatr Res 12, 297–300 (1978). https://doi.org/10.1203/00006450-197804000-00010
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DOI: https://doi.org/10.1203/00006450-197804000-00010