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Alpha-ketoadipic aciduria, a new inborn error of lysine metabolism; biochemical studies.

Investigation of a psychomotorically retarded girl showed excretion of abnormal amounts of alpha-ketoadipic acid, alpha-hydroxyadipic acid, alpha-aminoadipic acid, 1,2-butenedicarboxylic acid and elevation of plasma alpha-aminoadipic acid levels. The identity of these metabolities was established by various methods. The excretion of alpha-aminoadipic acid correlated to the lysine intake. Degradation studies with cultured fibroblasts indicate a defect in the oxidative decarboxylation of alpha-ketoadipic acid (see Clin. Chim. Acta, 58 (1975) 271.

Adipates↗

Alpha-ketoadipic aciduria: degradation studies with fibroblasts,.

Observation of one patient with alpha-ketoadipic aciduria initiated degradation studies with radiolabelled lysine metabolites in fibroblasts in order to localise the metabolic defect. Liberation of 14-CO-2 from alpha-D,L-(1-14-C) aminoadipate and alpha-(1-14-C) ketoadipate was considerably less in the patient's fibroblasts than in the patient's fibroblasts than in normal controls, whereas 14-CO-2 production from (1,5-14-C) glutarate was in the normal range. These results indicate a defect in the oxidative decarboxylation of alpha-ketoadipate as the probable cause of alpha-ketoadipic aciduria; Cultured amniotic fluid cells from pregnancies of the 15th and 16th week of gestation degrade alpha-(1-14-C) ketoadipate with a similar activity to fibroblast cultures from normal humans after birth.

Adipates↗

In vivo studies on the metabolism of hexanedioic acid.

1. Using the combined gas-liquid chromatography-mass spectrometry technique it was shown that ketotic patients excreted up to 273 mg of hexanedioic acid daily in their urine, whereas serum samples from these patients contained only trace amounts of this acid. Healthy humans excreted 2-5 mg daily. Hexanedioic acid was not detectable in normal serum. 2. An experiment with the infusion of large amounts of 3-hydroxybutyrate into a dog indicated that the increased urinary hexanedioic acid excretion in ketosis is not due to a competition between 3-hydroxybutyrate and hexanedioic acid for the same renal reabsorption mechanism. 3. [ 1,6-14-C]Hexanedioic acid intravenously injected into a dog was at first distributed in the extracellular space, followed by a partial equilibration with the intracellular space. About 11% of the injected dose was expired as 14-CO2 in 220 min. The maximal 14-CO2 production rate was obtained after about 20 min. In 240 min, 47% of the injected radioactivity was recovered in the urine. The large urinary excretion of labeled hexanedioic acid observed in the presence of only trace amounts in serum, showed that the high excretion by ketotic patients of the dicarboxylic acid may be explained without postulating an exclusive renal synthesis for hexanedioic acid.

Adipates↗

Inactivation of alpha-ketoglutarate dehydrogenase during oxidative decarboxylation of alpha-ketoadipic acid.

alpha-Ketoglutarate dehydrogenase was inactivated irreversibly and completely during oxidation of alpha-ketoadipic acid. The inactivation was revealed both in the model system with ferricyanide and in the overall reaction catalyzed by the alpha-ketoglutarate dehydrogenase complex. Neither substrate depletion nor product accumulation induced the inactivation. The results obtained were compared with recent data on the enzyme inactivation during oxidation of alpha-ketoglutaric acid. The differences in the inactivation kinetics observed with the two substrates of the enzyme were analyzed. They seem not to reflect the different mechanisms of the inactivation, but, rather, depend on the changes in the rates of the individual stages of the process.

Adipates↗

Synthesis, spectroscopic, cytotoxic, and DNA binding studies of binuclear 2,2'-bipyridine-platinum(II) and -palladium(II) complexes of meso-alpha,alpha'-diaminoadipic and meso-alpha,alpha'-diaminosuberic acids.

Four new binuclear complexes of formula [M2(bipy)2(BAA)]Cl2 (where M is Pt(II) or Pd(II), bipy is 2,2'-bipyridine, and BAA is a dianion of meso-alpha-alpha'-diaminoadipic acid (DAA) or meso-alpha,alpha'-diaminosuberic acid (DSA) have been synthesized. These complexes have been characterized by chemical analysis and ultraviolet-visible, infrared, and 1H NMR spectroscopy. The mode of binding of ligands in these complexes has been ascertained by infrared and detailed 1H NMR spectroscopy. These complexes are 1:2 electrolyte in conductivity water. They have also been tested against P388 lymphocytic leukemia cells and their target is DNA molecules. [Pt2(bipy)2(DSA)]Cl2, [Pd2(bipy)2(DSA)Cl2, and [Pd2(bipy)2(DAA)]Cl2 show I.D.50 values comparable or lower than cis-diamminedichloroplatinum(II) and [Pt(bipy)(Ala)]Cl. In addition, binding studies of [Pt2(bipy)2(DSA)]Cl2 and [Pd2(bipy)2(DAA)]Cl2 to calf thymus DNA have been carried out and the mode of binding seems to be hydrogen bonding, as suggested earlier for analogous mononuclear amino acid-DNA complexes.

Adipates↗