Regulation of aminotransferase-glutamate dehydrogenase interactions by carbamyl phosphate synthase-I, Mg2+ plus leucine versus citrate and malate.
Citrate, malate, and high levels of ATP dissociate the mitochondrial aspartate aminotransferase-glutamate dehydrogenase complex and have an inhibitory effect on the latter enzyme. These effects are opposed by Mg2+, leucine, Mg2+ plus ATP, and carbamyl phosphate synthase-I. In addition, Mg2+ directly facilitates formation of a complex between glutamate dehydrogenase and the aminotransferase and displaces the aminotransferase from the inner mitochondrial membrane which could enable it to interact with glutamate dehydrogenase in the matrix. Zn2+ also favors an aminotransferase-glutamate dehydrogenase complex. It, however, is a potent inhibitor of and has a high affinity for glutamate dehydrogenase. Leucine, however, enhances binding of Mg2+ and decreases binding of and the effect of Zn2+ on the enzyme. Thus, since both metal ions enhance enzyme-enzyme interaction and Zn2+ is a more potent inhibitor, the addition of leucine in the presence of both metal ions results in activation of glutamate dehydrogenase without disruption of the enzyme-enzyme complex. Furthermore, the combination of leucine plus Mg2+ produces slightly more activation than leucine alone. These results indicate that leucine, carbamyl phosphate synthase-I, and its substrate and cofactor, ATP and Mg2+, operate synergistically to facilitate glutamate dehydrogenase activity and interaction between this enzyme and the aminotransferase. Alternatively, Krebs cycle intermediates, such as citrate and malate, have opposing effects.
D000255:Adenosine Triphosphate / Q000494:pharmacology; D000818:Animals; D001219:Aspartate Aminotransferases / Q000378:metabolism*; D002222:Carbamoyl-Phosphate Synthase (Ammonia) / Q000494:pharmacology*; D002951:Citrates / Q000494:pharmacology; D019343:Citric Acid; D005969:Glutamate Dehydrogenase / Q000378:metabolism*; D066298:In Vitro Techniques; D007425:Intracellular Membranes / Q000378:metabolism; D007930:Leucine / Q000494:pharmacology; D008025:Ligases / Q000494:pharmacology*; D008274:Magnesium / Q000494:pharmacology; D008293:Malates / Q000494:pharmacology; D008930:Mitochondria, Liver / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D015032:Zinc / Q000494:pharmacology
D002951:Citrates; D008293:Malates; D019343:Citric Acid; C030298:malic acid; D000255:Adenosine Triphosphate; D005969:Glutamate Dehydrogenase; D001219:Aspartate Aminotransferases; D008025:Ligases; D002222:Carbamoyl-Phosphate Synthase (Ammonia); D007930:Leucine; D008274:Magnesium; D015032:Zinc