J. Biol. Chem., Vol. 260, Issue 10, 6069-6079, 05, 1985
Regulation of aminotransferase-glutamate dehydrogenase interactions by carbamyl phosphate synthase-I, Mg2+ plus leucine versus citrate and malate
LA Fahien, EH Kmiotek, G Woldegiorgis, M Evenson, E Shrago and M Marshall
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.
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