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Studies on the regulation of leucine catabolism

1980; Elsevier BV; Volume: 12; Issue: 1 Linguagem: Inglês

10.1016/0022-2828(80)90107-8

1095-8584

Ronald M. Sans, Walter W. Jolly, Robert A. Harris,

Amino Acid Enzymes and Metabolism

The effect of dichloroacetate, an activator of pyruvate dehydrogenase and a hypoglycemic agent, on the oxidation of leucine by the perfused rat heart was studied. Dichloroacetate is known to promote leucine oxidation by liver with the mechanism involving dichloroacetate conversion to glyoxylate which acts as a substrate for leucine transamination [10]. Dichloroacetate also promotes leucine oxidation by heart, but unlike liver, the site is at the α-ketoisocaproate dehydrogenase step. This conclusion is based on the observation that dichloroacetate increases l-[1-14C]leucine oxidation to 14CO2 but decreases the steady state concentration of α-ketoisocaproate. It also increases the oxidation of [1-14C]-ketoisocaproate but not that of [1-14C]isovalerate. 2-Chloropropionate, another activator of pyruvate dehydrogenase, also stimulates leucine oxidation in the heart. Since 2-chloropropionate is not converted to glyoxylate, it follows that activation of leucine oxidation in the heart by these activators of pyruvate dehydrogenase is not explained by glyoxylate formation. Pyruvate is a very effective inhibitor of α-ketoisocaproate oxidation by the perfused rat heart. Activation of the pyruvate dehydrogenase complex by dichloroacetate lowers the pyruvate content of glucose-perfused hearts and this appears to relieve the pyruvate-mediated inhibition of α-ketoisocaproate oxidation. The exact basis for pyruvate inhibition of α-ketoisocaproate oxidation remains to be established.