Studies on the regulation of leucine catabolism. II. Mechanism responsible for dichloroacetate stimulation of leucine oxidation by the liver

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Abstract

Dichloroacetate, an activator of the pyruvate dehydrogenase complex and a hypoglycemic agent, activates leucine oxidation by isolated liver cells. The α-ketoisocaproate dehydrogenase complex, which catalyzes the second step of leucine catabolism and is believed analogous to the pyruvate dehydrogenase complex, did not respond to dichloroacetate. Rather, dechlorination of dichloroacetate by liver cells produces glyoxylate which promotes leucine catabolism by serving as an amino group acceptor for either direct or indirect transamination of leucine. Support for this mechanism includes the following: (a) amino acids which serve as substrates for glyoxylate aminotransferase block the stimulatory effect of dichloroacetate on leucine oxidation; (b) glyoxylate stimulates the oxidation of leucine; (c) both dichloroacetate and glyoxylate increase the glycine content of isolated hepatocytes; (d) [2-14C]dichloroacetate is converted by isolated hepatocytes to [14C]glycine, [14C]oxalate, and 14CO2; (e) 2-chloropropionate, which also activates the pyruvate dehydrogenase complex but is not converted to glyoxylate, does not stimulate leucine oxidation; and (f) ethylene glycol, another compound known to be converted to glyoxylate by the liver, also stimulates leucine oxidation. Thus, in contrast to its mechanism of action on pyruvate metabolism, dichloroacetate promotes leucine catabolism by formation of glyoxylate which serves as substrate for the transamination of leucine by glyoxylate aminotransferase.

Original languageEnglish (US)
Pages (from-to)8-16
Number of pages9
JournalArchives of Biochemistry and Biophysics
Volume190
Issue number1
DOIs
StatePublished - Sep 1978

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry
  • Molecular Biology

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