Regulation of the branched-chain α-ketoacid dehydrogenase and elucidation of a molecular basis for maple syrup urine disease

Robert A. Harris, Bei Zhang, Gary W. Goodwin, Martha J. Kuntz, Yoshiharu Shimomura, Paul Rougraff, Paul Dexter, Yu Zhao, Reid Gibson, David W. Crabb

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59 Scopus citations


The hepatic branched-chain α-ketoacid dehydrogenase complex plays an important role in regulating branched-chain amino acid levels. These compounds are essential for protein synthesis but toxic if present in excess. When dietary protein is deficient, the hepatic enzyme is converted to the inactive, phosphorylated state to conserve branched-chain amino acids for protein synthesis. When dietary protein is excessive, the enzyme is in the active, dephosphorylated state to commit the excess branched-chain amino acids to degradation. Inhibition of protein synthesis by cycloheximide, even when the animal is starving for dietary protein, results in activation of the hepatic branched-chain α-ketoacid dehydrogenase complex to prevent accumulation of branched-chain amino acids. Likewise, the increase in branched-chain amino acids caused by body wasting during starvation and uncontrolled diabetes is blunted by activation of the hepatic branched-chain α-ketoacid dehydrogenase complex. The activity state of the complex is regulated in the short term by the concentration of branched-chain α-ketoacids (inhibitors of branched-chain α-ketoacid dehydrogenase kinase) and in the long term by alteration in total branched-chain α-ketoacid dehydrogenase kinase activity. cDNAs have been cloned and the primary structure of the mature proteins deduced for the E1α subunit of the human and rat liver branched-chain α-ketoacid dehydrogenase complex. The cDNA and protein sequences are highly conserved for the two species. Considerable sequence similarity is also apparent between the E1α subunits of the human branched-chain α-ketoacid dehydrogenase complex and the pyruvate dehydrogenase complex. Maple syrup urine disease is caused by an inherited deficiency in the branched-chain α-ketoacid dehydrogenase complex. The molecular basis of one maple syrup urine disease family has been determined for the first time. The patient was found to be a compound heterozygote, inheriting an allele encoding an abnormal E1α from the father, and an allele which is not expressed from the mother. The only known animal model for the disease (Polled Hereford cattle) has also been characterized. The mutation in these animals introduces a stop codon in the leader peptide of the E1α subunit, resulting in premature termination of translation. Two thiamine responsive patients have been studied. The deduced amino acid sequences of the mature E1α subunit and its leader sequence were normal, suggesting that the defect in these patients must exist in some other subunit of the complex. 3-Hydroxyisobutyrate dehydrogenase and methylmalonate-semialdehyde dehydrogenase, two enzymes of the valine catabolic pathway, were purified from liver tissue and characterized. The cDNA encoding the former enzyme was cloned. Isolation of the latter enzyme establishes that methylmalonate semialdehyde can be converted directly to propionyl-CoA and the nature of previously uncertain steps in the pathway of valine catabolism in animal tissues.

Original languageEnglish (US)
Pages (from-to)245-256
Number of pages12
JournalAdvances in Enzyme Regulation
Issue numberC
StatePublished - 1990

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Cancer Research

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