Mechanisms responsible for regulation of branched-chain amino acid catabolism

  • Harris R
  • Joshi M
  • Jeoung N
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Abstract

The branched-chain amino acids (BCAAs) are essential amino acids and therefore must be continuously available for protein synthesis. However, BCAAs are toxic at high concentrations as evidenced by maple syrup urine disease (MSUD), which explains why animals have such an efficient oxidative mechanism for their disposal. Nevertheless, it is clear that leucine is special among the BCAAs. Leucine promotes global protein synthesis by signaling an increase in translation, promotes insulin release, and inhibits autophagic protein degradation. However, leucine's effects are self-limiting because leucine promotes its own disposal by an oxidative pathway, thereby terminating its positive effects on body protein accretion. A strong case can therefore be made that the proper leucine concentration in the various compartments of the body is critically important for maintaining body protein levels beyond simply the need of this essential amino acid for protein synthesis. The goal of the work of this laboratory is to establish the importance of regulation of the branched chain alpha-ketoacid dehydrogenase complex (BCKDC) to growth and maintenance of body protein. We hypothesize that proper regulation of the activity state of BCKDC by way of its kinase (BDK) and its phosphatase (BDP) is critically important for body growth, tissue repair, and maintenance of body protein. We believe that growth and protection of body protein during illness and stress will be improved by therapeutic control of BCKDC activity. We also believe that it is possible that the negative effects of some drugs (PPARalpha ligands) and dietary supplements (medium chain fatty acids) on growth and body protein maintenance can be countered by therapeutic control of BCDKC activity. 2003 Elsevier Inc. All rights reserved.

Author-supplied keywords

  • 2 oxoisovalerate dehydrogenase (lipoamide)/ec [End
  • S6 kinase/ec [Endogenous Compound]
  • autophagy
  • binding protein/ec [Endogenous Compound]
  • body growth
  • branched chain amino acid
  • cachexia/et [Etiology]
  • cardiomyopathy
  • carnitine
  • clofibrate/to [Drug Toxicity]
  • clofibric acid/to [Drug Toxicity]
  • conference paper
  • diet supplementation
  • elongation factor 2
  • elongation factor 2 kinase/ec [Endogenous Compound
  • enzyme activation
  • enzyme activity
  • enzyme binding
  • enzyme inhibition
  • enzyme regulation
  • essential amino acid
  • fatty acid oxidation
  • glucocorticoid/to [Drug Toxicity]
  • growth disorder/et [Etiology]
  • human
  • initiation factor 2/ec [Endogenous Compound]
  • initiation factor 2alpha/ec [Endogenous Compound]
  • initiation factor 4E/ec [Endogenous Compound]
  • initiation factor 4G/ec [Endogenous Compound]
  • insulin release
  • isoleucine
  • leucine
  • lipid storage
  • liver
  • medium chain fatty acid
  • muscle atrophy/et [Etiology]
  • muscle protein/ec [Endogenous Compound]
  • muscle weakness
  • nonhuman
  • octanoic acid/to [Drug Toxicity]
  • oxidation
  • peroxisome proliferator activated receptor alpha
  • phosphatase/ec [Endogenous Compound]
  • phosphotransferase
  • priority journal
  • protein blood level
  • protein deficiency
  • protein degradation
  • protein dephosphorylation
  • protein expression
  • protein kinase/ec [Endogenous Compound]
  • protein localization
  • protein phosphorylation
  • protein protein interaction
  • protein synthesis
  • pyruvate carboxylase/ec [Endogenous Compound]
  • rhabdomyolysis
  • sepsis
  • signal transduction
  • skeletal muscle
  • stunting syndrome/et [Etiology]
  • target of rapamycin kinase/ec [Endogenous Compound
  • thyroid hormone/pd [Pharmacology]
  • tissue repair
  • transfer RNA/ec [Endogenous Compound]
  • translation initiation
  • unclassified drug
  • uremia
  • valine
  • weight gain

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Authors

  • R A Harris

  • M Joshi

  • N H Jeoung

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