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Department of Cellular and Molecular Physiology, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033
Previous studies indicated that amino acids may activate the
protein kinase activity of the target of rapamycin (TOR) and thereby
augment and/or mimic the effects of insulin on protein synthesis, p70S6k phosphorylation,
and multicellular clustering in adipocytes. To identify the individual
amino acids responsible for these effects, the present study focused on
the TOR substrate and translational repressor 4E-BP1. A complete
mixture of amino acids stimulated the phosphorylation of 4E-BP1,
decreasing its association with eukaryotic initiation factor eIF-4E.
Studies on subsets of amino acids and individual amino acids showed
that L-leucine was the amino
acid responsible for most of the effects on 4E-BP1 phosphorylation; however, the presence of other amino acids was required to observe a
maximal effect. The stimulatory effect of leucine was stereospecific and not mimicked by other branched chain amino acids but was mimicked by the leucine metabolite 
-ketoisocaproate (-KIC). The effect of
-KIC, but not leucine, was attenuated by the transaminase inhibitor
(aminooxy)acetate. The latter result indicates that the effects of
-KIC required its conversion to leucine. Half-maximal stimulation of
4E-BP1 phosphorylation occurred at ~430 µM; therefore, the response
was linear within the range of circulating concentrations of leucine
found in various nutritional states.
target of rapamycin; eukaryotic initiation factor 4E; -ketoisocaproic acid; multicellular clustering; metabolic
regulation; protein synthesis; (aminooxy)acetic acid
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