Multifunctional control of amino acids of deprivation-induced proteolysis in liver. Role of leucine.
The control of intracellular proteolysis by amino acids was investigated in rat livers perfused in the single pass mode with various mixtures at multiples of normal plasma concentrations. Twelve amino acids together exhibited no suppressive activity while the remainder (Leu, Phe, Tyr, Gln, Pro, His, Trp, and Met) were inhibitory. Because (a) the effects of phenylalanine and tyrosine were equal and nonadditive, and (b) the former is rapidly converted to the latter, tyrosine rather than phenylalanine was considered to be an active regulator. The inhibitory group, minus phenylalanine, duplicated responses of the complete mixture between 0 and 4 times (4x) normal plasma levels. When tested individually, leucine was the strongest inhibitor, suppressing deprivation-accelerated proteolysis by 63% at 4x and 10x. However, at lower concentrations its effects differed dramatically from those of the regulatory mixture in showing a sharp modal loss of responsiveness at approximately 1x, a finding which suggests that proteolytic regulation at normal levels is achieved largely by the remaining 6 amino acids. Leucine responses from 1x to 4x (0.2 to 0.8 mM) were mimicked by equimolar additions of alpha-ketoisocaproate. The fact that 0.8 mM alpha-ketoisocaproate increased intracellular leucine by only 7.8% of the value obtained with equimolar (4x) leucine supports observations of others that transamination limits interconversion between leucine and its alpha-ketoacid to 4-10% of total alpha-ketoisocaproate utilization at this level. We conclude that the effects of leucine and alpha-ketoisocaproate on hepatic proteolysis are mediated by separate pathways.
D000596:Amino Acids / Q000494:pharmacology*; D000818:Animals; D006868:Hydrolysis; D007651:Keto Acids / Q000494:pharmacology; D007930:Leucine / Q000494:pharmacology*; D008099:Liver / Q000378:metabolism*; D008297:Male; D010477:Perfusion; D010649:Phenylalanine / Q000494:pharmacology; D011506:Proteins / Q000378:metabolism*; D051381:Rats; D014443:Tyrosine / Q000494:pharmacology
D000596:Amino Acids; D007651:Keto Acids; D011506:Proteins; D014443:Tyrosine; D010649:Phenylalanine; C013082:alpha-ketoisocaproic acid; D007930:Leucine