Parallel control of hepatic proteolysis by phenylalanine and phenylpyruvate through independent inhibitory sites at the plasma membrane.
Intracellular protein degradation in the rat hepatocyte is regulated by 7 amino acids of which Leu, Gln, and Tyr play major roles. Although Phe is known to inhibit proteolysis as effectively as Tyr at high concentrations, it has not been regarded as an active regulator because of its rapid hydroxylation to Tyr. We now show that proteolytic responses to Phe during liver perfusion differ strikingly from effects of the multiphasic regulators Leu, Gln, and Tyr in eliciting mirror image responses at half-normal and normal plasma concentrations. Since response curves to phenylpyruvate and Phe were identical, we considered the possibility that phenylpyruvate mediated its anomalous inhibition intracellularly. However, when phenylpyruvate was produced from phenyllactate intracellularly at a rate providing the same rate of transamination (and intracellular concentration) as that derived from the uptake of phenylpyruvate, no response was obtained. Hence, the effect of phenylpyruvate was not initiated within the cell but more likely from the plasma membrane. Comparable evidence for Phe is less direct. Recent findings indicate that recognition sites for Leu and Gln are located at the plasma membrane. Since Phe augments the concerted inhibition by Leu and Gln at 4-fold normal levels, Phe is probably recognized in close proximity to them. However, the failure of phenylpyruvate to substitute for Phe in this interaction suggests that proteolytic inhibition by phenylpyruvate and Phe is mediated through similar, although independent, plasma membrane sites.
Kadowaki
M
M
Department of Cellular and Molecular Physiology, College of Medicine, Pennsylvania State University, Hershey 17033.
Pösö
A R
AR
Mortimore
G E
GE
D000818:Animals; D002462:Cell Membrane / Q000378:metabolism; D008099:Liver / Q000378:metabolism*; D010649:Phenylalanine / Q000378:metabolism*; D010667:Phenylpyruvic Acids / Q000378:metabolism*; D011506:Proteins / Q000378:metabolism*; D051381:Rats; D011917:Rats, Inbred Lew; D014443:Tyrosine / Q000378:metabolism
D010667:Phenylpyruvic Acids; D011506:Proteins; D014443:Tyrosine; D010649:Phenylalanine; C031606:phenylpyruvic acid