Effect of phenylalanine derivatives on the main regulatory enzymes of hepatic cholesterogenesis.
Phenylalanine, phenylpyruvate and phenylacetate produced a considerable inhibition of chick liver mevalonate 5-pyrophosphate decarboxylase while mevalonate kinase and mevalonate 5-phosphate kinase were not significantly affected. Phenolic derivatives of phenylalanine produced a similar inhibition of decarboxylase activity than that found in the presence of phenyl metabolites. The degree of inhibition was progressive with increasing concentrations of inhibitors (1.25-5.00 mM). Simultaneous supplementation of different metabolites in conditions similar to those in experimental phenylketonuria (0.25 mM each) produced a clear inhibition of liver decarboxylase and 3-hydroxy-3-methylglutaryl-CoA reductase. To our knowledge, this is the first report on the in vitro inhibition of both liver regulatory enzymes of cholesterogenesis in phenylketonuria-like conditions. Our results show a lower inhibition of decarboxylase than that of reductase but suggest an important regulatory role of decarboxylase in cholesterol synthesis.
Castillo
M
M
Department of Biochemistry and Molecular Biology, University of Granada, Spain.
Martinez-Cayuela
M
M
Zafra
M F
MF
Garcia-Peregrin
E
E
D000818:Animals; D002245:Carbon Dioxide / Q000032:analysis; D002262:Carboxy-Lyases / Q000032:analysis / Q000037:antagonists & inhibitors*; D002645:Chickens; D002784:Cholesterol / Q000096:biosynthesis*; D006903:Hydroxymethylglutaryl CoA Reductases / Q000032:analysis; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008099:Liver / Q000187:drug effects* / Q000201:enzymology; D008297:Male; D008798:Mevalonic Acid / Q000378:metabolism; D010648:Phenylacetates / Q000494:pharmacology; D010649:Phenylalanine / Q000494:pharmacology*; D010667:Phenylpyruvic Acids / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects
D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D010648:Phenylacetates; D010667:Phenylpyruvic Acids; D002245:Carbon Dioxide; D010649:Phenylalanine; D002784:Cholesterol; D006903:Hydroxymethylglutaryl CoA Reductases; D002262:Carboxy-Lyases; C022503:pyrophosphomevalonate decarboxylase; C025136:phenylacetic acid; D008798:Mevalonic Acid; C031606:phenylpyruvic acid