4‐Phenyl‐3‐butenoic acid, an in vivo inhibitor of peptidylglycine hydroxylase (peptide amidating enzyme)

Alan F. BRADBURY, Jashu MISTRY, Bernard A. ROOS, Derek G. SMYTH

Research output: Contribution to journalArticlepeer-review

46 Scopus citations


The ability of a series of non-peptide carboxylic acids to act as substrates or inhibitors of the peptide-amidating enzyme (peptidyl-glycine hydroxylase) was assessed by determining their ability to reduce the rate of enzymic conversion of D-tyrosyl-valyl-glycine or D-tyrosyl-phenylalanyl-glycine to the corresponding dipeptide amide. The inclusion of a phenyl substituent in a position distal to the carboxyl group promoted the inhibitory action. The inhibition was found to be irreversible when an olefinic double bond, α or β to the carboxyl group, was present in the molecule; the inhibition appeared to be associated with a covalent interaction between the amidating enzyme and the inhibitor. With 4-phenyl-3-butenoic acid the inhibitory properties were manifest only in the presence of cofactros of the enzyme. When 4-phenyl-3-[2-14C]butenoic acid was used, the radioactivity was shown to be incorporated into protein that co-chromatographed with active enzyme. Incubation of rat thyroid carcinoma CA77 cells in the presence of 4-phenyl-3-butenoic acid led to a decrease in the levels of intracellular amidating activity and of thyrotropin-releasing hormone, an amidated peptide produced by these cells. The inhibitory effects reached a maximum at approximately 15 h after which the enzyme levels returned to the control values even though the concentration of 4-phenyl-3-butenoic acid in the cells remained unchanged. The results indicate that a mechanism exists in these cells for regulation of amidating activity.

Original languageEnglish (US)
Pages (from-to)363-368
Number of pages6
JournalEuropean Journal of Biochemistry
Issue number2
StatePublished - Apr 1990

ASJC Scopus subject areas

  • Biochemistry


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