J. Biol. Chem., Vol. 262, Issue 26, 12583-12588, 09, 1987
Product inhibition of carboxypeptidase H
VY Hook and EF LaGamma
Carboxypeptidase H is one of several enzymes required for the processing of
peptide hormone precursors. In this study, inhibition of carboxypeptidase H
by its peptide products was investigated. Carboxypeptidase H activity in
bovine adrenal medulla chromaffin granules and rat adrenal medulla
homogenate was inhibited by the peptides Met- and Leu-enkephalin,
vasopressin, oxytocin, luteinizing hormone-releasing hormone, substance P,
and thyrotropin-releasing hormone, with oxytocin and ACTH 1-14 having the
least effect, at concentrations of 2-20 mM. Inhibition by amidated peptide
products (vasopressin, oxytocin, luteinizing hormone-releasing hormone,
substance P, and thyrotropin-releasing hormone) show that the final
products of the precursor processing pathway can regulate carboxypeptidase
H. These levels of peptides are similar to known intragranular peptide
concentrations indicating that product and feedback inhibition of
carboxypeptidase H may play a role in the control of neuropeptide
synthesis. The proenkephalin-derived peptides Met-enkephalin,
Leu-enkephalin, Met-enkephalin-Arg6-Gly7-Leu8, and Met-
enkephalin-Arg6-Phe7 competitively inhibited bovine and rat
carboxypeptidase H with Ki values of 12.0, 6.5, 7.0, and 5.5 mM,
respectively. The significantly greater Ki for Met-enkephalin may reflect
the effects of higher intragranular concentration of Met- enkephalin, since
one proenkephalin molecule contains four copies of Met-enkephalin and only
one copy of each of the other enkephalin peptides. Thus, the products from
one multivalent precursor molecule may equivalently inhibit
carboxypeptidase H activity. Product inhibition of carboxypeptidase H and
perhaps other processing enzymes may serve to limit the maximum peptide
concentration within the secretory vesicle.
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