Processing and metabolism of peptide-YY: pivotal roles of dipeptidylpeptidase-IV, aminopeptidase-P, and endopeptidase-24.11.

Abstract

The processing of peptide-YY (PYY) by purified membrane peptidases and brush border membrane preparations from human kidney and jejunum has been compared. Dipeptidyl peptidase-IV hydrolyzes PYY at the Pro2-Ile3 bond, producing PYY-(3-36), which is a Y2 receptor-selective ligand. Aminopeptidase-P removes the N-terminal tyrosine from PYY, but the intact peptide is not a substrate for aminopeptidase-N. Endopeptidase-24.11 (neutral endopeptidase; enkephalinase) metabolizes PYY efficiently, with a major site of hydrolysis at the Asn29-Leu30 bond, an inactivating cleavage. Angiotensin-converting enzyme does not hydrolyze PYY. In renal brush border membranes, hydrolysis of PYY is substantially (> 75%) inhibited by phosphoramidon, suggesting that endopeptidase-24.11 initiates hydrolysis of PYY in this preparation. In jejunal brush border membranes, phosphoramidon has a much smaller effect (15% inhibition), and contributions due to the actions of aminopeptidase-P and dipeptidyl peptidase-IV were evident. Few physiological substrates have yet been identified for aminopeptidase-P and dipeptidyl peptidase-IV; the pancreatic polypeptide fold family, of which PYY is a member, may well represent endogenous substrates for those cell surface ectoenzymes. Dipeptidyl peptidase-IV converts PYY to a metabolite PYY-(3-36), a highly selective agonist for the Y2 receptor type. Thus, the relative levels of the three membrane peptidases at different tissue locations and on different cell types may play a pivotal role in postsecretory processing and metabolism of PYY to receptor-selective agonists or inactive metabolites.