Oxytocin (Figure 5) is a potent and specific stimulant of myometrial contractions commonly used to induce labor. This peptide is of interest here due to it being a natural peptide and being degraded by a variety of peptidases. Thus, cleavage of the N-terminal cysteine is catalyzed by an aminopeptidase now known as cystinyl aminopeptidase (EC 188.8.131.52; oxytocinase), an enzyme found in the placenta and in the serum of pregnant women.23 The enzyme acts efficiently to hydrolyze the Cys1-Tyr2 bond, thus opening the ring structure of oxytocin, and then cleaves successive residues from the N-terminal end. At the C-terminus, prolyl oligopeptidase (EC 184.108.40.206; postproline endopeptidase) cleaves the C-terminal dipeptide.24 The resulting oxytocin-(1-7) is also a substrate for aminopeptidase activity. Furthermore, neprilysin (EC 220.127.116.11) can also play a role in oxytocin degradation, although it seems to act with less efficiency than the two other enzymes.
Our last example here is cetrorelix (Figure 6), a potent antagonist of LHRH receptors. The compound is an N- and C-protected decapeptide containing D-Nal, D-(p-chloro)Phe, D-(3-pyridyl)Ala, D-Orn and D-Ala as D- or artificial residues. Following subcutaneous administration, the plasma half-life was 35-40h in rats and 100-130h in dogs, indicating a remarkable metabolic stability.25 In both species, only unchanged compound was found in urine, whereas the bile contained up to four metabolites, namely the (1-9)-nonapeptide, the (1-7)-heptapeptide, the (1-6)-hexapeptide, and the (1-4)-tetrapeptide. This indicates that peptidase-related products were the only products identified. Interestingly, the relative abundance of the metabolites changed between bile and feces, indicating additional intestinal breakdown by enteral peptidases or bacteria.
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