Thiorphan, enzyme inhibition

These zinc-dependent endopeptidases (meprin A [EC 3.4.24.18] and meprin B [EC 3.4.24.63] ) are members of the peptidase family M12A. They catalyze the hydrolysis of peptide bonds in proteins and peptide substrates. Meprin A, a membrane-bound enzyme that has been isolated from mouse and rat kidney and intestinal brush borders as well as salivary ducts, acts preferentially on carboxyl side of hydrophobic amino acyl residues. Meprin A and B are insensitive to inhibition by phosphora-midon and thiorphan. 

Studies of peptidase inhibitors in brain slices indicate the importance of inhibiting both enzymes in order to significantly increase the concentrations of the endogenous opioid peptides (see Refs. 973-976). Thus, inhibiting NEP with thiorphan decreases the formation of [ H]Tyr-Gly-Gly from [ H]Met-enkephalin, but increases the production of [ H]Tyr, whereas the opposite results were found with the APN inhibitor bestatin. Both APN and NEP, as well as the other enzymes involved in enkephalin metabolism, are zinc metallopep-tidases. Thus it is possible to design mixed inhibitors capable of blocking multiple enzymes that more effectively protect the opioid peptides from metabolism (see below). 

The reversal of the peptidic functional groups is often used in peptide chemistry. The obtained retropeptides are generally more resistant to enzymatic attacks (Figure For thiorphan and rctro-thiorphan an identical binding mode to the zinc protease thermolysin was demonstrated. Similar inhibition values for thermolysin and neutral endopeptidase were observed, whereas, for another zinc protease, angiotensin-converting enzyme (ACE), noticeable differences for inhibition were found (Figure 15.47). 

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