Activation and Inhibition of Cerebral Prolidase

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Abstract
Purification of prolidase from calf brain (acetone and [NH4]2SO4 fractionation) separated this enzyme from proteases, leucine aminopeptidase, master dipeptidase and Gly-Gly dipeptidase. Prolidase is a key enzyme for termination of the function of some neuroactive peptides. Activation or inhibition of prolidase may have an important influence on the distribution and levels of proline. Prolidase was tested with peptidase and protease inhibitors, used at higher levels (35 times or more) than their ID50 [median inhibitory dose] for peptidases and proteases. Bacitracin, leupeptin, chymostatin and antipain had no effect; pepstatin slightly increased activity, and only bestatin was inhibitory. Antibiotics [puromycin, actinomycin, tetracycline, streptomycin, cycloheximide, N-hydroxyurea, rifampicin] that affect protein synthesis did not inhibit prolidase. Peptides with proline at the NH2 end activated prolidase; those with proline at the carboxyl end inhibited it. Di, tri and tetra-Pro peptides increased prolidase activity. Thyrotropin-releasing hormone had no effect on prolidase; its analog Pro-His-Pro-NH2 gave high activation and decreased the Km from 20 mM to 1.54 mM. Pro-peptide inhibitors and activators were not split by prolidase. Specific peptides influence the inhibition and activation of prolidase activity.