Bestatin inhibition of human tissue carnosinase, a non-specific cytosolic dipeptidase

• Published in: Biological chemistry Hoppe-Seyler Vol. 369; no. 12; p. 1281
• Main Authors: Peppers, S C, Lenney, J F
• Format: Journal Article
• Language: English
• Published: Germany 01.12.1988
• Subjects: Aminopeptidases - antagonists & inhibitors; Animals; Cytosol - enzymology; Dipeptidases - antagonists & inhibitors; Dipeptidases - blood; Humans; Kidney - enzymology; Kinetics; Leucine - analogs & derivatives; Leucine - pharmacology; Leucyl Aminopeptidase - antagonists & inhibitors; Swine
• ISSN: 0177-3593
• DOI: 10.1515/bchm3.1988.369.2.1281

Bestatin is a dipeptide containing a unique beta-amino acid. It is usually referred to as an aminopeptidase inhibitor. Current interest has focused on the immunostimulating activity of bestatin and several clinical trials have demonstrated that it is an effective adjunct to radiation or chemotherapy in the treatment of certain types of cancer. We found that bestatin was much more effective against human tissue carnosinase than against aminopeptidases. Inhibition was competitive, with a Ki of 0.5nM. Carnosinase did not hydrolyse bestatin and the enzyme-inhibitor complex formed rapidly. A hog kidney dipeptidase similar to human tissue carnosinase was equally sensitive to this inhibitor. Bestatin has a backbone structure identical to that of carnosine; however, our results indicate that the inhibitory activity of this compound is primarily attributable to the side chains of the beta-amino-acid moiety. Human tissue carnosinase is a non-specific dipeptidase, actively hydrolysing many dipeptides, including prolinase substrates. Inhibition of this cytosolic enzyme is probably at least partially responsible for the intracellular accumulation of dipeptides which occurs following the in vivo administration of bestatin.