MET-ENKEPHALIN-ARG6-PHE7 METABOLISM - CONVERSION TO MET-ENKEPHALIN BY BRAIN AND KIDNEY DIPEPTIDYL CARBOXYPEPTIDASES

Enzymes degrading Met-enkephalin-Arg6-Phe7, an endogenous brain peptide with enhanced opiate activity in vivo, were isolated from membrane preparations of rabbit kidney and brain, and their specificity was compared. A preparation from kidney or brain containing the angiotensin converting enzyme (EC 3.4.15.1) released with time Arg-Phe, Met-enkephalin, Phe-Met and Tyr-Gly-Gly. Kinetic analysis revealed a product precursor relationship with conversion of hepta- to pentapeptide (Met-enkephalin) followed by release of Tyr-Gly-Gly and Phe-Met indicating sequential cleavage at the Met5-Arg6 and Gly3-Phe4 bonds. A 2nd preparation devoid of angiotensin converting enzyme activity released the same products and in addition of tetrapeptide Phe-Met-Arg-Phe. Release of products with time indicated cleavage at Gly3Phe4 by an endopeptidase and at the Met5-Arg6 and Gly3-Phe4 bonds by a dipeptidyl carboxypeptidase. The dipeptidyl carboxypeptidases thus provide a mechanism for the formation of Met-enkephalin from a potential precursor.