Molecular Structure of Neutral Endopeptidase 24.11 (Enkephalinase)
Whereas termination of the action of classical neurotransmitters is known to occur either by reuptake or degradation, inactivation has been proposed to be a major mechanism for terminating peptidergic signals. When incubated in vitro with crude brain extracts, the neuropeptides Leu- and Met-enkephalins are rapidly hydrolysed to inactive metabolites2,3. In the perfused brain in vivo, the tripeptide Tyr-Gly-Gly has been found to be a major metabolite of the enkephalins arising by hydrolysis of the Gly3-Phe4 bond. Preparations from the striatum, a brain region rich in peptidergic nerve terminals, contain a membrane-bound enzyme that is able to hydrolyse the enkephalins at the same position4. This enzyme termed “enkephalinase” was detected in other tissues and was shown to be particularly enriched in the kidney cortex. Its identity with Neutral Endopeptidase (NEP: E.C.188.8.131.52), has been established using specificity, sensitivity to inhibitors and immunological criteria5. Both renal and brain enzymes hydrolyse peptides on the amino-terminal side of a hydrophobic residue. The enzyme has therefore the potential to hydrolyse a wide range of regulatory peptides6. Although the enkephalins may be important physiological substrates for the enzyme, evidence is accumulating that the tachykinin peptides such as substance P may also be inactivated by this enzyme in the brain7,8. There is little to support the concept of specific peptide hydrolases tailored for individual neuropeptides9.
KeywordsNeutral Endopeptidase Cyanogen Bromide Fragment CNBr Fragment Kidney Brush Border Membrane Crude Brain Extract
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