Cell-surface peptidases involved in neuropeptide metabolism: an overview

Summary

There is general agreement that secreted neuropeptides are not degraded within the cell, but are hydrolysed at the cell-surface by ectoenzymes. An earlier view implied the existence of a battery of peptide-specific enzymes; it is now clear that most neuropeptides are degraded by a relatively small number of peptidases which are not special to the nervous system, but have a broad distribution on the surfaces of many different cell types. The kidney provides an ideal source for the isolation and study of most of the cell-surface peptidases. There are now more than a dozen well-characterized enzymes in this group (most have been cloned). Three of these: endopeptidase—24.11 (E—24.11), endopeptidase—24.18 (E—24.18) and aminopeptidase-W (AP—W) were discovered in the course of my research in Leeds. Over the last 20 years some unpredictable developments ensured that endopeptidase—24.11 grew in scientific and medical popularity. First came the proof that it was responsible for the ”enkephalinase” activity in brain; second, the realization of its crucial role in inactivating atrial natriuretic peptides and third, the discovery (as a result of molecular cloning) of its identity to CD-10 (CALLA). endopeptidase—24.11 seems to be the principal enzyme in the brain and elsewhere for initiating the degradation of many, but not all neuropeptides. Endopeptidase—24.18 has, by contrast, a limited distribution, essentially restricted to brush borders, with none so far revealed in the nervous system. Kinetically, it is much less efficient in hydrolysing neuropeptides than is endopeptidase—24.11, but capable of attacking some more complex molecules. Aminopeptidase W has a strong preference for dipeptides in which the second residue is aromatic. It is a neuronal marker in peripheral nerves, contrasting with endopeptidase—24.11, which is neuronal in the central but located on Schwann cells in the peripheral nervous system.