Brain-specific aminopeptidase: from enkephalinase to protector against neurodegeneration.
The major breakthrough discovery of enkephalins as endogenous opiates led our attempts to determine their inactivation mechanisms. Because the NH2-terminal tyrosine is absolutely necessary for the neuropeptides to exert analgesic effects, and aminopeptidase activities are extraordinarily high in the brain, a specific "amino-enkephalinase" should exist. Several aminopeptidases were identified in the central nervous system during the search. In fact, our laboratory found two novel neuron-specific aminopeptidases: NAP and NAP-2. NAP is the only functionally active brain-specific enzyme known. Its synaptic location coupled with its limited substrate specificity could constitute a "functional" specificity and contribute to enkephalin-specific functions. In addition, NAP was found to be essential for neuron growth, differentiation, and death. Thus, aminopeptidases are likely important for mental health and neurological diseases. Recently, puromycin-sensitive aminopeptidase (PSA) was identified as a modifier of tau-induced neurodegeneration. Because the enzymatic similarity between PSA and NAP, we believe that the depletion of NAP in Alzheimer's disease (AD) brains plays a causal role in the development of AD pathology. Therefore, use of the puromycin-sensitive neuron-aminopeptidase NAP could provide neuroprotective mechanisms in AD and similar neurodegenerative diseases.
Hui
Koon-Sea
KS
Peptide Research Laboratory, Neurochemistry Division, Nathan S. Kline Institute for Psychiatric Research, Orangeburg, NY 10962, USA. Hui@nki.rfmh.org
D000626:Aminopeptidases / Q000378:metabolism / Q000502:physiology*; D000818:Animals; D001921:Brain / Q000201:enzymology*; D004745:Enkephalins / Q000378:metabolism; D006801:Humans; D006868:Hydrolysis; D015260:Neprilysin / Q000502:physiology*; D019636:Neurodegenerative Diseases / Q000473:pathology*; D009474:Neurons / Q000201:enzymology; D018847:Opioid Peptides / Q000378:metabolism
D004745:Enkephalins; D018847:Opioid Peptides; D000626:Aminopeptidases; D015260:Neprilysin