DESCRIPTION (from applicant's abstract): Neuropeptide action can be terminated by proteolytic inactivation. In some cases the products of neuropeptide degradation can also have biological activity (biotransformation). We and others have recently obtained evidence to support the hypothesis that part or all of the biological activity of the brain renin-angiotensin (ang) system is mediated by the ang II (Asp-Arg-Val-Tyr-Ile-His-Pro-Phe) metabolite ang III (des Asp-ang II). The conversion of ang II to and III is catalyzed by two acidic amino acid proferring aminopeptidases. In addition to the well known enzyme isolated rabbit brain and termed aspartyl aminopeptides (D-AP). Its substrates can include angiotensins I and II, cholecystokinin-8, and neuropeptide K. The sole produce of the action of D-AP on ang II is and III. The specificity constant (kcat/Km) of ang II is similar with both enzymes. We obtained sequences of three tryptic peptides from the purified rabbit brain enzyme and located these sequences within the expressed sequence tag data base. Full length human and mouse cDNA's were found and the human enzyme expressed. Aspartyl aminopeptidase is the first mammalian member of the M18 family of metalloproteinases, and has been assigned to chromosome 2q. It is an abundant ezyme (0.1% of brain soluble protein) and its sequence is highly conserved. Levels of D-AP were reported to be lowered in the frontal cortex of aged rats. To explore the physiological significance of brain D-AP, we propose characterization of its mechanism of action by site-directed mutagenesis, studies on the relationship of subunit structure to activity, determination of its localization, synthesis and evaluation of new thiol containing inhibitors and identification of endogenous interacting proteins.
|Effective start/end date||1/07/85 → 30/11/03|
- National Institute of Neurological Disorders and Stroke: $12,625.00
- National Institute of Neurological Disorders and Stroke: $287,786.00
- National Institute of Neurological Disorders and Stroke: $296,028.00
- National Institute of Neurological Disorders and Stroke: $583,432.00
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