New properties of murine Angiotensin I-converting Enzyme (mACE) and its catalytic domains
Xiaoou Sun · Universitätsbibliothek der FU Berlin Hochschulschriftenstelle u. Dokumentenserver · 2011
Angiotensin-converting enzyme (ACE; EC 3.4.15.1, a metallopeptidase of the M-2 family) is known as most typical dipeptidyl-carboxypeptidase. Via this mechanism, ACE degrades important peptides like angiotensin-I (Ang I) and bradykinin (BK), and plays consequently a crucial role in several circulatory processes. Besides these well described processes, ACE evinces some unusual, not fully clarified functions. Among these are (i) unexpected endopeptidolytic activities of ACE on a few substrates (ii), receptor-like mechanisms (outside- in actions) of cell-bound ACE, and (iii) the molecular mechanisms of the sperm-bound ACE in the processes of fertilization and sperm-egg-contact, Using self-produced domain-selective forms of murine ACE (mACE), the experiments and data presented here should be regarded as contributing to the elucidation of such processes: (a) Studying the slow degradation of amyloid-beta peptides (Aβ), it has been demonstrated that unexpectedly both catalytic domains of mACE have similar hydrolytic activity on the N-terminal part of Aβ. Moreover, the results confirm that mACE has unequivocal endopeptidolytic activities. (b) Moreover, it is described here that ACE has GPI-targeted properties. This process is completely independent of its known peptidase activities. Such activity has been controversially discussed with respect to the essential function of ACE in the process of fertilization. The results presented here indicate that a spatial proximity between membrane-bound mACE and the endogenous, GPI-anchored CPM enables an ACE evoked release of CPM. (c) Finally, using mACE-transfected CHO-cells, the intracellular signaling after interaction with typical ACE-substrates or with inhibitors in living cells was analyzed. The data suggest that the two catalytic domains of mACE do not function independently, which means that the signal transduction in the mACE is influenced by negative cooperatives of the two catalytic domains. After all, these effects characterize ACE as an enzyme with multiple facets, far from being a simple dipeptidyl-carboxypeptidase. Bearing in mind that ACE is one of the most commonly used targets in modern medicine, further exploration of ACE should be more in the focus of research and will surely yield exiting news.