Date Published: December 14, 2009
Publisher: Public Library of Science
Author(s): Andrew B. Nesterovitch, Kyle D. Hogarth, Vyacheslav A. Adarichev, Elena I. Vinokour, David E. Schwartz, Julian Solway, Sergei M. Danilov, Mikhail V. Blagosklonny. http://doi.org/10.1371/journal.pone.0008282
Abstract: Angiotensin-converting enzyme (ACE) metabolizes many peptides and plays a key role in blood pressure regulation and vascular remodeling. Elevated ACE levels may be associated with an increased risk for different cardiovascular or respiratory diseases, including asthma. Previously, a molecular mechanism underlying a 5-fold familial increase of blood ACE was discovered: Pro1199Leu substitution enhanced the cleavage-secretion process. Carriers of this mutation were Caucasians from Europe (mostly Dutch) or had European roots.
Partial Text: Angiotensin I-converting enzyme (ACE, CD143) is a Zn2+ carboxydipeptidase which plays key roles in the regulation of blood pressure and in the development of vascular pathology and remodeling –. ACE is constitutively expressed on the surface of endothelial cells, different absorptive epithelial and neuroepithelial cells –, and cells of the immune system (macrophages, dendritic cells) –. Somatic ACE contains two catalytic centers in N- and C-terminal domains ), whereas a short testis-specific isoform expressed in germ cells contains an identical C-domain and only one catalytic center –. ACE was assigned as a common differentiation marker – CD143 , .
Recently, a molecular mechanism underlying the marked (5-fold) familial increase of plasma ACE was discovered: P1199L substitution leads to more accessibility at the stalk region for ACE secretase and for the enhancement of the cleavage-secretion process –. We developed a convenient assay for the detection of this particular mutation based on analysis of the plasma ACE binding to mAb 1B3 (directed to the C-terminal part of soluble ACE) and binding to mAb 9B9 (on the N-terminal domain of ACE). The observed 1B3/9B9 binding ratio was 3-fold lower for affected individuals, thus allowing identification of this particular mutation in the stalk region of human somatic ACE with high sensitivity and specificity and without labor-time and cost-consuming sequencing or restriction analysis of the PCR products .