Research Article: Angiotensin I-Converting Enzyme Mutation (Trp1197Stop) Causes a Dramatic Increase in Blood ACE

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.

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 [1]–[3]. ACE is constitutively expressed on the surface of endothelial cells, different absorptive epithelial and neuroepithelial cells [4]–[7], and cells of the immune system (macrophages, dendritic cells) [8]–[9]. Somatic ACE contains two catalytic centers in N- and C-terminal domains [10]), whereas a short testis-specific isoform expressed in germ cells contains an identical C-domain and only one catalytic center [11]–[12]. ACE was assigned as a common differentiation marker – CD143 [7], [13].

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 [28]–[29]. 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 [39].



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