ABSTRACT
Angiotensin !-converting enzyme (ACE; peptidyl dipeptidase A; EC 3.4.15.1) cleaves the C-terminal dipeptide from angiotensin I to produce the potent vasopressor peptide angiotensin II and inactivates the vasodilatory peptide bradykinin by the sequential removal of two C-terminal dipeptides. The involvement of ACE in the metabolism of these two vasoactive peptides has led to the development of highly potent and specific ACE inhibitors which have become clinically important in the treatment of hypertension and congestive heart failure. ACE is primarily expressed as an ectoenzyme at the surface of endothelial, epithelial and neuroepithelial cells (somatic ACE). A distinct isoenzyme of ACE is found in male germinal cells (germinal ACE). Somatic ACE has a molecular mass of 170 kDa (in humans) and contains two homologous domains (N-and C-domains) each of which are catalytically active. In contrast, germinal ACE has a molecular mass of 100 kDa (in humans) and corresponds to the C-domain of somatic ACE. These two isoenzymes are transcribed from a single gene consisting of 26 exons and their respective mRNAs are produced by the initiation of transcription from alternative start sites under the control of separate promoters. The N-and C-domains of somatic ACE exhibit different enzymatic properties. Several substrates are hydrolysed at different rates by the two active sites and several specific ACE inhibitors interact differently with each domain. Chloride activates ACE activity and the C-domain of somatic ACE is more chloride dependent compared with the N-domain in terms of enzymatic activity and inhibitor interaction. Such observations provide strong evidence for structural/functional differences between the two active sites. The serum ACE concentration is stable within a given individual but varies markedly between individuals. A 287 bp insertion/deletion polymorphism has been identified within intron 16 of the ACE gene and is in strong association with serum ACE levels. Individuals who are homozygous for the deletion polymorphism (DD) display serum ACE levels almost twice as high as individuals who are homozygous for the insertion allele (II). In addition, an increased frequency of the DD genotype has been detected in individuals who have suffered a myocardial infarction. Thus it appears that the DD genotype is associated with an increased relative risk of myocardial infarction.
