The Angiotensin I-Converting Enzyme (Kininase II)

Abstract

The complete amino acid sequence of the human angiotensin I-converting enzyme (ACE) has been determined by protein sequencing of the purified kidney enzyme and cDNA cloning in endothelial cell libraries. The ACE molecule comprises 1,306 amino acids. It possesses a signal peptide of 29 residues cleaved off during maturation. The enzyme is most likely anchored to the plasma membrane by a short transmembrane domain situated near the carboxy-terminal extremity. Interestingly, the molecule presents a high degree of internal homology between two large peptidic domains. Each of these domains contains short sequences identical to zinc binding and active site sequences of other zinc metallopeptidases and therefore bears a putative active site. However, earlier experiments indicate only one zinc atom bound per molecule of ACE. Competitive inhibitors seem to interact with a unique class of high-affinity binding site. These observations may suggest that, despite the duplicated structure of the enzyme, there is only one functional active site per molecule of ACE. The respective role of the two homologous domains in this active site remains to be determined. A single gene coding for ACE is present in humans, transcribed as a 4.3-kilobase mRNA species in endothelial cells. In other studies, evidence for a genetic polymorphism in plasma ACE levels has been obtained by analyzing a large group of "healthy" nuclear families. A familial association of plasma ACE levels was observed. A major gene effect can possibly explain part of the interindividual variability observed in this enzyme.