Commentary on Tikellis et al: There is more to discover about angiotensin-converting enzyme.

Irvine H. Page used to say that the regular occurrence of constant amounts of a substance in the body is seldom without purpose and that organisms exhibit an inner economy and prudence by using one substance for several functions. Almost 50 years later, we are now challenged again to decipher just how complicated and how physiologically relevant are newly discovered biochemical pathways contributing to the formation of biologically active forms of angiotensin peptides. The need to revisit the role of angiotensin-forming enzymes was stimulated by the finding of a new gene encoding a protein having highest homology to the testes-specific isoform of angiotensin-converting enzyme (ACE).1,2 In 1991, we first suggested3 that angiotensin II (Ang II) should be viewed as one but not the sole principal product of the renin-angiotensin system. The proposal was based on the characterization of biological actions of the heptapeptide angiotensin-(1–7) [Ang-(1–7)] and its forming enzymes. There was reluctance to accept this concept in part because the potential role of Ang-(1–7) in cardiovascular regulation was still at an embryonic stage, there was little evidence that Ang II could act at more than one receptor, and a full characterization of other enzymic pathways for angiotensin peptide formation had not been achieved yet. The situation is quite different today; a growing body of literature now implicates Ang-(1–7)3–7 and angiotensin IV (Ang-3–8)8 as components of the system, and additional work has identified chymase, prolyl endopeptidase 24.26, neutral endopeptidase 24.11, metalloendopeptidase 24.15,9 and now a homologue of ACE10 as angiotensin prohormone convertases. Fifty years after the discovery of ACE, a homologue of human ACE has been reported from genomics-based strategies. The protein identified by Tipnis et al1 and named ACEH was cloned from a human lymphoma cDNA library, and an identical human protein termed ACE2 was cloned from a cDNA library prepared from ventricular tissue from a patient with heart failure by Donoghue and associates.2 To prevent confusion and prudently wait for the International Enzyme Nomenclature Committee to define the proper nomenclature, we will refer to this discovery as ACEH/ACE2, recognizing that it is the name but not the nature of the enzyme that remains at question. ACEH/ACE2 is a zinc metalloprotease consisting of 805 amino acids with considerable homology to ACE, but unlike somatic ACE, it functions as a carboxypeptidase rather than a dipeptidyl carboxypeptidase.1,2 The full-length cDNA encoding ACEH/ACE2 includes an N-terminal signal sequence and a hydrophobic region near the C-terminus with an overall 40% identity to the Nand C-domains of ACE. Contrasting with ACE, ACEH/ACE2 hydrolyses Ang I into Ang-(1–9), Ang II into Ang-(1–7), and bradykinin to [des-Arg9]bradykinin (Figure). In other words, ACEH/ACE2 does not convert Ang I into Ang II; it does not cleave bradykinin itself, and, importantly, its enzymatic activity is inhibited by neither captopril or lisinopril. ACEH/ACE2 is a type I membrane protein that is primarily localized to the heart (myocytes), kidney (endothelium and tubular elements), and testes.2,10 A glimpse into the potential importance of ACEH/ACE2 in the regulation of cardiovascular function was demonstrated by Crackower et al,11 who localized the ACEH/ACE2 gene to the human X chromosome. This is an exciting finding, since the same locus on the X chromosome has been reported to show a significant logarithm-of-the-odds score in rat models of hypertension.12 Crackower and associates11 also found severe cardiac contractile dysfunction associated with mild ventricular dilation in ACEH/ACE2 knockout mice [(ACEH/ ACE2]. These changes in cardiac function were associated with upregulation of hypoxia-induced genes. Ablation of both the ACE and ACEH/ACE2 genes completely abolished the cardiac abnormalities, linking the cardiac abnormality to