**3. Angiotensin-converting enzyme**

The predominant pathway of the classical RAS for the conversion of Ang I to the bioactive peptide Ang II is catalyzed by the metallopeptidase ACE [EC 3.4.15.1], a dipeptidyl carboxypeptidase that cleaves two residues from the carboxy terminus of Ang I (**Figure 1)**. The peptidase is a membrane-bound, glycosylated protein (120–180 kDa) ubiquitously expressed in multiple tissues [29]. Soluble forms of the enzyme are present in the circulation, cerebrospinal fluid (CSF), lymph fluid, and urine that fully retain peptidase activity [29]. The soluble form of ACE arises from the hydrolysis of the membrane-anchoring or stalk region of the protein that may reflect the processing by A Disintegrin and Metalloproteinase (ADAM) family of metalloenzymes, although the precise role of ACE shedding in cardiovascular disease is presently unclear. Somatic ACE is characterized by two active sites termed N and C terminal domains that likely arose from the gene duplication of germinal or testicular ACE that contains only the single C terminal-active site. Importantly, in addition to forming Ang II, ACE degrades a number of other peptides that exhibit cardiovascular actions including bradykinin, substance P, acetyl-SDKP, and Ang-(1-7) [29]. Indeed, the cardioprotective effects of ACE inhibitors may reflect the protection of these peptides from metabolism in addition to the blockade of Ang II formation. We showed that ACE hydrolyzes Ang-(1-7) to the pentapeptide Ang-(1-5) and that ACE inhibition markedly reduced the clearance of the peptide [30, 31]. The reduced metabolism of Ang-(1-7) likely contributes to the elevation in circulating levels of Ang-(1-7) following the chronic treatment with ACE inhibitors in experimental animals and in humans [32]. Moreover, treatment with an ACE inhibitor was required to clearly demonstrate the accumulation of Ang-(1-7) derived from either Ang II or Ang I in isolated proximal tubules [33]. These data suggest a pivotal role for ACE to regulate the balance of Ang II and Ang-(1-7), two peptides within the RAS that exhibit strikingly different actions from one another [7].
