Angiotensin-I-converting enzyme and its relatives

Abstract

Angiotensin-I-converting enzyme (ACE) is a monomeric, membrane-bound, zinc- and chloride-dependent peptidyl dipeptidase that catalyzes the conversion of the decapeptide angiotensin I to the octapeptide angiotensin II, by removing a carboxy-terminal dipeptide. ACE has long been known to be a key part of the renin angiotensin system that regulates blood pressure, and ACE inhibitors are important for the treatment of hypertension. There are two forms of the enzyme in humans, the ubiquitous somatic ACE and the sperm-specific germinal ACE, both encoded by the same gene through transcription from alternative promoters. Somatic ACE has two tandem active sites with distinct catalytic properties, whereas germinal ACE, the function of which is largely unknown, has just a single active site. Recently, an ACE homolog, ACE2, has been identified in humans that differs from ACE in being a carboxypeptidase that preferentially removes carboxy-terminal hydrophobic or basic amino acids; it appears to be important in cardiac function. ACE homologs (also known as members of the M2 gluzincin family) have been found in a wide variety of species, even in those that neither have a cardiovascular system nor synthesize angiotensin. X-ray structures of a truncated, deglycosylated form of germinal ACE and a related enzyme from Drosophila have been reported, and these show that the active site is deep within a central cavity. Structure-based drug design targeting the individual active sites of somatic ACE may lead to a new generation of ACE inhibitors, with fewer side-effects than currently available inhibitors.

Figure 1

Schematic representation of the primary structure of several members of the ACE protein family. The locations of the active-site zinc-binding motifs are indicated by HEXXH; transmembrane domains are in black. The sequence of gACE is identical to that of the C domain of sACE, except for its first 36 residues. Human gACE and sACE have the same carboxy-terminal transmembrane and cytosolic sequences, whereas ACE2 has a distinct transmembrane and cytosolic sequence. Neither of the Drosophila ACEs, AnCE and Acer, has a membrane-anchoring sequence. Dimensions are not to scale. N, amino terminus; C, carboxyl terminus. The single lines are regions of sequence with no similarity to other proteins. The carboxyl end of ACE2 is homologous to collectin, a non-enzymatic protein associated with renal injury [18].

Figure 2

A schematic representation of the structure of truncated, deglycosylated human gACE in a complex with the inhibitor lisinopril [11]. The gACE molecule can be divided into two halves, subdomains I (light gray) and II (dark gray), that enclose the substrate-binding site. The active-site zinc atom is shown coordinated to lisinopril (in stick representation). Two bound chloride ions are designated Cl1 and Cl2. N, amino terminus; C, carboxyl terminus.