Not just angiotensinases: new roles for the angiotensin-converting enzymes

Abstract

The renin-angiotensin system (RAS) is a critical regulator of blood pressure and fluid homeostasis. Angiotensin II, the primary bioactive peptide of the RAS, is generated from angiotensin I by angiotensin-converting enzyme (ACE). A homologue of ACE, ACE2, is able to convert angiotensin II to a peptide with opposing effects, angiotensin-(1-7). It is proposed that disturbance of the balance of ACE and ACE2 expression and/or function is important in pathologies in which angiotensin II plays a role. These include cardiovascular and renal disease, lung injury and liver fibrosis. The critical roles of ACE and ACE2 in regulating angiotensin II levels have traditionally focussed attention on their activities as angiotensinases. Recent discoveries, however, have illuminated the roles of these enzymes and of the ACE2 homologue, collectrin, in intracellular trafficking and signalling. This paper reviews the key literature regarding both the catalytic and non-catalytic roles of the angiotensin-converting enzyme gene family.

Fig. 1

Membrane topology and homology between ACE, ACE2 and its homologue collectrin. The ACE isoforms somatic ACE (sACE) and germinal ACE (gACE), ACE2 and its homologue collectrin, are type I transmembrane proteins with an intracellular C-terminal domain and an extracellular N-terminal domain. In the case of the ACE isoforms and ACE2, the N-terminal extracellular domains contain HEMGH zinc-dependent catalytic domains (denoted as ‘Pacman’ symbols); two in ACE and one in both gACE and ACE2. Collectrin contains no catalytic residues. Germinal ACE is entirely homologous to the C-terminal domain of sACE except for an O-glycosylated region at its N-terminus. ACE2 shares homology in its ectodomain with the N-terminal domain of sACE but has no homology with its C-terminal cytoplasmic domain; instead, it shares a number of residues with the intracellular domain of collectrin

Fig. 2

ACE and ACE2 as outside-in signalling molecules. Both ACE and ACE2 are subject to regulated ectodomain shedding involving members of the ADAM family of proteinases. The identity of the ACE sheddase remains to be established. Shedding of both enzymes is regulated by calmodulin (Cam) and may generate intracellular signals. The intracellular domain of ACE is known to dimerise, become phosphorylated and associate with CK2 (casein kinase-2) in response to inhibitor binding, triggering downstream signalling events involving JNK (c-Jun NH₂-terminal kinase) and c-Jun and culminating in transcriptional upregulation of ACE and COX-2 (cyclooxygenase-2) in endothelial cells. In adipocytes, inhibitor binding to ACE results in upregulation of CRBP (cellular retinol binding protein) and adiponectin expression (not shown). A role for ACE2 in intracellular signalling modulation is unclear

Fig. 3

ACE2 is a critical regulator of amino acid transporter function in small intestine. ACE2 regulates the function of the amino acid transporters B⁰AT1 and B⁰AT3 in the small intestinal enterocyte brush border. Mutations in a number of residues in the B⁰AT1 transporter block the association between ACE2 and the transporter and lead to the amino acid uptake defect observed in human Hartnup disorder. The ACE2 homologue, collectrin, carries out this role in the tubular cells of the kidney and is similarly influenced by mutations in B⁰AT1 (not shown in this diagram)