Metabolism of angiotensin peptides by angiotensin converting enzyme 2 (ACE2) and analysis of the effect of excess zinc on ACE2 enzymatic activity

After decades of notoriety for its adverse cardiovascular, proinflammatory and profibrotic actions, the reninangiotensin system (RAS) began to be cast in a more favorable light with the discovery of angiotensin-converting enzyme-2 (ACE2) in 2000. This monocarboxypeptidase, best known for its ability to metabolize angiotensin (Ang) II to Ang 1-7, counteracts the adverse effects of Ang II mediated by the AT(1) Ang II receptor. Ang peptides are classically considered to be metabolized by aminopeptidases, by which the nomenclature Ang III (des-Asp(1)Ang II, 2-8 heptapeptide) and Ang IV (des-Asp(1)des-Arg(2)Ang II, 3-8 hexapeptide) are derived. This report compares the ability of recombinant human ACE2 (rhACE2) to metabolize Ang III, Ang IV and Ang V, (4-8 pentapeptide) relative to Ang II to form corresponding des-omega-Phe metabolites. rhACE2 has highest affinity (lowest K-m) for Ang III, followed by Ang II similar to Ang V, followed by Ang IV. However, rhACE2 has the highest Kcat for metabolising Ang IV followed by Ang V, Ang III and Ang II. The enzymatic efficiency (Kcat/Km) is highest for Ang V and Ang III followed by Ang IV and is lowest for Ang II. As a gluzincin metallopeptidase, ACE2 requires a zinc molecule at its active site for catalysis. This report also documents inhibition of ACE2 activity by concentrations of zinc exceeding 10 mu M. These observations extend the functional significance of ACE2 to include the metabolic inactivation of Ang III, Ang IV and Ang V, reemphasizing the importance of monitoring zinc intake to maintain metabolic homeostasis.