see also:

• ACE inhibitors

• there are 2 main very differently acting ACE homologues:

• a zinc metallopeptidase which removes dipeptides from the C-terminus of a peptide and thus converts angiotensin I to the active vasocontrictor peptide angiotensin II
• present on all endothelial cells, but especially on pulmonary and renal endothelium
• it also hydrolyzes bradykinin, a vasodilator
• actions are blocked by ACE inhibitors

• discovered in 2000
• gene is on the X chromosome
• expressed mainly on renal endothelium but also in the general vasculature and GIT
• ACE2 expression in the lung increases with age ¹⁾
• catalytic domain is 42% identical with ACE
• actions are not generally blocked by ACEIs, does not generate angiotensin II and does not hydrolyze Bradykinin and kinin physiology and pharmacology
• a cell membrane bound zinc metallopeptidase which acts as a carboxypeptidase, removing single amino acids from a variety of peptides:
  • converts Ang II to its vasodilator metabolite angiotensin-(1–7)
  • Ang 1-7 can also be converted from Ang 1 directly by endopeptidases other than ACE2 and ACE, including neprilsyn, prolyl endopeptidase, and thimet oligopeptidase
  • can also cleave a single residue from angiotensin I (Ang I) to generate angiotensin 1–9 (Ang 1–9), which has no known function, however, this reaction is unlikely to occur in vivo as the action of ACE is much more favourable
    • Angiotensin 1–9 cannot be converted to Ang II by ACE2, but can be converted by ACE to Ang 1–7, a vasodilator with its own G-coupled receptor targets
  • can hydrolyse (des-Arg9)-bradykinin, which is the endogenous ligand of the bradykinin B1 receptor
  • also cleaves neurotensin 1–13, kinetensin, apelin-13 and dynorphin A 1–13
• ACE2 is a key regulator of cardiac function and counter-balance to ACE
  • Ace2 knockout mice show major cardiac contractility defects and increased levels of Ang II
  • double knockouts, in which both Ace and Ace2 genes have been deleted, do not show the cardiac defects of the Ace2 knockout alone
  • over-expression of ACE2:
    • When Ace2 is transgenically overexpressed in mouse heart, cardiac defects are again observed, most notably a lethal ventricular arrhythmia, which is associated with disruption of gap junction formation, emphasizing the Yin–Yang nature of ACE and ACE2 expression
  • may be cardio-protective and theoretically may reduce risk of pre-eclampsia and eclampsia
• it is the functional receptor for cellular entry of SARS virus and COVID-19 coronavirus (2019-nCoV / SARS-CoV-2)
  • residues near lysine 31, and tyrosine 41, 82–84, and 353–357 in human ACE2 were important for the binding of the spike protein in SARS virus and DC‐SIGNR (L‐SIGN, CD209L) and DC‐SIGN (CD209) have been shown to enhance infection of ACE2‐expressing cells²⁾
  • the major viral coronavirus target cells are type II pneumocytes and enterocytes
  • severity of these infections appears to correlate with the degree of expression of ACE2 in pulmonary cells
• Ang II decreases ACE2 expression in a tissue-dependent manner, by internalization into lysosomes, and these effects were prevented by both the Ang-II type 1 receptor (AT1R) blocker losartan and the lysosomal inhibitor leupeptin ³⁾
• ACE2 rs4646188 variant may be a potential genetic susceptibility marker for essential hypertension, dyslipidemia and its related ischemic stroke ⁴⁾
• ACE2 rs2106809 polymorphism is an important predictive factor of the response to antihypertensive treatment with ACE inhibitors in Chinese female hypertensive patients ⁵⁾