This Editorial, written by Guest Editors Professor Michael Bader, Professor Anthony J. Turner and Dr Natalia Alenina, proudly introduces the Clinical Science-themed collection on angiotensin-converting enzyme 2 (ACE2), a multifunctional protein – from cardiovascular regulation to coronavirus disease 2019 (COVID-19).
Angiotensin-converting enzyme 2 (ACE2) was discovered independently by two groups in 2000 [1,2]. On its 20th anniversary, it has gained unforeseeable notoriety as receptor for the severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) causing the coronavirus disease 2019 (COVID-19) pandemic . Its yearly citation numbers in PubMed exploded from approximately 150 per year between 2010 and 2019 to approximately 3000 in 2020. Accordingly, it probably holds the record of the protein with the most publications this year. However, this sudden popularity based on its hijacking by a wicked pathogen is undeserved, since its physiological functions are interesting enough to render ACE2 a fascinating protein in its own right. This Themed Collection of Clinical Science hopes to rescue the reputation of ACE2 as a physiologically important protein by summarizing the immense knowledge collected in the last 20 years from basic enzymology to its structure, physiology and pathology. In this issue, Hooper et al. report on their discovery of the protein [2,4]. As they revealed, the protein consists of two domains which have been glued together in evolution by the fusion of two genes, ACE and collectrin (Figure 1). It is still unclear what the evolutionary drive for this merger was and whether the two parts need to interact for any of the functions of ACE2. The carboxy-terminal collectrin domain anchors the protein in the plasma membrane and contains the domains responsible for dimerization and shedding by proteases such as a disintegrin and metalloproteinase domain-containing protein 17 (ADAM17) and transmembrane protease, serine 2 (TMPRSS2) (Figure 1) [5–9]. Moreover it confers a trafficking and stabilization function to the protein which is essential for the functional expression of the amino acid uptake transporter B0AT1 (broad neutral amino acid transporter 1) (SLC6A19) in the gut. As a consequence, ACE2 knockout mice develop a deficiency in some amino acids, mainly tryptophan. As we could recently show this also leads to a marked reduction in the tryptophan metabolite, serotonin, in blood and brain . Camargo et al. summarize the knowledge on this ‘collectrin function’ of ACE2 in their contribution to this issue .
Structure of human ACE2
The amino-terminal domain, which is homologous to ACE is responsible for the carboxypeptidase activity of the protein (Figure 1). Lubbe et al. compare the structures of ACE and ACE2 in this issue and highlight that despite considerable homologies, the specificities of the two enzymes are different and that therefore inhibitors for ACE, which are popular antihypertensive drugs, do not affect ACE2 . The carboxypeptidase function of ACE2 is the most important one for its physiological effects. It cuts off the C-terminal amino acid of several peptide hormones which mostly carry a proline at the penultimate position  and thereby either diminishes their activity, such as for des-Arg9-bradykinin and apelin-13, or changes the receptor specificity, as for angiotensin (Ang) II. Hydrolysis of Ang II by ACE2 results in generation of Ang-(1-7), a heptapeptide that interacts with its receptor, Mas  and not with the Ang II receptors, AT1 and AT2 . In this issue Verano-Braga et al. and Chatterjee et al. review the effects of ACE2 in the renin–angiotensin system (RAS) and the apelin system, respectively [16,17]. The modulations of the cardiovascular peptide hormone systems have profound effects on physiology and pathophysiology in several organs. In the cardiovascular system the pro-hypertensive and target-organ damaging peptide Ang II is converted by ACE2 into the vasodilatory and tissue-protective peptide Ang-(1-7). The consequences on the heart and kidney are reviewed by Sharma et al. and Lores et al. in this issue [18,19]. Ferrario et al. discuss the role of the antiinflammatory effects of Ang-(1-7) and ACE2 in the pathogenesis of cardiovascular diseases . In COVID-19, ACE2 activity is reduced compromising the protective RAS; and in this issue Steckelings and Sumners suggest this imbalance as a major pathogenetic factor for severe courses of the disease . In the brain, ACE2 also limits the actions of Ang II with marked effects on cardiovascular physiology as reviewed by Mohammed et al. . However, the effects of the RAS go beyond cardiovascular control and therefore ACE2 also acts in other tissues such as the liver, skeletal muscle and reproductive organs. These functions of the jubilee are reviewed by Herath et al., Yamamoto et al., and Reis et al., respectively, in this issue [23–25]. More reviews on the functions of ACE2 in other tissues will be added to this Themed Collection.
The multiple and mainly curative functions of ACE2 render it a popular drug target. However, while very efficient inhibitors have been described , it is activators that are desirable. Li et al. discuss the approaches pursued to increase ACE2 activity in patients in this issue . These include recombinant human ACE2 which has become also a very promising therapeutic agent in COVID-19. This soluble form of ACE2 binds SARS-CoV2 as a decoy inhibiting virus entry into cells via the membrane-bound ACE2. At the same time, it restores ACE2 activity which is lost during SARS-CoV2 infection resulting in an overactivity of the pro-inflammatory peptides Ang II and des-Arg9-bradykinin . Promising preclinical studies in cell and organoid cultures  prompted the investigation of therapeutic effects of recombinant ACE2 in COVID-19 patients and first encouraging results have been reported . Thus, although being a mediator of SARS-CoV2 infection, ACE2 still exerts an important protective role against the disastrous actions of the virus. We hope that this Themed Collection will redirect the attention to the fascinating spectrum of physiological and pathophysiological functions of ACE2 and away from it being the victim of a virus. ACE2 deserves a more appreciative celebration on its 20th birthday!
The authors declare that there are no competing interests associated with the manuscript.
This work was supported by the Deutsche Forschungsgemeinschaft [grant number SFB 1365 (to M.B. and N.A.)].