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Review
. 2004 Jun;25(6):291-4.
doi: 10.1016/j.tips.2004.04.001.

ACE2: from vasopeptidase to SARS virus receptor

Anthony J Turner  1 , Julian A Hiscox, Nigel M Hooper
Affiliations
Review

ACE2: from vasopeptidase to SARS virus receptor

Anthony J Turner et al. Trends Pharmacol Sci. 2004 Jun.

Abstract

The zinc metallopeptidase angiotensin-converting enzyme 2 (ACE2) is the only known human homologue of the key regulator of blood pressure angiotensin-converting enzyme (ACE). Since its discovery in 2000, ACE2 has been implicated in heart function, hypertension and diabetes, with its effects being mediated, in part, through its ability to convert angiotensin II to angiotensin-(1-7). Unexpectedly, ACE2 also serves as the cellular entry point for the severe acute respiratory syndrome (SARS) virus and the enzyme is therefore a prime target for pharmacological intervention on several disease fronts.

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Figures

Figure 1
Figure 1
The counter-actions of angiotensin-converting enzyme (ACE) and angiotensin-converting enzyme 2 (ACE2) in angiotensin metabolism. In the classical renin–angiotensin pathway, the decapeptide Ang I (i.e. Ang1–10), derived from angiotensinogen via the action of renin, is converted by ACE to the vasoactive Ang II (Ang1–8) through the removal of the C-terminal dipeptide His-Leu , . There is increasing evidence that Ang1–7 can counterbalance some of the actions of Ang II , being formed from Ang II by the action of ACE2, or possibly from Ang I by the action of neprilysin (NEP). Although ACE2 can convert Ang I to Ang1–9, which can in turn be converted to Ang1–7 by ACE or NEP, this pathway is unlikely to occur at significant levels in vivo because the metabolism of Ang I by ACE2 is kinetically unfavourable compared with its conversion of Ang II (G.I. Rice. et al., unpublished) and hence is not shown.
Figure 2
Figure 2
The replication strategy of the severe acute respiratory syndrome coronavirus (SARS-CoV). The replication and genome expression strategy of coronaviruses is complex. (a) The SARS-CoV spike glycoprotein recognizes angiotensin-converting enzyme 2 (ACE2) as a receptor on the cell surface. (b) Upon entering the cytoplasm, the virus core particle, which contains the genomic RNA bound to the virus nucleoprotein, is released. (c) The 5′ two-thirds of the genomic RNA is translated by host ribosomes to generate the virus replicase polyprotein (green; RNA-dependent RNA polymerase and other proteins). (d) The replicase attaches to the 3′ end of the input genome and begins (e) replication of a full-length anti-genome and (f) synthesis of negative strand subgenomic RNAs that serve as templates for the synthesis of (g) new genomic RNA and (h) viral subgenomic mRNAs (sgRNAs), respectively. All coronavirus mRNAs have conserved 5′ ends (dark blue box) and are 3′ co-terminal and polyadenylated. There are thought to be eight sgRNAs produced in SARS-CoV infected cells; (i) some of these encode the viral structural proteins (shown here). (j) Release of virus occurs after processing and assembly of virus particles in the Golgi apparatus and rough endoplasmic reticulum. Although primary replication occurs in the cytoplasm, recent evidence suggests that coronaviruses and related viruses use nuclear factors to facilitate the replication process .
Figure 3
Figure 3
The corona virus-infected cell. (a) A confocal microscope image shows the infection of primary cells by coronaviruses. Viral proteins are shown in red and nucleolar fibrillarin is shown in green. Most viral proteins remain in the cytoplasm, although nucleoprotein can localize to the nucleolus and redistribute fibrillarin. Studies of coronavirus infection have been helped greatly by the expression of individual proteins (and mutants) and, following their cellular localization; examples of the localization of (b) membrane protein and (c) nucleoprotein are shown. (b) Membrane protein is shown in green and nucleic acid is stained with propidium iodide (red). (c) Phase-contrast image of cells expressing a green fluorescence protein–nucleoprotein fusion protein (green). Images (a) and (b) are courtesy of Torsten Wurm, and image (c) is courtesy of Jae-Hwan You.
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References

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