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Questions And Answer

• Structure

  Two isozymes of ACE are present in mammals: somatic ACE and testis ACE. Somatic ACE possesses two catalytic domains (N- and C-domains) and a C-terminal transmembrane segment (stalk). Both catalytic domains are zinc-metallopeptidase with the active motif HEMGH where the two histidine residues coordinate the zinc ion. The Km for Hip-His-Leu is 2.51mM. The stalk anchors the enzyme on the membrane and is suspectible to be cleaved by shedding enzymes, resulting in plasma ACE activity. ACE2 is a chimera protein with a single catalytic domain of ACE, and a C-terminal that highly resembles collectrin, which may act as a chaperone protein to deliver other proteins to the brush border membrane. Somatic and testis ACEs in humans contain 1306 and 665 aa residues, respectively. The testis ACE only possesses one catalytic domain.
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• Gene, mRNA, and mRNA

  The ACE and ACE2 genes are located at chromosomes 17q23 and Xp22 in humans, respectively. The testis ACE is transcribed from the same gene with an alternative transcription starting site on the 13th intron of ACE, resulting in only a C-domain and a stalk segment with a unique additional 67 aa N-terminal sequence in humans. The two catalytic domains are the result of gene/domain duplication. The duplication occurred multiple times in evolution as the cnidarians, crustaceans, insects, and vertebrates possess ACE-like enzymes with one or two catalytic domains. No expression studies so far have been performed for nonmammalian ACE and ACE2. ;

• Synthesis and release

  The expression of ACE is affected by steroids and the thyroid hormone, but the details of the regulation are not clear. ACE is under promoter regulation by hypoxiainducing factor 1α (HIF-1α), which upregulates the ACE expression under hypoxic conditions, resulting in an increase in Ang II concentration. Under hypoxia, ACE2 will be downregulated; it was shown that it is indirectly controlled by Ang II, but not HIF-1α.  Testis ACE expression control is highly specific and regulated by a tissue-specific promoter located immediately -59 bp of the transcription start site, which is frequently used in testis-specific overexpression studies. Hypoxia induced by high temperature decreased the gill ACE activity but had no effect on the kidney in the carp. Promoters of ACE2 from mammals, amphibians, and teleosts drive specific expression in the heart. Cis-Element search results discovered WGATAR motifs in all putative ACE2 promoters from different vertebrates, suggesting a possible role of GATA family transcriptional factors in ACE2 expression regulation.;

• Inhibitors

  The first ACE inhibitor was a peptide antagonist called SQ 20,881 (GWPRPEIPP); it was discovered from snake venom but was not orally active. The snake venom peptides were further studied to produce the first orally active form, captopril, which lowers the blood pressure of essential hypertensive patients. The most common side effects of captopril are a cough, skin rash, and loss of taste. Therefore, derivatives such as enalapril, lisinopril, and ramipril were developed with fewer side effects. After the discovery of the N- and C-domains of ACE, specific domain inhibitors were developed to increase specificity. Ang I is mainly hydrolyzed by the C-domain in vivo, but BK is hydrolyzed by both domains. Developing a C-domain selective inhibitor (RXPA380) would permit some degradation of BK by the N-domain; this degradation could be enough to prevent the accumulation of excess BK causing angioedema.;

• Biological functions

  The well-known function of ACE is the conversion of Ang I to Ang II and the degradation of BK, which plays an important role in controlling the blood pressure. ACE also acts on other natural substrates, including encephalin, neurotensin, and substance P. Besides being involved in blood pressure control, ACE possesses widespread functions including renal development, male fertility, hematopoiesis, erythropoiesis, myelopoiesis, and immune responses. ACE2 can convert Ang II to Ang1–7, thereby reducing the concentration of Ang II and increasing that of Ang1–7. ACE2 can also convert Ang I to Ang1–9, which is subsequently converted into Ang1–7 by ACE. The high expression of ACE2 favors the balance of Ang1–7 over Ang II, which accounts for the cardioprotective role of ACE2 via the Ang1–7/Mas signaling pathway.;

• Clinical implications

  The inclusion (II) or deletion (DD) of the 287 bp Alu repeat in the 16th intron affects the human plasma ACE levels. The DD genotype is more frequently found in patients with myocardial infarction but no convincing evidence is available on the association of the DD genotype with hypertension. ACE2 was identified as the receptor for the SARS (severe acute respiratory syndrome) coronavirus. The SARS virus binding downregulates the cellular expression of ACE2, and the binding induces the clathrin-dependent internalization of the virus/receptor (SARS/ACE2) complex. Not only has ACE2 facilitated the invasion of the SARS virus for rapid replication, but also ACE2 is depleted from the cell membrane. Therefore, the damaging effects of Ang II are enhanced, resulting in the acute deterioration of lung tissues.;

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