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Angiotensin converting enzyme

Angiotensin converting enzyme (ACE) is well known for its dual actions to convert inactive Ang I to active Ang II, and degrades active bradykinin (BK), which plays an important role in controlling blood pressure. Because it is the bottleneck step for the production of pressor Ang II, it was targeted pharmacologically in the 1970s. Successful ACE inhibitors such as captopril were produced to treat hypertension. Studies on domain-specific ACE inhibitors are continuing to produce effective hypertension-controlling drugs with fewer side effects. ACE2 was discovered in 2000 and it converts Ang II into Ang(1–7), thereby reducing the concentration of Ang II as well as increasing that of Ang(1–7), an important enzyme for Ang(1–7)/Mas receptor signaling. ACE2 also acts as the receptor in the lung for the coronavirus, causing the infamous severe acute respiratory syndrome (SARS) in 2003.


Discovery
ACE was discovered in the mid-1950s through the observation that the dialysis of plasma and kidney extract with water and saline before incubation produced two separate pressor substances, Ang I and Ang II, respectively. 1 It was discovered for a second time in 1966 during the characterization of a bradykinin (BK)-degrading enzyme from the kidney. This was named kininase II, which later was found to be the same enzyme as ACE. ACE2 was discovered in 2000 when two independent research groups cloned homologous ACE that could convert Ang I to Ang [1][2][3][4][5][6][7][8][9] and yet also be captopril-insensitive. 2,3 Structure

Structural features
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) (Fig. 42D.1). Both catalytic domains are zinc-metallopeptidase with the active motif HEMGH where the two histidine residues coordinate the zinc ion. The K m for Hip-His-Leu is 2.51 mM. The stalk anchors the enzyme on the membrane and is suspectible to be cleaved by shedding enzymes, resulting in plasma ACE activity (Fig. 42D.1). 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.

Primary structure
Somatic and testis ACEs in humans contain 1306 and 665 aa residues, respectively ( Fig. 42D.S1). The testis ACE only possesses one catalytic domain.

Properties
Mr. of ACE 195 kDa; Mr. of testis ACE 90 kDa; and Mr. of ACE2 92 kDa. ACEs are membrane-bound enzymes.

Synthesis and release
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.

Distribution of mRNA
Somatic ACE is expressed in various tissues, including the blood vessels, kidney, intestine, adrenal gland, liver, uterous, etc.; it is especially abundant in highly vascular organs such as the retina and lung. Testis ACE is expressed by postmeiotic male germ cells and high level expression is found in round and elongated spermatids. ACE2 is expressed in the lung, liver, intestine, brain, testis, heart, and kidney.

Tissue contents
The lung possesses the highest amount of ACE, and contributes to 0.1% of the total protein. Several enzymatic assays have been developed for the measurement of ACE activity in plasma and tissues. These assays utilized artificial substrates such as hipuryl-His-Leu or N-[3-(2-furyl) acryloyl]L-phenylalanyl-glycyl-glycine (FAPGG), in combination with ACE inhibition by captopril, to estimate the inhibitor-dependent consumption rate of the artificial substrates. These methods were developed in mammals but were also extended to other vertebrates, including birds, amphibians, and fish. 4 However, these enzymatic methods may be erroneous because the enzyme specificity on the artificial substrates could be different. Lamprey ACE activities in different tissues were measured but captopril failed to decrease the ACE activities, indicating a possible nonspecific enzyme measurement. In amphibians, high captopril-sensitive ACE activities were found in the gonad, intestine, kidney, and lung; moderate activities were presented in the liver, heart, and skin; and low or negligible activities were observed in the plasma, muscle, and erythrocytes.

Regulation of 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. 6 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.

Receptors 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. 7 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. 8

Biological functions Target cells/tissues and 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. 1 ACE2 can convert Ang II to Ang 1-7 , thereby reducing the concentration of Ang II and increasing that of Ang 1-7 . ACE2 can also convert Ang I to Ang 1-9 , which is subsequently converted into Ang 1-7 by ACE. The high expression of ACE2 favors the balance of Ang 1-7 over Ang II, which accounts for the cardioprotective role of ACE2 via the Ang 1-7 /Mas signaling pathway. 9 Phenotype in gene-modified animals Ace-knockout mice display normal blood pressure under normal conditions, but are sensitive to changes in blood pressure such as through exercise. Ace-knockout also affected renal function, renal development, serum and urine electrolyte composition, hematocrit, and male reproductive capacity. 10 Deficiency in testis Ace affects male fertility but its exact role is still not clear. Although the mice with testis Ace deficiency mate normally and their sperm quantity and motility are no different from wild-type mice, the survival of sperm in the oviduct and the fertilization rate are highly reduced. 1 The overexpression of Ace2 in hypertensive models, but not in normotensive animals, reduced the blood pressure. Ace2-knockout mice displayed progressive cardiac dysfunction resembling long-term hypoxia after coronary artery disease or bypass surgery in humans, which could be reversed by concurrent Ace-knockout. It was suggested that the cardioprotective function of ACE2 is to counterbalance the effects of ACE.

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. 5 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.

Use for diagnosis and treatment
ACE has been the target of hypertension control since the 1970s. ACE inhibitors are prescribed as the sole or combinational treatment for high blood pressure, for its dual effects of lowering Ang II and slowing down BK degradation. In human hypertensive patients, ACE2 levels are lower in both the kidney and heart compared to normotensive volunteers.