Angiotensin-converting enzyme (EC3.4.15.1), or ACE, is a central component of the renin–angiotensin system (RAS), which controls blood pressure by regulating the volume of fluids in the body. It converts the hormone angiotensin I to the active vasoconstrictorangiotensin II. Therefore, ACE indirectly increases blood pressure by causing blood vessels to constrict. ACE inhibitors are widely used as pharmaceutical drugs for treatment of cardiovascular diseases.[5]
"hypertensin converting enzyme" peptidyl dipeptidase I
peptidyl-dipeptide hydrolase
peptidyldipeptide hydrolase
endothelial cell peptidyl dipeptidase
peptidyl dipeptidase-4
PDH
peptidyl dipeptide hydrolase
DCP
CD143
Function
ACE hydrolyzes peptides by the removal of a dipeptide from the C-terminus. Likewise it converts the inactive decapeptide angiotensin I to the octapeptide angiotensin II by removing the dipeptide His-Leu.[9]
Proposed ACE catalytic mechanism
ACE is a central component of the renin–angiotensin system (RAS), which controls blood pressure by regulating the volume of fluids in the body.
Kininase II is the same as angiotensin-converting enzyme. Thus, the same enzyme (ACE) that generates a vasoconstrictor (ANG II) also disposes of vasodilators (bradykinin).[11]
Mechanism
ACE is a zinc metalloproteinase.[13] The zinc center catalyses the peptide hydrolysis. Reflecting the critical role of zinc, ACE can be inhibited by metal-chelating agents.[14]
ACE in complex with inhibitor lisinopril, zinc cation shown in grey, chloride anions in yellow. Based on PyMOL rendering of PDB 1o86. The picture shows that lisinopril is a competitive inhibitor, since it and angiotensin I are similar structurally. Both bind to the active site of ACE. The structure of the ACE-lisinopril complex was confirmed by X-ray crystallography.[15]
The E384 residue is mechanistically critical. As a general base, it deprotonates the zinc-bound water, producing a nucleophilic Zn-OH center. The resulting ammonium group then serves as a general acid to cleave the C-N bond.[16]
The function of the chloride ion is very complex and is highly debated. The anion activation by chloride is a characteristic feature of ACE.[17] It was experimentally determined that the activation of hydrolysis by chloride is highly dependent on the substrate. While it increases hydrolysis rates for e.g. Hip-His-Leu it inhibits hydrolysis of other substrates like Hip-Ala-Pro.[16] Under physiological conditions the enzyme reaches about 60% of its maximal activity toward angiotensin I while it reaches its full activity toward bradykinin. It is therefore assumed that the function of the anion activation in ACE provides high substrate specificity.[17] Other theories say that the chloride might simply stabilize the overall structure of the enzyme.[16]
Genetics
The ACE gene, ACE, encodes two isozymes. The somatic isozyme is expressed in many tissues, mainly in the lung, including vascular endothelial cells, epithelial kidney cells, and testicularLeydig cells, whereas the germinal is expressed only in sperm. Brain tissue has ACE enzyme, which takes part in local RAS and converts Aβ42 (which aggregates into plaques) to Aβ40 (which is thought to be less toxic) forms of beta amyloid. The latter is predominantly a function of N domain portion on the ACE enzyme. ACE inhibitors that cross the blood–brain barrier and have preferentially selected N-terminal activity may therefore cause accumulation of Aβ42 and progression of dementia.[citation needed]
ACE inhibitors inhibit ACE competitively.[18] That results in the decreased formation of angiotensin II and decreased metabolism of bradykinin, which leads to systematic dilation of the arteries and veins and a decrease in arterial blood pressure. In addition, inhibiting angiotensin II formation diminishes angiotensin II-mediated aldosterone secretion from the adrenal cortex, leading to a decrease in water and sodium reabsorption and a reduction in extracellular volume.[19]
ACE's effect on Alzheimer's disease is still highly debated. Alzheimer patients usually show higher ACE levels in their brain. Some studies suggest that ACE inhibitors that are able to pass the blood-brain-barrier (BBB) could enhance the activity of major amyloid-beta peptide degrading enzymes like neprilysin in the brain resulting in a slower development of Alzheimer's disease.[20] More recent research suggests that ACE inhibitors can reduce risk of Alzheimer's disease in the absence of apolipoprotein E4 alleles (ApoE4), but will have no effect in ApoE4- carriers.[21] Another more recent hypothesis is that higher levels of ACE can prevent Alzheimer's. It is assumed that ACE can degrade beta-amyloid in brain blood vessels and therefore help prevent the progression of the disease.[22]
A negative correlation between the ACE1 D-allele frequency and the prevalence and mortality of COVID-19 has been established.[23]
The angiotensin converting enzyme gene has more than 160 polymorphisms described as of 2018.[24]
Studies have shown that different genotypes of angiotensin converting enzyme can lead to varying influence on athletic performance.[25][26] However, these data should be interpreted with caution due to the relatively small size of the investigated groups.
The rs1799752 I/D polymorphism (aka rs4340, rs13447447, rs4646994) consists of either an insertion (I) or deletion (D) of a 287 base pair sequence in intron 16 of the gene.[24] The DD genotype is associated with higher plasma levels of the ACE protein, the DI genotype with intermediate levels, and II with lower levels.[24] During physical exercise, due to higher levels of the ACE for D-allele carriers, hence higher capacity to produce angiotensin II, the blood pressure will increase sooner than for I-allele carriers. This results in a lower maximal heart rate and lower maximum oxygen uptake (VO2max). Therefore, D-allele carriers have a 10% increased risk of cardiovascular diseases. Furthermore, the D-allele is associated with a greater increase in left ventricular growth in response to training compared to the I-allele.[27] On the other hand, I-allele carriers usually show an increased maximal heart rate due to lower ACE levels, higher maximum oxygen uptake and therefore show an enhanced endurance performance.[27] The I allele is found with increased frequency in elite distance runners, rowers and cyclists. Short distance swimmers show an increased frequency of the D-allele, since their discipline relies more on strength than endurance.[28][29]
History
The enzyme was reported by Leonard T. Skeggs Jr. in 1956.[30] The crystal structure of human testis ACE was solved in the year 2002 by Ramanathan Natesh, Sylva Schwager, and Edward Sturrock in the lab of K. Ravi Acharya.[15] It is located mainly in the capillaries of the lungs but can also be found in endothelial and kidney epithelial cells.[31]
^"Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^"Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^Kaplan's Essentials of Cardiac Anesthesia. Elsevier. 2018. doi:10.1016/c2012-0-06151-0. ISBN978-0-323-49798-5. Mechanisms of Action:ACE inhibitors act by inhibiting one of several proteases responsible for cleaving the decapeptide Ang I to form the octapeptide Ang II. Because ACE is also the enzyme that degrades bradykinin, ACE inhibitors increase circulating and tissue levels of bradykinin (Fig. 8.4).
^Fillardi PP (2015). ACEi and ARBS in Hypertension and Heart Failure. Vol. 5. Switzerland: Springer International Publishing. pp. 10–13. ISBN978-3-319-09787-9.
^Coates D (June 2003). "The angiotensin converting enzyme (ACE)". The International Journal of Biochemistry & Cell Biology. Renin–Angiotensin Systems: State of the Art. 35 (6): 769–773. doi:10.1016/S1357-2725(02)00309-6. PMID12676162.
^ ab"Integration of Salt and Water Balance". Medical Physiology: a Cellular and Molecular Approach. Philadelphia, PA: Elsevier Saunders. 2005. pp. 866–867. ISBN978-1-4160-2328-9.
^Bünning P, Riordan JF (July 1985). "The functional role of zinc in angiotensin converting enzyme: implications for the enzyme mechanism". Journal of Inorganic Biochemistry. 24 (3): 183–198. doi:10.1016/0162-0134(85)85002-9. PMID2995578.
^ abcZhang C, Wu S, Xu D (June 2013). "Catalytic mechanism of angiotensin-converting enzyme and effects of the chloride ion". The Journal of Physical Chemistry B. 117 (22): 6635–6645. doi:10.1021/jp400974n. PMID23672666.
^ abBünning P (1983). "The catalytic mechanism of angiotensin converting enzyme". Clinical and Experimental Hypertension. Part A, Theory and Practice. 5 (7–8): 1263–1275. doi:10.3109/10641968309048856. PMID6315268.
^Klabunde RE. "ACE-inhibitors". Cardiovascular Pharmacology Concepts. cvpharmacology.com. Archived from the original on 2 February 2009. Retrieved 26 March 2009.
^Wang P, Fedoruk MN, Rupert JL (2008). "Keeping pace with ACE: are ACE inhibitors and angiotensin II type 1 receptor antagonists potential doping agents?". Sports Medicine. 38 (12): 1065–1079. doi:10.2165/00007256-200838120-00008. PMID19026021. S2CID7614657.
^ abMontgomery HE, Clarkson P, Dollery CM, Prasad K, Losi MA, Hemingway H, et al. (August 1997). "Association of angiotensin-converting enzyme gene I/D polymorphism with change in left ventricular mass in response to physical training". Circulation. 96 (3): 741–747. doi:10.1161/01.CIR.96.3.741. PMID9264477.
^Sanders J, Montgomery H, Woods D (2001). "Kardiale Anpassung an Körperliches Training" [The cardiac response to physical training] (PDF). Deutsche Zeitschrift für Sportmednizin (in German). 52 (3): 86–92. Archived(PDF) from the original on 8 March 2016. Retrieved 1 March 2016.
^Costa AM, Silva AJ, Garrido ND, Louro H, de Oliveira RJ, Breitenfeld L (August 2009). "Association between ACE D allele and elite short distance swimming". European Journal of Applied Physiology. 106 (6): 785–790. doi:10.1007/s00421-009-1080-z. hdl:10400.15/3565. PMID19458960. S2CID21167767.
Roĭtberg GE, Tikhonravov AV, Dorosh ZV (2004). "Rol' polimorfizma gena angiotenzinprevrashchaiushchego fermenta v razvitii metabolicheskogo sindroma" [Role of angiotensin-converting enzyme gene polymorphism in the development of metabolic syndrome]. Terapevticheskii Arkhiv (in Russian). 75 (12): 72–77. PMID14959477.
Vynohradova SV (2005). "[The role of angiotensin-converting enzyme gene I/D polymorphism in development of metabolic disorders in patients with cardiovascular pathology]". TSitologiia I Genetika. 39 (1): 63–70. PMID16018179.
Sabbagh AS, Otrock ZK, Mahfoud ZR, Zaatari GS, Mahfouz RA (March 2007). "Angiotensin-converting enzyme gene polymorphism and allele frequencies in the Lebanese population: prevalence and review of the literature". Molecular Biology Reports. 34 (1): 47–52. doi:10.1007/s11033-006-9013-y. PMID17103020. S2CID9939390.
Castellon R, Hamdi HK (2007). "Demystifying the ACE polymorphism: from genetics to biology". Current Pharmaceutical Design. 13 (12): 1191–1198. doi:10.2174/138161207780618902. PMID17504229.
Lazartigues E, Feng Y, Lavoie JL (2007). "The two fACEs of the tissue renin-angiotensin systems: implication in cardiovascular diseases". Current Pharmaceutical Design. 13 (12): 1231–1245. doi:10.2174/138161207780618911. PMID17504232.
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