Angiotensin-converting enzyme
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| MetaCyc | metabolic pathway | ||||||||
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| PDB structures | RCSB PDB PDBe PDBsum | ||||||||
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| Location (UCSC) | Chr 17: 63.48 – 63.5 Mb | Chr 11: 105.86 – 105.88 Mb | |||||||
| PubMed search | [3] | [4] | |||||||
| View/Edit Human | View/Edit Mouse |
Angiotensin-converting enzyme (
Other lesser known functions of ACE are degradation of bradykinin,[6] substance P[7] and amyloid beta-protein.[8]
Nomenclature
ACE is also known by the following names:
- dipeptidyl carboxypeptidase I
- peptidase P
- dipeptide hydrolase
- peptidyl dipeptidase
- angiotensin converting enzyme
- kininase II
- angiotensin I-converting enzyme
- carboxycathepsin
- dipeptidyl carboxypeptidase
- "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]
ACE is a central component of the renin–angiotensin system (RAS), which controls blood pressure by regulating the volume of fluids in the body.
ACE is also part of the
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
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
Disease relevance
ACE inhibitors are widely used as pharmaceutical drugs in the treatment of conditions such as
ACE inhibitors inhibit ACE competitively.
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]
Pathology
- Elevated levels of ACE are also found in . It is also noted in some patients with extensive plaque psoriasis.
- Serum levels are decreased in obstructive pulmonary disease, and hypothyroidism.
Influence on athletic performance
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]
The rs1799752 I/D polymorphism consists of either an insertion (I) or absence (D) of a 287 base pair alanine 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.
See also
- ACE inhibitors
- Angiotensin-converting enzyme 2 (ACE2)
- Hypotensive transfusion reaction
- Renin–angiotensin system
References
- ^ a b c GRCh38: Ensembl release 89: ENSG00000159640 - Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000020681 - Ensembl, May 2017
- ^ "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.
- ISBN 978-0-323-49798-5.
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).
- ISBN 978-3-319-09787-9.
- PMID 16428706.
- PMID 16154999.
- PMID 12676162.
- PMID 10790312.
- ^ ISBN 978-1-4160-2328-9.
- PMID 14757781.
- S2CID 829514.
- PMID 2995578.
- ^ from the original on 26 November 2022. Retrieved 22 May 2020.
- ^ PMID 23672666.
- ^ PMID 6315268.
- ^ "Angiotensin converting enzyme (ace) inhibitors" (PDF). British Hypertension Society. Archived from the original (PDF) on 18 November 2017.
- ^ Klabunde RE. "ACE-inhibitors". Cardiovascular Pharmacology Concepts. cvpharmacology.com. Archived from the original on 2 February 2009. Retrieved 26 March 2009.
- ^ "The Importance of Treating the Blood Pressure: ACE Inhibitors May Slow Alzheimer's Disease". Medscape. Medscape Cardiology. 2004. Archived from the original on 31 August 2016. Retrieved 1 March 2016.
- PMID 23948883.
- ^ "ACE Enzyme May Enhance Immune Responses And Prevent Alzheimer's". Science 2.0. 27 August 2014. Archived from the original on 7 March 2016. Retrieved 1 March 2016.
- PMID 32220422.
- ^ PMID 30570054.
- PMID 31139091.
- S2CID 7614657.
- ^ PMID 9264477.
- ^ 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.
- S2CID 21167767.
- PMID 13295487.
- ISBN 978-0-323-04527-8.
Further reading
- Niu T, Chen X, Xu X (2002). "Angiotensin converting enzyme gene insertion/deletion polymorphism and cardiovascular disease: therapeutic implications". Drugs. 62 (7): 977–993. S2CID 46986772.
- 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. PMID 14959477.
- 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. PMID 16018179.
- König S, Luger TA, Scholzen TE (October 2006). "Monitoring neuropeptide-specific proteases: processing of the proopiomelanocortin peptides adrenocorticotropin and alpha-melanocyte-stimulating hormone in the skin". Experimental Dermatology. 15 (10): 751–761. S2CID 32034934.
- 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. S2CID 9939390.
- Castellon R, Hamdi HK (2007). "Demystifying the ACE polymorphism: from genetics to biology". Current Pharmaceutical Design. 13 (12): 1191–1198. PMID 17504229.
- 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. PMID 17504232.
External links
- Proteopedia Angiotensin-converting_enzyme – the Angiotensin-Converting Enzyme Structure in Interactive 3D
- Angiotensin+Converting+Enzyme at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
- Human ACE genome location and ACE gene details page in the UCSC Genome Browser.
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