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The enzyme, Angiotensin Converting Enzyme, plays a critical role in the Renin - Angiotensin - Aldosterone System Basso N and Terrango N. 2001. This system controls the amount of Arteriolar Vasoconstriction and blood pressure levels within the body. Angiotensin Converting Enzyme is found in the pulmonary endothelium in the Lungs and in the renal endothelium in the Kidneys (Page, M et al. 2004. Page 117).
Angiotensin Converting Enzyme has a quaternary structure, as shown in Figure 1, which has two polypeptide chains. The C- Terminal is critical for blood pressure regulation (Junot C et al. 2001). There is also an N- Terminal, shown in Figure 1, which is highly glycosylated, making it very hydrophobic (Brew K. 2003). It is a relatively small enzyme, weighing between 130,000 - 140,000 Daltons (Cookson W et al. 2013). Figure 1 shows the enzyme also contains both zinc and chloride ions (Natesh R, et al. 2003). This metallopeptidase is a vital part of the metabolism of biologically active peptides (Sturrock ED, et al. 2004).
Figure 1: A 3D structure of Angiotensin Converting Enzyme.( this picture is from this website: http://www.esrf.eu/UsersAndScience/Publications/Highlights/2003/MX/MX10)
There is an abundance of Î± - helices in the molecule, shown in Figure 1, which help to constrict the zinc - binding active site (Acharya KR, et al. 2003). The limited size of the active site (Acharya KR, et al. 2003) has stopped inhibitors, such as Lisinopril, from competing with the active site of the enzyme (Ehrlich JR, et al. 2006). The inhibitors are non - competitive and bind to a different part of the molecule, thus stopping the active site from working (Ehrlich JR, et al. 2006). Skeggs (et al. 1956) first discovered Angiotensin Converting Enzyme was able to catalyse the hydrolysis of both internal and external amino acids. Peptide bonds in both the interior and at the end of peptide bonds were successfully hydrolysed. Making Angiotensin Converting Enzyme both an endopeptindase and an exopeptidase (Skeggs et al 1956).
The Renin - Angiotensin - Aldosterone system starts when the protein Angiotensinogen is cleaved into the smaller decapeptide Angiotensin I in the Liver. It then enters the bloodstream and travels to the lungs (Cohen E, et al. 2000). Angiotensin Converting Enzyme is released from the pulmonary endothelium into the bloodstream (Page, M et al. 2004. Page 196-7). This is where the cleaving of the dipeptide His - Leu on Angiotensin I takes place, forming a smaller octapeptide Angiotensin II (Natesh R, et al. 2003). The production of Angiotensin II causes vasoconstriction of the arteries and veins, which leads to hypertension (Natesh R, et al. 2003).
Figure 2: Shows the inhibition of the N- Terminal of Angiotensin Converting Enzyme (blue molecule) by Lisinopril (green molecule). From Crystal structure of the N domain of human somatic angiotensin I-converting enzyme provides a structural basis for domain-specific inhibitor design., Corradi HR, Schwager SL, Nchinda AT, Sturrock ED, Acharya KR, J Mol Biol. 2006 Mar 31;357(3):964-74. Epub 2006 Jan 31.
However, Angiotensin Converting Enzyme Inhibitors are used to reverse the constriction of blood vessels by inhibiting or stopping the enzyme from catalysing reactions, shown in Figure 2 (Simpson K and Jarvis B. 2000). The reduction of Angiotensin II is vital when treating problems such as heart failure and Hypertension because Angiotensin II is a powerful vasoconstrictor. There are many Angiotensin Converting Enzyme Inhibitors available to use, such as Ramipril and Lisinopril, which are mainly used to treat Hypertension (Henry J, 1998. 387). However, as more research is carried out on these Inhibitors, is has been found that they are suitable to use when treating other health problems linked to both the cardiovascular system and the Renal system (Bristol Laboratories Ltd. 2013). These drugs join to the N- Terminal of Angiotensin Converting Enzyme, shown in Figure 2, causing the active site to change shape. Thus, stopping Angiotensin I being cleaved into Angiotensin II by the enzyme (Simpson K and Jarvis B. 2000).
The inhibition of Angiotensin Converting Enzyme stops the inactivation of the biological molecule Bradykinin (Simpson K and Jarvis B. 2000). This allows the formation of nitric oxide in the endothelium, promoting Bradykinin's vasodilatory and cardio - protective properties (Simpson K and Jarvis B. 2000). The importance of Angiotensin Converting Enzyme and its role in the homeostasis of blood pressure has been proven by Cole (et al. 2011). Cole found that knockout mice that had less Angiotensin Converting Enzyme and therefore a reduced blood pressure, which resulted in Hypotension and organ damage (Pandey, Kailash N. 2010). This research has shown only a certain percentage of Angiotensin Converting Enzyme should be inhibited to allow the body to maintain a healthy blood pressure (Cole et al. 2011).
Angiotensin Converting Enzyme and its inhibitors are a major target for pharmaceutical companies because of the amount of illnesses which can be improved by the use of the inhibitors (Bristol Laboratories Ltd. 2013). Research by Miners (et al) in 2008 has shown that Angiotensin Converting Enzyme can help treat types of Dementia by increasing the supply of oxygen to the brain (Henry J, 1998, page 98). It is also used as a way to treat patients with renal diseases such as Diabetic Nephropathy (Bristol Laboratories Ltd. 2013). It is also used as a secondary precaution to reduce the risk of heart failure in patients showing symptoms within 48 hours of a Myocardial Infarction (Henry J, 1998, page 98). New research has shown that Angiotensin Converting Enzyme has a reducing effect on blood vessels which have atherosclerosis (Rushworth C et al. 2008). This is because the chloride ion within the Enzyme is sensitive to certain substances which are found within the blood of patients with atherosclerosis.
Overall, Angiotensin Converting Enzyme is a vital enzyme in the human body, and it is also a very important enzyme for pharmaceutical companies. It is a very important enzyme as it is able to control a number of conditions within the body. Without this enzyme the homeostasis of blood pressure would be impossible to maintain. The use of x-ray crystallography has allowed scientists to find out the shape of Angiotensin Converting Enzyme. Knowing the structure of Angiotensin Converting Enzyme has helped Pharmaceutical Companies to produce drugs which inhibit the enzyme and help to reduce high blood pressure and a wide range of other diseases. As the research into this drug improves and becomes more in depth, more will be found out about this enzyme and how important it's medical significance is will become clearer.
http://biochem.uvm.edu/courses/files/381_fall_2006_crystal_structure_of_the_human.pdf - "Angiotensin converting enzyme has a critical role in the cardiovascular function by cleaving the carboxy terminal His-Leu dipeptide from Angiotensin I to produce a potent vasopressor octapeptide Angiotensin II."
Hypertension: recommended first-line antihypertensive in diabetics and younger (<55 years) patients with hypertension, and second-line for other patients if blood pressure (BP) is not adequately controlled on thiazide or a calcium-channel blocker (or if these drugs are not tolerated or are contra-indicated). See separate article Management of Hypertension.
Heart failure: (particularly in patients with left ventricular dysfunction); reduces both mortality and hospital admissions in these patients. More recently data are emerging that ACE inhibitors are also beneficial in patients with heart failure and normal left ventricular systolic function. See separate article Heart Failure Management.
Post-myocardial infarction (MI): ACE inhibitors reduce ischaemic events, mortality and hospital admissions (heart failure or further MI) in this group of patients. There is good evidence to suggest that they should be started early.
Diabetic nephropathy: as well as lowering BP, ACE inhibitors reduce the rate of albumin excretion in normotensive diabetic patients (types 1 and 2), and there is reduced mortality (all causes).
Non-diabetic renal disease: ACE inhibitors can lower urinary protein excretion in patients with proteinuria and slow progression to renal failure (evidence for white populations only) - hence they are indicated for most patients with chronic renal disease.
From: The British Medical Association. New Guide to Medicines and Drugs. Henry, JA (1997). Star Standard Industries: Singapore. Page 98.
Angiotensin Converting Enzyme inhibitors are often used in Medicine as a Vasodilator.
Vasodilators are drugs that widen blood vessels. Their most obvious use is to reverse the narrowing of the blood vessels when this leads to reduced blood flow and a lower oxygen supply to parts of the body. This problem occurs in Angina. Vasodilators are often used to treat hypertension.
Why they are used:
Trials for using ACE inhibitors to treat dementia.
To treat Peripheral Vascular disease, which is narrow blood vessels in the legs.
Further developments of the drug is to find a way for it to treat atherosclerosis.
References - list of journals and books to look at:
Human body 2004(book)
http://web.ebscohost.com/ehost/detail?vid=3&sid=e878ce41-3af5-4894-85c1-aef6723d5f83%40sessionmgr115&hid=124&bdata=JnNpdGU9ZWhvc3QtbGl2ZQ%3d%3d#db=afh&AN=19215776 - Structural diversity of angiotensin-converting enzyme.
R. Natesh (a), S.L.U. Schwager (b), E.D. Sturrock (b) and K.R. Acharya (a),Nature 421, 551 (2003).
http://www.ncbi.nlm.nih.gov/pubmed/15549168 [Accessed: 01/03/2013].
http://www.ncbi.nlm.nih.gov/pubmed/12915047 [Accessed: 01/03/2013].
http://www.ncbi.nlm.nih.gov/pubmed/11303049 [Accessed: 01/03/2013].
http://eurheartj.oxfordjournals.org/content/27/5/512.full.pdf+html [Accessed: 03/03/2013].
http://web.ebscohost.com/ehost/detail?vid=3&sid=e878ce41-3af5-4894-85c1-aef6723d5f83%40sessionmgr115&hid=124&bdata=JnNpdGU9ZWhvc3QtbGl2ZQ%3d%3d#db=afh&AN=2803619 - Angiotensin II receptor antagonists.
Simpson K and Jarvis B (2000) Lisinopril: A review of its Use in Congestive Heart Failure. Drugs. Volume 59 (5). Page 1 - 5.
http://hyper.ahajournals.org/content/38/6/1246.full ]Accessed: 01/03/2013].
Renin-angiotensin-aldosterone system blockade for cardiovascular diseases: current status ebsco host
Control of radiation-induced pneumopathy and lung fibrosis by angiotensin-converting enzyme inhibitors and an angiotensin II type 1 receptor blocker. - ebsco host.
Regulation of cardiac angiotensin-converting enzyme and angiotensin AT1 receptor gene expression in Npr1 gene-disrupted mice. Pandey, Kailash N Vellaichamy, Elangovan Source: Clinical & Experimental Pharmacology & Physiology; Feb2010, Vol. 37 Issue 2, pe70-e77, 8p, 1 Diagram, 1 Chart, 2 Graphs
Residues affecting the chloride regulation and substrate
selectivity of the angiotensin-converting enzymes (ACE
and ACE2) identified by site-directed mutagenesis
Christopher A. Rushworth, Jodie L. Guy and Anthony J. Turner
Institute of Molecular and Cellular Biology, Faculty of Biological Sciences, University of Leeds, UK 2008.