Lisinopril-Angiotensin Converting Enzyme

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Angiotensin Converting Enzyme is an enzyme that is found in the renin system that converts the hormone angiotensin I into angiotensin II which affects blood pressure by regulating the volume of fluids. The drug Lisinopril is an Angiotensin Converting Enzyme Inhibitor, which lowers the blood pressure in the body.

Contents

Structure of Enzyme

The [1] is a type- 1 membrane bound protein that has 28 residue C- terminal cytosolic domains as well as 22- residue hydrophobic transmembrane domains and it has 1227 residue extracellular domain. The main structural feature of this enzyme is mainly helical with a central channel that extends into the molecule. On the enzyme are the extracellular domain has two more isoforms of ACE, which are N- domains and C-domains. The N-domain plays a role in hematopoietic stem cell differentiation and proliferation while C-domain is mainly involved in blood pressure regulation. In each of these domains are two histidine residues which are used to binding zinc ligands with glutamine to make the geometry tetrahedral. Through mutational analyses and detailed kinetics, it is clear that both zinc sites have activity which is considered to be catalytic [2]

Function of ACE

The angiotensin converting enzyme (ACE) is an enzyme that is found renin angiotensin system which is often known as RAS. Renin is an enzyme that is found in the liver and it cleaves angiotensinogen into angiotensin I. RAS is a hormone system that regulates blood pressure and fluids as well as electrolyte balance. It is a zinc and chloride dependent metallopeptidase that is membrane bound. The job of the enzyme is to catalyze the conversion of to the physiologically active peptide . It does this cleaving C-terminal (His-Leu) dipeptide on the angiotensin I. When Angiotensin II binds to angiotensin I, vasoconstriction occurs by the smooth muscle cells. As a result of this, blood pressure increases. [3] The ACE enzyme is known for being identical to the kinase which is an enzyme that degrades bradykinin. These two systems work very similarly.

Structure of Lisinopril

[4] (S)-1-[(N^2-carboxyl-3-phenylpropyl]-L-lysyl-L-proline diyhdrate) is a drug was patented by Merck and Co in 1987. It is a drug that is used to inhibit the Angiotensin converting enzyme to treat hypertension, congestive heart failure and improve survival after a heart attack. Its molecular formula is C21H31N3O5•2H2O. This drug is soluble in water, and is insoluble in ethanol and slightly soluble in methanol.This is a prescription only medication that comes in three different strengths, 5, 10, 20mg. The active ingredient in this drug is Lisinopril but there are a few inactive ingredients. Those of which include, calcium phosphate, mannitol, magnesium stearate and starch. These inactive ingredients are in all three strengths however, in the 10mg and 20mg strength there is an extra ingredient added which is iron oxide. [5]

Image:Lisinopril.png

Mechanism of Action

Angiotensin Converting Enzyme inhibitors have many uses in the treatment of cardiovascular and renal diseases. Lisinopril is known as an Angiotensin Converting Enzyme inhibitor and it works by preventing the conversation of angiotensin I to angiotensin II by binding the Angiotensin Converting Enzyme. When there is a decrease in angiotensin II, it causes a reduction in aldosterone section and this in turn causes a decrease in sodium reabsorption within the collecting ducts as well as decrease potassium excretion. In the end by removing the negative feedback of angiotensin II, the drug can lead to an increase in serum renin activity.[6] As explained in the previous section, there are two isoforms of the enzyme ACE, C- domain and N- Domain. While both of these domains play different roles the medication inhibits both domain’s activity however, the active part of this drug is the peptides derivatives that contain the C-terminal proline.[7] The drug binding is highly ordered and extended conformation. When binding there is not significant rearrangement that occurs at the active site. The carboxylic carboxylate of Lisinopril is positioned to create an ionic bond to the [8] active site. There are three ligands that are created and the three ligands line (two histidine and a glutamic acid) up perfectly between the two structures of Lisinopril and the angiotensin converting enzyme.[9] The proline forms a hydrogen bond with Lisinopril as well as the active site of the enzyme which has an ammonia cation group, binds to the carboxylic acid of the drug.

Side Effects of ACE Inhibitors

ACE inhibitors are used for many different treatments of cardiovascular and renal diseases. These drugs are used to alter the balance of a few different systems including, vasoconstrictive, salt- retentive and hyperopic properties. Lisinopril is one of the drugs that is used to treat hypertension however it is not just effecting the blood pressure. When Lisinopril is introduced into the body and attaches to the active site of the angiotensin converting enzyme through competitive inhibition it causes the levels of bradykinin found with kinase which is very similar to ACE, in the blood stream to rise. This is because ACE helps break down bradykinin and when Lisinopril is used the enzyme is inhibited which is also inhibiting the breakdown of bradykinin. So not only does Lisinopril cause a decrease in blood pressure but it also causes an increase in vasodilation.[10]This often causes the person taking the medication of have a dry cough as a side effect of the medication.

References

  1. Akif M, Georgiadis D, Mahajan A, Dive V, Sturrock ED, Isaac RE, Acharya KR. High-resolution crystal structures of Drosophila melanogaster angiotensin-converting enzyme in complex with novel inhibitors and antihypertensive drugs. J Mol Biol. 2010 Jul 16;400(3):502-17. Epub 2010 May 19. PMID:20488190 doi:10.1016/j.jmb.2010.05.024
  2. Riordan, James F. “Angiotensin-I-Converting Enzyme and Its Relatives.” Genome Biology, BioMed Central, 2003, www.ncbi.nlm.nih.gov/pmc/articles/PMC193637/.
  3. Sturrock, E.D., Natesh, R., van Rooyen, J.M. et al. CMLS, Cell. Mol. Life Sci. (2004) 61: 2677. https://doi.org/10.1007/s00018-004-4239-0
  4. Canner, D. Lisinopril http://proteopedia.org/wiki/index.php/prinivil (accessed May 2, 2019).
  5. PRINIVIL® (lisinopril) https://www.merck.com/product/usa/pi_circulars/p/prinivil/prinivil_pi.pdf
  6. Lopez, Edgardo Olvera. “Lisinopril.” StatPearls [Internet]., U.S. National Library of Medicine, 20 Jan. 2019, www.ncbi.nlm.nih.gov/books/NBK482230/
  7. Sondes Bouabdallah, Med Thaieb Ben Dhia, and Med Rida Driss, “Study of a Conformational Equilibrium of Lisinopril by HPLC, NMR, and DFT,” International Journal of Analytical Chemistry, vol. 2014, Article ID 494719, 8 pages, 2014. https://doi.org/10.1155/2014/494719.
  8. http://proteopedia.org/wiki/index.php/ACE_Inhibitor_Prinivil
  9. Sturrock, E D, et al. “Structure of Angiotensin I-Converting Enzyme.” Cellular and Molecular Life Sciences, vol. 61, 2004, doi:10.18411/a-2017-023.
  10. Brown , Nancy J, and Douglas E Vaughan. “Angiotensin-Converting Enzyme Inhibitors.” Circulation, www.ahajournals.org/doi/10.1161/01.CIR.97.14.1411.

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