Penicillins Structure and Function

Penicillins Structure and FunctionRachael Sim Hwee LingA Molecule that Shapes the World C16H18N2O4SThe ba call in of penicillin has revolutionized the world of medicine and saved millions of lives. Penicillin is a collection of antibiotics derived from Penicillium fungi1. Antibiotics are specific substances derived from active organisms that fucking inhibit the life processes of other organisms2. Penicillin is effective against a range of bacterium such as staphylococciand streptococci and bacteria causing diseases like meningitis and gonorrhea3. Unlike sulfanilamide which is toxic to the kidney, penicillin has no harsh effects. It is non-irritating and can be applied to tissues directly4. Du echo World War II, the administration of penicillin to the wounded soldiers greatly strike downd their chanceS of defect infection and raised their survival chances in the interim time between the wounding and surgery (14 hours for the affiliate Forces), thus dramatically reducing the need for amputations and the death toll from infected wounds5. Today, penicillin is still commonly utilize to treat conditions. Penicillin is often prescribed after dental surgery to prevent infections6.The diseases and infections mentioned above are caused by bacteria. Al nearly all bacteria bear mobile phone moles made up of peptidoglycan, a rigid but elastic structure, that protects the underlying protoplast from mechanical damage and prevent it from bursting under osmotic pressure. Peptidoglycan is made up of long polysaccharide chains that are cross-linked via flexible peptide bridges7. The synthesis of bacterial cell seawall is catalyzed by the enzyme transpeptidase. Such synthesis is essential to the growth, cellular reproduction and maintaining the structure of bacteria.In 1965, Tipper and Strominger hypothe surfaced that penicillin kills bacteria by blocking the action of the transpeptidase that catalyzes the last step of synthesis which involves the cross-linking of different peptidoglycan chains, thus inhibiting the synthesis of the cell wall8. Water then enters the cell causing it to swell and explode. This essay volition discuss how penicillins design, structure, instability enable it to inhibit the action of transpeptidase, examine the science behind penicillins fight backion, how the structure and size influence its effectiveness and the significance of the lack of symmetry.Penicillin structure consists of a thiazolidine think fused to a -lactum ring to which a variable R assembly is attached by a peptide bond. (Fig 1) Penicillin G (Fig 2), which has a benzyl side-chain, is often regarded as the prototype of the class as it is one of the first-generation penicillin that can be obtained directly from the fungi. It is the most potent of the class against suasible gram-positive bacteria and is still widely used.9 Penicillin G is only effective against gram-positive bacteria in which the transpeptidases are directly accessible.Fig 1 Ge neral Penicillin molecule withR side chain, 3 chiral centres (*) anda -lactum ring (blue)Fig 2 Natural penicillin-G where R = benzyl groupFig 3 D-Alanyl-D-alanine which closely resembles penicillin (In D-amino acid, with the H mote pointing up and looking down from the H atom and moving anti-CW, the amino acid has the order cooH, R, NH2)One explanation about the mechanism of action of penicillin is that it mimics the shape and structure of the D-alanine-D-alanine termini of bacterial peptidoglycan (the usual substrate) and is thus recognized by transpeptidases10. The transpeptidase enzyme reacts preferentially and binds irreversibly with penicillin. The penicilloyl-enzyme formed is invariable and does not react any further11. The free COOH group present mimics that of terminal carboxyl of D-alanine-D-alanine and is necessary for penicillin to bind at the active site12. The similarities in their molecular structures can be clearly discover in Fig1 and Fig3. Furthermore, as penicil lin lacks symmetry, its mirror images are non-super-imposable. In order for penicillin to be biologically active, the 3 chiral centres in penicillin must be in the configuration in Fig113. As penicillins exercise is stereo-dependent, penicillin synthesized must be enantiopure and the arrangement of the groups relative to one another should resemble that of D-alanine-D-alanine. This also explains penicillin non-toxicity. D-alanine only occurs in the cell wall of bacteria and all the proteins within our body are built up from L-amino acids. Hence, penicillin kills bacteria but will not adversely affect humans.14Another explanation also relates to the structure of penicillin and the instability of the cyclic amide in -lactum ring which is fused to the thiazolidine ring. Research by Strominger has shown that the activity of penicillin is due to the inherent strain of the four-membered ring or to the reduced amide resonance15. In the four-membered ring, the C and N atoms are forced to h ave a bond rake of approximately 90 which is far below the preferred bond angle for singly-bonded sp3 hybridised carbon and nitrogen atoms (109.5) and doubly-bonded sp2 hybridised carbon atom (120). This put the small ring under great ring strain which is further aggravated by the five-membered thiazolidine ring fused with it. X-ray crystallography has also showed that the 2 fused rings and the amide bond is non-planar. This leads to a loss of resonance stabilization normally found in these amide bonds16. These make the amide group more reactive. Penicillin acylates the enzyme and form an open chain compound to relieve the strain.Furthermore, it is hypothesized that the COOH group in penicillins structure contributes to penicillins widely varying acylating ability and its ability to travel through natural fluids unaltered and only target transpeptidase in bacteria. Experimental data obtained from inelastic neutrons and quantum chemical theory suggests that the activity of penicil lin is pH dependent17. Under physiological conditions (pH = 7.4), penicillins -COOH group is deprotonated. As COO and the lone braces of negatrons of N are on the same face of the molecule, the COO will repel the lone gibe of electrons on the N atom. This shortens the amide bond, increases its strength and decrease the acylating power of the lactam ring18. When near the active site of transpeptidase, COO group is protonated and the -lactum amide bond regains its strong acylating power19. The 2 CH3 group is also important for activation as research has found no activity for penicillin analogues with these groups removed.20At the active site, the science of reaction is as follows. The nucleophilic OH group of the serine residue attacks and opens the ring. A covalent bond is formed between the serine on the enzyme and the penicillin molecule21, irreversibly inhibiting the normal function of the enzyme and kills the bacterial cell.The R group in the penicillin structure determines th e effectiveness of the penicillin drug. Penicillin-G cannot be consumed orally as gastric acid will catalyze the hydrolysis of the highly unstable -lactum ring, destroying its antibiotic properties. The -lactum ring is also susceptible to attack by O atom of the neighboring carbonyl group. To prevent this, we can choose an electron withdrawing R group to decrease the nucleophilicity of the carbonyl oxygen on the acyl side chain to reduce the self destructive mechanism22. To avoid degradation by penicillinase enzyme, we can choose a colossal R group as a steric shield.The small size of penicillin molecules increases their potency as it enables them to penetrate the full(a) depth of the cell wall.In conclusion, penicillin-G is a molecule that was cleverly designed molecule by nature. tout ensemble features in its structure its bicyclic system, unstable -lactum ring, COOH group, stereochemistry and size is essential and influence its effectiveness. They enable penicillin to irrever sibly react with transpeptidases, kill harmful bacteria and by doing so, save lives and shape the world.1 penicillin. (n.d.)The American Heritage Medical Dictionary. (2007). Retrieved January 31 2015 fromhttp//medical dictionary.thefreedictionary.com/penicillin2 antibiotic. (n.d.)The American Heritage Medical Dictionary. (2007). Retrieved January 31 2015 fromhttp//medical-dictionary.thefreedictionary.com/antibiotic3 penicillin. (n.d.)Dorlands Medical Dictionary for Health Consumers. (2007). Retrieved January 31 2015 fromhttp//medical-dictionary.thefreedictionary.com/penicillin4 Fleming, A. (1929). On the antibacterial action of cultures of a penicillium, with special reference to their use in the isolation of B. influenzae.British ledger of experimental pathology,10(3), 226.Couteur, P., Burreson, J. (2004). Wonder Drugs. InNapoleons buttons 17 molecules that changed history. Jeremy P. Tarcher/Penguin raw(a) York.5 Medicine and World War Two. (2014, January 1). Retrieved January 3 1, 2015, from http//www.historylearningsite.co.uk/medicine_and_world_war_two.htm6 Ross-Flanigan, Nancy Uretsky, Samuel. Penicillins.Gale Encyclopedia of Childrens Health early childhood through Adolescence. 2006. Retrieved January 31, 2015 from Encyclopedia.comhttp//www.encyclopedia.com/doc/1G2-3447200431.html7 Graumann, P. (2007).Bacillus Cellular and molecular biology(p. 333). Norfolk Caister Academic Press.8 Tipper, D., Strominger, J. (1965.). weapon Of Action Of Penicillins A Proposal ground On Their Structural Similarity To Acyl-D-alanyl-D-alanine.Proceedings of the National Academy of Sciences,1133-11419 Penicillins. (n.d.). Retrieved January 31, 2015, from http//www.emedexpert.com/compare/penicillins.shtml410Tipper, D., Strominger, J. (1965.). Mechanism Of Action Of Penicillins A Proposal Based On Their Structural Similarity To Acyl-D-alanyl-D-alanine.Proceedings of the National Academy of Sciences,1133-1141.11 Berg, J., Tymoczko, J. (2002). Enzymes Basic Concepts and K inetics. InBiochemistry(5th ed.). New York W.H. Freeman.12 Tipper, D., Strominger, J. (1965.). Mechanism Of Action Of Penicillins A Proposal Based On Their Structural Similarity To Acyl-D-alanyl-D-alanine.Proceedings of the National Academy of Sciences,1133-1141.13 Bentley, R. (2004). The molecular(a) Structure of Penicillin.Journal of Chemical Education,1462-1462.14 Otter, C. (2008). Chemical ideas (3ed. ed.). Oxford u.a. Heinemann Educational.15 Strominger, J.L. (1967) . Enzymatic reactions in bacterial cell wall synthesis highly sensitive to penicillins, cephalosprins and other antibacterial agents. Antibiotics, 70571316 J. C. Sheeman, The enchanted Ring The Untold Story of Penicillin, The MIT Press, Cambridge, Massachusetts, 1982J. R. Johnson, R. B. Woodward and R. Robinson, in The Chemistry of Penicillin, ed. H. T. Clarke, J. R. Johnson and R. Robinson, Princeton University Press Princeton, New Jersey, 1949, ch. 15, pp. 443449.17,18,19 Mucsi, Z. Chass, G.A. Abranyi-Balogh, P. Jozart, B. Fang, D.-C. Ramirez-Cuesta, A.J. Viskolcz, B. Csizmadia, I.G. Penicillins catalytic mechanism revealed by inelastic neutrons and quantum chemical theory. Phys. Chem. Chem. Phys. 2013, 15, 2044720455181920 S. Wolfe, J. C. Godfrey, C. T. Holdrege and Y. G. Perron, J. Am. Chem. Soc., 1963, 85, 643 S. Wolfe, J. C. Godfrey, C. T. Holdrege and Y. G. Perron, Can. J. 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