Sandbox Reserved 992: Difference between revisions

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== Function and Mechanism ==

[[Image:Beta-lactam.jpg|200px|thumb|left|A [http://en.m.wikipedia.org/wiki/Beta-lactam_antibiotic β-lactam antibiotic] ([http://en.m.wikipedia.org/wiki/Penicillin Penicillin])]]Clinically, [http://en.m.wikipedia.org/wiki/Beta-lactam_antibiotic β-lactam antibiotics], characterized by their central chemical structure, are utilized to combat bacterial infections by targeting [http://proteopedia.org/wiki/index.php/Penicillin-binding_protein penicillin-binding proteins] (PBPs), also known as [http://en.m.wikipedia.org/wiki/DD-transpeptidase transpeptidases]. PBPs are enzymes that are located in the cell membrane of bacteria and function in [http://en.wikipedia.org/wiki/Cross-link cross-linking] to form the [http://en.m.wikipedia.org/wiki/Peptidoglycan peptidoglycan] layer. PBPs have a conserved [http://en.m.wikipedia.org/wiki/Deprotonation deprotonated] serine which executes [http://en.m.wikipedia.org/wiki/Nucleophile nucleophilic] attack on the [http://en.m.wikipedia.org/wiki/Carbonyl carbonyl] carbon. The PBP is then covalently attached to one unit of peptidoglycan. The amino group of an alanine on a second unit of peptidoglycan then performs a second nucleophilic attack on the carbonyl carbon, resulting in two covalently cross-linked peptidoglycan units and the regeneration of the catalytic PBP.<ref>"Peptidoglycan cell wall." The University of Warwick. n.d. Web. 25 Jan 15</ref>

[[Image:Beta-lactam.jpg|200px|thumb|left|A [http://en.m.wikipedia.org/wiki/Beta-lactam_antibiotic β-lactam antibiotic] ([http://en.m.wikipedia.org/wiki/Penicillin Penicillin])]]Clinically, [http://en.m.wikipedia.org/wiki/Beta-lactam_antibiotic β-lactam antibiotics], characterized by their central chemical structure, are utilized to combat bacterial infections by targeting [http://proteopedia.org/wiki/index.php/Penicillin-binding_protein penicillin-binding proteins] (PBPs), also known as [http://en.m.wikipedia.org/wiki/DD-transpeptidase transpeptidases]. PBPs are enzymes that are located in the cell membrane of bacteria and function in [http://en.wikipedia.org/wiki/Cross-link cross-linking] to form the [http://en.m.wikipedia.org/wiki/Peptidoglycan peptidoglycan] layer. PBPs have a conserved, [http://en.m.wikipedia.org/wiki/Deprotonation deprotonated] serine which executes [http://en.m.wikipedia.org/wiki/Nucleophile nucleophilic] attack on the [http://en.m.wikipedia.org/wiki/Carbonyl carbonyl] carbon. The PBP is then covalently attached to one unit of peptidoglycan. The amino group of an alanine on a second unit of peptidoglycan then performs a second nucleophilic attack on the carbonyl carbon, resulting in two covalently cross-linked peptidoglycan units and the regeneration of the catalytic PBP.<ref>"Peptidoglycan cell wall." The University of Warwick. n.d. Web. 25 Jan 15</ref>

[[Image:Peptidoglycan_cross_linking.png|400px|thumb|left|Peptidoglycan with PBP Cross-linking Mechanism]]

Line 36:

Bush, Karen. The ABCD’s of β-lactamase nomenclature. J Infect chemother. (2013) 19, 549-559.</ref>

Class C β-lactamases share a very similar mechanism as the Class A β-~~lactams~~, acylation followed by hydrolytic deacylation.4 Class C differs from A in that the hydrolytic water, activated by tyrosine 150, approaches the enzyme from the opposite side. This activated water is what allows β-lactamases to deacylation and maintain their catalytic function, while PBPs cannot.<ref name="Bush 2013" /> Class D differs from A and C in that it has an N-carboxylated active site lysine which hydrogen bonds with the active site serine.<ref>Mobashery, Shahriar. Bacterial Resistance to β-Lactam Antibiotics: Compelling Opportunism, Compelling Opportunity. Chem. Rev. (2005) 105, 395-424.</ref>

Class C β-lactamases share a very similar mechanism as the Class A β-lactamases, acylation followed by hydrolytic deacylation.4 Class C differs from A in that the hydrolytic water, activated by tyrosine 150, approaches the enzyme from the opposite side. This activated water is what allows β-lactamases to deacylation and maintain their catalytic function, while PBPs cannot.<ref name="Bush 2013" /> Class D differs from A and C in that it has an N-carboxylated active site lysine which hydrogen bonds with the active site serine.<ref>Mobashery, Shahriar. Bacterial Resistance to β-Lactam Antibiotics: Compelling Opportunism, Compelling Opportunity. Chem. Rev. (2005) 105, 395-424.</ref>

Class C β-lactamases functions as a monomer and among many other enzyme types, contains a structural component known as an [http://en.m.wikipedia.org/wiki/Oxyanion_hole oxyanion hole]. This pocket of [http://en.m.wikipedia.org/wiki/Hydrophile hydrophilic] residues directly stabilizes the high-energy [http://en.m.wikipedia.org/wiki/Tetrahedral_carbonyl_addition_compound tetrahedral intermediate], lowering the [http://en.m.wikipedia.org/wiki/Activation_energy activation energy] and promoting a faster overall reaction.<ref>Albert Lehninger et al. (2008). Principles of Biochemistry (5th ed.). Macmillan. p. 207.</ref><ref>Livermore, David. β-Lactamase mediated resistance and opportunities for its control. J. Antimicrob. Chemother. (1998) 41 (suppl 4): 25-41.</ref> The hydrophobicity of ADC-1, a class C β-lactamase, is shown <scene name='69/691534/Hydrophobicity_in_adc-1/1'>here</scene><ref>Bhattacharya, M., Toth, M., Antunes, N.T., Smith, C.A., Vakulenko, S.B. Structure of the extended-spectrum class C β-lactamase ADC-1 from Acinetobacter baumannii. Acta Crystallogr. (2014),Sect.D 70: 760-771</ref>. In the structure, red regions denote charged residues, while purple represent hydrophillic residues and grey, hydrophobic.

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@@ Line 19: / Line 19: @@
 == Function and Mechanism ==
-[[Image:Beta-lactam.jpg|200px|thumb|left|A [http://en.m.wikipedia.org/wiki/Beta-lactam_antibiotic β-lactam antibiotic] ([http://en.m.wikipedia.org/wiki/Penicillin Penicillin])]]Clinically, [http://en.m.wikipedia.org/wiki/Beta-lactam_antibiotic β-lactam antibiotics], characterized by their central chemical structure, are utilized to combat bacterial infections by targeting [http://proteopedia.org/wiki/index.php/Penicillin-binding_protein penicillin-binding proteins] (PBPs), also known as [http://en.m.wikipedia.org/wiki/DD-transpeptidase transpeptidases]. PBPs are enzymes that are located in the cell membrane of bacteria and function in [http://en.wikipedia.org/wiki/Cross-link cross-linking] to form the [http://en.m.wikipedia.org/wiki/Peptidoglycan peptidoglycan] layer. PBPs have a conserved [http://en.m.wikipedia.org/wiki/Deprotonation deprotonated] serine which executes [http://en.m.wikipedia.org/wiki/Nucleophile nucleophilic] attack on the [http://en.m.wikipedia.org/wiki/Carbonyl carbonyl] carbon. The PBP is then covalently attached to one unit of peptidoglycan. The amino group of an alanine on a second unit of peptidoglycan then performs a second nucleophilic attack on the carbonyl carbon, resulting in two covalently cross-linked peptidoglycan units and the regeneration of the catalytic PBP.<ref>"Peptidoglycan cell wall." The University of Warwick. n.d. Web. 25 Jan 15</ref>
+[[Image:Beta-lactam.jpg|200px|thumb|left|A [http://en.m.wikipedia.org/wiki/Beta-lactam_antibiotic β-lactam antibiotic] ([http://en.m.wikipedia.org/wiki/Penicillin Penicillin])]]Clinically, [http://en.m.wikipedia.org/wiki/Beta-lactam_antibiotic β-lactam antibiotics], characterized by their central chemical structure, are utilized to combat bacterial infections by targeting [http://proteopedia.org/wiki/index.php/Penicillin-binding_protein penicillin-binding proteins] (PBPs), also known as [http://en.m.wikipedia.org/wiki/DD-transpeptidase transpeptidases]. PBPs are enzymes that are located in the cell membrane of bacteria and function in [http://en.wikipedia.org/wiki/Cross-link cross-linking] to form the [http://en.m.wikipedia.org/wiki/Peptidoglycan peptidoglycan] layer. PBPs have a conserved, [http://en.m.wikipedia.org/wiki/Deprotonation deprotonated] serine which executes [http://en.m.wikipedia.org/wiki/Nucleophile nucleophilic] attack on the [http://en.m.wikipedia.org/wiki/Carbonyl carbonyl] carbon. The PBP is then covalently attached to one unit of peptidoglycan. The amino group of an alanine on a second unit of peptidoglycan then performs a second nucleophilic attack on the carbonyl carbon, resulting in two covalently cross-linked peptidoglycan units and the regeneration of the catalytic PBP.<ref>"Peptidoglycan cell wall." The University of Warwick. n.d. Web. 25 Jan 15</ref>
 [[Image:Peptidoglycan_cross_linking.png|400px|thumb|left|Peptidoglycan with PBP Cross-linking Mechanism]]
@@ Line 36: / Line 36: @@
 Bush, Karen. The ABCD’s of β-lactamase nomenclature. J Infect chemother. (2013) 19, 549-559.</ref>
-Class C β-lactamases share a very similar mechanism as the Class A β-lactams, acylation followed by hydrolytic deacylation.4 Class C differs from A in that the hydrolytic water, activated by tyrosine 150, approaches the enzyme from the opposite side. This activated water is what allows β-lactamases to deacylation and maintain their catalytic function, while PBPs cannot.<ref name="Bush 2013" /> Class D differs from A and C in that it has an N-carboxylated active site lysine which hydrogen bonds with the active site serine.<ref>Mobashery, Shahriar. Bacterial Resistance to β-Lactam Antibiotics:  Compelling Opportunism, Compelling Opportunity. Chem. Rev. (2005) 105, 395-424.</ref>
+Class C β-lactamases share a very similar mechanism as the Class A β-lactamases, acylation followed by hydrolytic deacylation.4 Class C differs from A in that the hydrolytic water, activated by tyrosine 150, approaches the enzyme from the opposite side. This activated water is what allows β-lactamases to deacylation and maintain their catalytic function, while PBPs cannot.<ref name="Bush 2013" /> Class D differs from A and C in that it has an N-carboxylated active site lysine which hydrogen bonds with the active site serine.<ref>Mobashery, Shahriar. Bacterial Resistance to β-Lactam Antibiotics:  Compelling Opportunism, Compelling Opportunity. Chem. Rev. (2005) 105, 395-424.</ref>
 Class C β-lactamases functions as a monomer and among many other enzyme types, contains a structural component known as an [http://en.m.wikipedia.org/wiki/Oxyanion_hole oxyanion hole]. This pocket of [http://en.m.wikipedia.org/wiki/Hydrophile hydrophilic] residues directly stabilizes the high-energy [http://en.m.wikipedia.org/wiki/Tetrahedral_carbonyl_addition_compound tetrahedral intermediate], lowering the [http://en.m.wikipedia.org/wiki/Activation_energy activation energy] and promoting a faster overall reaction.<ref>Albert Lehninger et al. (2008). Principles of Biochemistry (5th ed.). Macmillan. p. 207.</ref><ref>Livermore, David. β-Lactamase mediated resistance and opportunities for its control. J. Antimicrob. Chemother. (1998) 41 (suppl 4): 25-41.</ref> The hydrophobicity of ADC-1, a class C β-lactamase, is shown <scene name='69/691534/Hydrophobicity_in_adc-1/1'>here</scene><ref>Bhattacharya, M.,  Toth, M.,  Antunes, N.T.,  Smith, C.A.,  Vakulenko, S.B. Structure of the extended-spectrum class C β-lactamase ADC-1 from Acinetobacter baumannii. Acta Crystallogr. (2014),Sect.D 70: 760-771</ref>. In the structure, red regions denote charged residues, while purple represent hydrophillic residues and grey, hydrophobic.