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{{Sandbox_gvsu_chm463}}<!-- PLEASE ADD YOUR CONTENT BELOW HERE --> | {{Sandbox_gvsu_chm463}}<!-- PLEASE ADD YOUR CONTENT BELOW HERE --> | ||
'''Class C β-lactamases''' are a subcategory of β-lactamase enzymes. These enzymes are produced by some bacteria and result in their resistance to a variety of β-lactam antibiotics. β-lactam antibiotics are classified based on their chemical structure which contains a four membered, amide containing ring known as the β-lactam ring. Class C β-lactamases specifically target [http://en.m.wikipedia.org/wiki/Cephalosporin cephalosporin] antibiotics and deactivate their antimicrobial activity by hydrolyzing the [http://en.m.wikipedia.org/wiki/Β-lactam β-lactam ring]. | '''Class C β-lactamases''' are a subcategory of β-lactamase enzymes. These enzymes are produced by some bacteria and result in their resistance to a variety of β-lactam antibiotics. β-lactam antibiotics are classified based on their chemical structure which contains a four membered, amide containing ring known as the β-lactam ring. <scene name='69/691534/Class_c_beta-lactamase/1'>Class C β-lactamases</scene><ref>Powers, Rachel, Hollister C. Swanson, Magdalena A. Taracila, Nicholas W. Florek, Chiara Romagnoli, Emilia Caselli, Fabio Prati, Robert A. Bonomo, and Bradley J. Wallar. Biochemical and Structural Analysis of Inhibitors Targeting the ADC-7 Cephalosporinase of Acinetobacter baumannii. Biochemistry, 2014, 53 (48), 7670-7679.</ref> specifically target [http://en.m.wikipedia.org/wiki/Cephalosporin cephalosporin] antibiotics and deactivate their antimicrobial activity by hydrolyzing the [http://en.m.wikipedia.org/wiki/Β-lactam β-lactam ring]. | ||
<Structure load='1ke4' size='400' frame='true' color='white' align='right' caption='Class C Beta-lactamase' /> | <Structure load='1ke4' size='400' frame='true' color='white' align='right' caption='Class C Beta-lactamase' scene='69/691534/Class_c_beta-lactamase/1'/> | ||
{| class="wikitable" border="1" cellpadding="5" cellspacing="0" align="center" style="float: right; border: 1px solid #BBB; margin: .46em 0 0 .2em;" | {| class="wikitable mw-collapsible" border="1" cellpadding="5" cellspacing="0" align="center" style="float: right; border: 1px solid #BBB; margin: .46em 0 0 .2em;" | ||
|+ Class C β-lactamase | |+ Class C β-lactamase | ||
|- | |- | ||
! style="background: #efefef;" colspan="2" |Identifiers | ! style="background: #efefef;" colspan="2" |Identifiers | ||
|- | |- | ||
| [http://en.wikipedia.org/wiki/Enzyme_Commission_number EC number] || [http://www.chem.qmul.ac.uk/iubmb/enzyme/EC3/5/2/8.html 5.2.8], [http://www.chem.qmul.ac.uk/iubmb/enzyme/EC3/5/2/ | | [http://en.wikipedia.org/wiki/Enzyme_Commission_number EC number] || [http://www.chem.qmul.ac.uk/iubmb/enzyme/EC3/5/2/8.html 3.5.2.8], [http://www.chem.qmul.ac.uk/iubmb/enzyme/EC3/5/2/6.html 3.5.2.6] | ||
|- | |- | ||
| [http://en.wikipedia.org/wiki/CAS_Registry_Number CAS number] || [http://tools.wmflabs.org/magnustools/cas.php?language=en&cas= | | [http://en.wikipedia.org/wiki/CAS_Registry_Number CAS number] || [http://tools.wmflabs.org/magnustools/cas.php?language=en&cas=9012-26-4&title= 9012-26-4] | ||
|- | |- | ||
! style="background: #efefef;" colspan="2" |Databases | |||
|- | |||
| [http://en.wikipedia.org/wiki/KEGG KEGG] || [http://www.genome.jp/dbget-bin/www_bget?ec:3.5.2.6 β-lactamases] | |||
|- | |||
! class="mw-collapsible mw-collapsed wikitable" style="background: #efefef;" colspan="2" |Search | |||
|- | |||
|[http://en.wikipedia.org/wiki/National_Center_for_Biotechnology_Information NCBI] || [http://www.ncbi.nlm.nih.gov/protein?term=3.5.2.6%5BEC/RN%20Number%5D%20AND%20%28cephalosporinase%5BAll%20Fields%5D%20OR%20%22class%20c%20beta%20lactamase%22%5BAll%20Fields%5D%29&cmd=DetailsSearch proteins] | |||
|} | |} | ||
== Function and Mechanism == | == 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]] | [[Image:Peptidoglycan_cross_linking.png|400px|thumb|left|Peptidoglycan with PBP Cross-linking Mechanism]] | ||
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</ref> | </ref> | ||
One of the main causes of [http://en.wikipedia.org/wiki/Antimicrobial_resistance resistance] to β-lactam drugs is caused by β-lactamases. Chemically, β-lactamases bind to β-lactams the same way β-lactams bind to PBPs. However, the β-lactamases are then able to deactivate the antimicrobial activity of the β-lactams by cleaving the β-lactam bound in the active site through a molecular process called [http://en.m.wikipedia.org/wiki/Acetylation deacylation], rendering it incapable of inhibiting the PBPs and ultimately, allowing cross-linking to occur for adequate cell wall formation. | One of the main causes of [http://en.wikipedia.org/wiki/Antimicrobial_resistance resistance] to β-lactam drugs is caused by β-lactamases. Chemically, β-lactamases bind to β-lactams the same way β-lactams bind to PBPs. However, the β-lactamases are then able to deactivate the antimicrobial activity of the β-lactams by cleaving the β-lactam bound in the <scene name='69/691534/Class_c_beta-lactamase_as/2'>active site</scene><ref>Powers, Rachel, Hollister C. Swanson, Magdalena A. Taracila, Nicholas W. Florek, Chiara Romagnoli, Emilia Caselli, Fabio Prati, Robert A. Bonomo, and Bradley J. Wallar. Biochemical and Structural Analysis of Inhibitors Targeting the ADC-7 Cephalosporinase of Acinetobacter baumannii. Biochemistry, 2014, 53 (48), 7670-7679.</ref> through a molecular process called [http://en.m.wikipedia.org/wiki/Acetylation deacylation], rendering it incapable of inhibiting the PBPs and ultimately, allowing cross-linking to occur for adequate cell wall formation. | ||
[[Image:Beta-lactam inhibition.png|500px|thumb|center|Image showing mechanism performed by β-lactam antibiotic within PBP [http://en.m.wikipedia.org/wiki/Active_site active site].]] | [[Image:Beta-lactam inhibition.png|500px|thumb|center|Image showing mechanism performed by β-lactam antibiotic within PBP [http://en.m.wikipedia.org/wiki/Active_site active site].]] | ||
== Class C Mechanism == | == Class C Mechanism == | ||
| Line 36: | Line 47: | ||
Bush, Karen. The ABCD’s of β-lactamase nomenclature. J Infect chemother. (2013) 19, 549-559.</ref> | 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- | 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. | 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. | ||
