Sandbox Reserved 992: Difference between revisions

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[[Image:Beta lactamase mechaism.jpg|1000px|thumb|center|Class C β-lactamase general mechanism, showing covalently bound β-lactam antibiotic in intermidiate state.]]

Class C β-lactamases, among many other enzyme types, also contain 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 <scene name='69/691534/Hydrophobicity_in_adc-1/1'>ADC-1</scene>, a class C β-lactamase, is shown here.

Class C β-lactamases, among many other enzyme types, also contain 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 <scene name='69/691534/Hydrophobicity_in_adc-1/1'>ADC-1</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>, a class C β-lactamase, is shown here.

== Clinical Significance ==

Line 50:

With the mechanistic knowledge of β-lactamases, there are two apparent options for clinical treatment of β-lactam resistant bacteria. Scientists could either (a) design an entirely new class of antibiotic that are not reliant on the chemical structure of the β-lactam ring, or (b) use the current arsenal of antibiotics in combination with an inhibitor that will deactivate the β-lactamase. A β-lactamase inhibitor is a compound that could form a tight complex to the active site of the enzyme and causes the β-lactamase to be unable to bind and inactivate another antibiotic molecule.<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> This is the active site of AmpC bound with a

<scene name='69/691534/Ampc_in_complex_with_inhibitor/1'>boronic acid transition state inhibitor</scene>.

<scene name='69/691534/Ampc_in_complex_with_inhibitor/1'>boronic acid transition state inhibitor</scene><ref>Powers, R.A., Shoichet, B.K. Structure-based approach for binding site identification on AmpC beta-lactamase. J.Med.Chem. (2002) 45: 3222-3234</ref>.

==References==

Sandbox Reserved 992: Difference between revisions

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@@ Line 41: / Line 41: @@
 [[Image:Beta lactamase mechaism.jpg|1000px|thumb|center|Class C β-lactamase general mechanism, showing covalently bound β-lactam antibiotic in intermidiate state.]]
-Class C β-lactamases, among many other enzyme types, also contain 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 <scene name='69/691534/Hydrophobicity_in_adc-1/1'>ADC-1</scene>, a class C β-lactamase, is shown here.
+Class C β-lactamases, among many other enzyme types, also contain 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 <scene name='69/691534/Hydrophobicity_in_adc-1/1'>ADC-1</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>, a class C β-lactamase, is shown here.
 == Clinical Significance ==
@@ Line 50: / Line 50: @@
 With the mechanistic knowledge of β-lactamases, there are two apparent options for clinical treatment of β-lactam resistant bacteria. Scientists could either (a) design an entirely new class of antibiotic that are not reliant on the chemical structure of the β-lactam ring, or (b) use the current arsenal of antibiotics in combination with an inhibitor that will deactivate the β-lactamase. A β-lactamase inhibitor is a compound that could form a tight complex to the active site of the enzyme and causes the β-lactamase to be unable to bind and inactivate another antibiotic molecule.<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> This is the active site of AmpC bound with a
-<scene name='69/691534/Ampc_in_complex_with_inhibitor/1'>boronic acid transition state inhibitor</scene>.
+<scene name='69/691534/Ampc_in_complex_with_inhibitor/1'>boronic acid transition state inhibitor</scene><ref>Powers, R.A.,  Shoichet, B.K. Structure-based approach for binding site identification on AmpC beta-lactamase. J.Med.Chem. (2002) 45: 3222-3234</ref>.
 ==References==
 <references/>