Structure-Based Design Guides the Improved Efficacy of Deacylation Transition State Analogue Inhibitors of TEM-1 -Lac
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- 作者：Steven Ness ; Richard Martin ; Alois M. Kindler ; Mark Paetzel ; Marvin Gold ; Susan E. Jensen ; J. Bryan Jones ; and Natalie C. J. Strynadka
- 刊名：Biochemistry
- 出版年：2000
- 出版时间：May 9, 2000
- 年：2000
- 卷：39
- 期：18
- 页码：5312 - 5321
- 全文大小：1076K
- 年卷期：v.39,no.18(May 9, 2000)
- ISSN：1520-4995
文摘
Transition state analogue boronic acid inhibitors mimicking the structures and interactions ofgood penicillin substrates for the TEM-1 
-lactamase of Escherchia coli were designed using graphicanalyses based on the enzyme's 1.7 Å crystallographic structure. The synthesis of two of these transitionstate analogues, (1R)-1-phenylacetamido-2-(3-carboxyphenyl)ethylboronic acid (1) and (1R)-1-acetamido-2-(3-carboxy-2-hydroxyphenyl)ethylboronic acid (2), is reported. Kinetic measurements show that, asdesigned, compounds 1 and 2 are highly effective deacylation transition state analogue inhibitors of TEM-1-lactamase, with inhibition constants of 5.9 and 13 nM, respectively. These values identify them asamong the most potent competitive inhibitors yet reported for a -lactamase. The best inhibitor of thecurrent series was (1R)-1-phenylacetamido-2-(3-carboxyphenyl)ethylboronic acid (1, KI = 5.9 nM), whichresembles most closely the best known substrate of TEM-1, benzylpenicillin (penicillin G). The high-resolution crystallographic structures of these two inhibitors covalently bound to TEM-1 are also described.In addition to verifying the design features, these two structures show interesting and unanticipated changesin the active site area, including strong hydrogen bond formation, water displacement, and rearrangementof side chains. The structures provide new insights into the further design of this potent class of -lactamaseinhibitors.
-lactamase of Escherchia coli were designed using graphicanalyses based on the enzyme's 1.7 Å crystallographic structure. The synthesis of two of these transitionstate analogues, (1R)-1-phenylacetamido-2-(3-carboxyphenyl)ethylboronic acid (1) and (1R)-1-acetamido-2-(3-carboxy-2-hydroxyphenyl)ethylboronic acid (2), is reported. Kinetic measurements show that, asdesigned, compounds 1 and 2 are highly effective deacylation transition state analogue inhibitors of TEM-1-lactamase, with inhibition constants of 5.9 and 13 nM, respectively. These values identify them asamong the most potent competitive inhibitors yet reported for a -lactamase. The best inhibitor of thecurrent series was (1R)-1-phenylacetamido-2-(3-carboxyphenyl)ethylboronic acid (1, KI = 5.9 nM), whichresembles most closely the best known substrate of TEM-1, benzylpenicillin (penicillin G). The high-resolution crystallographic structures of these two inhibitors covalently bound to TEM-1 are also described.In addition to verifying the design features, these two structures show interesting and unanticipated changesin the active site area, including strong hydrogen bond formation, water displacement, and rearrangementof side chains. The structures provide new insights into the further design of this potent class of -lactamaseinhibitors.