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首页> 外文期刊>Journal of Molecular Biology >Multiple global suppressors of protein stability defects facilitate the evolution of extended-spectrum TEM beta-lactamases.
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Multiple global suppressors of protein stability defects facilitate the evolution of extended-spectrum TEM beta-lactamases.

机译：蛋白质稳定性缺陷的多种全局抑制因子促进了广谱TEMβ-内酰胺酶的进化。

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摘要

The introduction of extended-spectrum cephalosporins and beta-lactamase inhibitors has driven the evolution of extended-spectrum beta-lactamases (ESBLs) that possess the ability to hydrolyze these drugs. The evolved TEM ESBLs from clinical isolates of bacteria often contain substitutions that occur in the active site and alter the catalytic properties of the enzyme to provide an increased hydrolysis of extended-spectrum cephalosporins or an increased resistance to inhibitors. These active-site substitutions often result in a cost in the form of reduced enzyme stability. The evolution of TEM ESBLs is facilitated by mutations that act as global suppressors of protein stability defects in that they allow the enzyme to absorb multiple amino acid changes despite incremental losses in stability associated with the substitutions. The best-studied example is the M182T substitution, which corrects protein stability defects and is commonly found in TEM ESBLs or inhibitor-resistant variants from clinical isolates. In this study, a genetic selection for second-site mutations that could partially restore function to a severely destabilized primary mutant enabled the identification of A184V, T265M, R275Q, and N276D, which are known to occur in TEM ESBLs from clinical isolates, as suppressors of TEM-1 protein stability defects. Further characterization demonstrated that these substitutions increased the thermal stability of TEM-1 and were able to correct the stability defects of two different sets of destabilizing mutations. The acquisition of compensatory global suppressors of stability costs associated with active-site mutations may be a common mechanism for the evolution of novel protein function.
机译：广谱头孢菌素和β-内酰胺酶抑制剂的引入推动了具有水解这些药物能力的广谱β-内酰胺酶（ESBLs）的发展。从细菌临床分离株进化得到的TEM ESBLs通常包含在活性位点发生的取代，并改变酶的催化特性，以提供扩大的广谱头孢菌素的水解或对抑制剂的抵抗力。这些活性位点取代经常导致酶稳定性降低的形式产生成本。 TEM作为蛋白质稳定性缺陷的整体抑制因子，可促进TEM ESBLs的进化，因为突变使酶能够吸收多种氨基酸变化，尽管与取代相关的稳定性不断增加。研究最多的例子是M182T取代，它可纠正蛋白质稳定性缺陷，通常在TEM ESBLs或临床分离株的抗药性变异体中发现。在这项研究中，对第二位点突变的遗传选择可以部分恢复严重不稳定的一级突变体的功能，从而能够鉴定出A184V，T265M，R275Q和N276D，它们在临床分离株的TEM ESBLs中作为抑制物而存在TEM-1蛋白稳定性缺陷。进一步的表征表明，这些取代增加了TEM-1的热稳定性，并能够纠正两组不同的不稳定突变组的稳定性缺陷。与活动位点突变相关的稳定性成本的补偿性全局抑制因子的获得可能是新型蛋白质功能进化的常见机制。

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