Enabling Role of Ligand-Driven Conformational Changes in Enzyme Evolution.
Enabling Role of Ligand-Driven Conformational Changes in Enzyme Evolution.
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配体驱动构象变化在酶进化中的作用。
DOI：
10.1021/acs.biochem.2c00178
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发表时间：
2022-08-02
期刊：
影响因子：
2.9
通讯作者：
Richard, John P.
中科院分区：
文献类型：
--
作者：
Richard, John P.
许多在以比底物更高的亲和力结合酶促过渡态方面显示出大的特异性的酶利用底物结合能来驱动蛋白质构象变化以形成笼状底物复合物。这些蛋白质笼提供酶促过渡态的强稳定性。使用部分底物结合能来驱动蛋白质构象变化避免了米氏复合物的类似强稳定性和不可逆配体结合。现代酶催化剂发展的一个开创性步骤是将底物结合与构象变化偶联的酶的进化。这些酶包括在糖酵解（磷酸丙糖异构酶）、脂质生物合成（磷酸甘油脱氢酶）、己糖单磷酸分流（6-磷酸葡萄糖酸脱氢酶）和甲羟戊酸途径（异戊烯基二磷酸异构酶）中起作用的酶，催化嘧啶核苷酸生物合成的最后一步（乳清酸核苷单磷酸脱羧酶），以及调节腺嘌呤核苷酸的细胞水平（腺苷酸激酶）。进化的酶，经历配体驱动的构象变化，形成活性蛋白质-底物笼建议进行选择的变体，其中所选择的侧链取代不稳定的第二个蛋白质构象，显示补偿增强的结合与基板的相互作用。将构象变化纳入催化循环的酶所固有的优势为TIM桶等柔性蛋白质折叠的进化提供了强大的驱动力。这些折叠的出现代表了酶进化中的分水岭事件，使酶超家族内酶活性的快速繁殖成为可能。
Many enzymes that show a large specificity in binding the enzymatic transition state with a higher affinity than the substrate utilize substrate binding energy to drive protein conformational changes to form caged substrate complexes. These protein cages provide strong stabilization of enzymatic transition states. Using part of the substrate binding energy to drive the protein conformational change avoids a similar strong stabilization of the Michaelis complex and irreversible ligand binding. A seminal step in the development of modern enzyme catalysts was the evolution of enzymes that couple substrate binding to a conformational change. These include enzymes that function in glycolysis (triosephosphate isomerase), the biosynthesis of lipids (glycerol phosphate dehydrogenase), the hexose monophosphate shunt (6-phosphogluconate dehydrogenase), and the mevalonate pathway (isopentenyl diphosphate isomerase), catalyze the final step in the biosynthesis of pyrimidine nucleotides (orotidine monophosphate decarboxylase), and regulate the cellular levels of adenine nucleotides (adenylate kinase). The evolution of enzymes that undergo ligand-driven conformational changes to form active protein–substrate cages is proposed to proceed by selection of variants, in which the selected side chain substitutions destabilize a second protein conformer that shows compensating enhanced binding interactions with the substrate. The advantages inherent to enzymes that incorporate a conformational change into the catalytic cycle provide a strong driving force for the evolution of flexible protein folds such as the TIM barrel. The appearance of these folds represented a watershed event in enzyme evolution that enabled the rapid propagation of enzyme activities within enzyme superfamilies.
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Tim Barrel结构促进了蛋白质介导的代谢的早期演变。
影响因子：
3.9
作者：
Goldman AD;Beatty JT;Landweber LF
通讯作者：
Landweber LF
影响因子：
2.9
作者：
Cristobal JR;Brandão TAS;Reyes AC;Richard JP
通讯作者：
Richard JP
影响因子：
2.9
作者：
Brandao, Tiago A. S.;Richard, John P.
通讯作者：
Richard, John P.
影响因子：
2.9
作者：
BELASCO, JG;KNOWLES, JR
通讯作者：
KNOWLES, JR
AMP在碎片中的腺苷酸激酶催化反应：磷酸化转移至磷酸二角体的酶激活。
影响因子：
2.9
作者：
Fernandez PL;Richard JP
通讯作者：
Richard JP