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Hydrazides Are Potent Transition-State Analogues for Glutaminyl Cyclase Implicated in the Pathogenesis of Alzheimer's Disease.
Biochemistry ( IF 2.9 ) Pub Date : 2020-06-17 , DOI: 10.1021/acs.biochem.0c00337
Oliver Kupski 1, 2 , Lisa-Marie Funk 1, 2 , Viktor Sautner 1, 2 , Franziska Seifert 1 , Brigitte Worbs 3 , Daniel Ramsbeck 4 , Franc Meyer 5 , Ulf Diederichsen 3 , Mirko Buchholz 4 , Stephan Schilling 4 , Hans-Ulrich Demuth 4 , Kai Tittmann 1, 2
Affiliation  

Amyloidogenic plaques are hallmarks of Alzheimer’s disease (AD) and typically consist of high percentages of modified Aβ peptides bearing N-terminally cyclized glutamate residues. The human zinc(II) enzyme glutaminyl cyclase (QC) was shown in vivo to catalyze the cyclization of N-terminal glutamates of Aβ peptides in a pathophysiological side reaction establishing QC as a druggable target for therapeutic treatment of AD. Here, we report crystallographic snapshots of human QC catalysis acting on the neurohormone neurotensin that delineate the stereochemical course of catalysis and suggest that hydrazides could mimic the transition state of peptide cyclization and deamidation. This hypothesis is validated by a sparse-matrix inhibitor screening campaign that identifies hydrazides as the most potent metal-binding group compared to classic Zn binders. The structural basis of hydrazide inhibition is illuminated by X-ray structure analysis of human QC in complex with a hydrazide-bearing peptide inhibitor and reveals a pentacoordinated Zn complex. Our findings inform novel strategies in the design of potent and highly selective QC inhibitors by employing hydrazides as the metal-binding warhead.

中文翻译:

酰肼是涉及阿尔茨海默氏病发病机理的谷氨酰胺基环化酶的有效过渡态类似物。

淀粉样蛋白斑块是阿尔茨海默氏病(AD)的标志,通常由高百分比的带有N末端环化谷氨酸残基的修饰Aβ肽组成。已显示,人锌(II)酶谷氨酰胺环化酶(QC)在体内可催化Aβ肽的N末端谷氨酸的环化,从而将QC确立为AD治疗的可治疗靶标。在这里,我们报告人QC催化作用于神经激素神经降压素的晶体学快照,描绘了催化的立体化学过程,并表明酰肼可以模拟肽环化和脱酰胺的过渡状态。这一假设通过稀疏基质抑制剂筛选活动得到了验证,该活动将酰肼确定为与经典Zn粘合剂相比最有效的金属结合基团。肼的抑制作用的结构基础是通过人QC与带有酰肼的肽抑制剂形成复合物的X射线结构分析得到的,并揭示了五配位的Zn络合物。我们的发现通过使用酰肼作为结合金属的战斗部,为有效和高度选择性的QC抑制剂的设计提供了新的策略。
更新日期:2020-07-21
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