Insulin-Degrading Enzyme: Paradoxes and Possibilities.
Insulin-Degrading Enzyme: Paradoxes and Possibilities.
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胰岛素降解酶：悖论和可能性。
DOI：
10.3390/cells10092445
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发表时间：
2021-09-16
期刊：
影响因子：
6
通讯作者：
Leissring MA
中科院分区：
文献类型：
--
作者：
Leissring MA
自从在粗组织提取物中发现蛋白水解活性以来，已经过去了七十多年，这种蛋白水解活性被称为胰岛素降解酶（IDE）。当然，人们对这种非典型的锌金属肽酶已经有了很多了解;然而，与此同时，我们的理解中仍然存在许多基本的空白。在这里，我概述了我认为是该领域内最关键的未解决的问题，许多提出了有趣的悖论。例如，IDE是一种主要的胞质蛋白，没有信号肽或明确的分泌机制，在哪里与胰岛素和其他细胞外底物相互作用？IDE在细胞内的确切位置，以及它在这些隔室中的功能作用是什么？IDE是一种完全包裹其底物的碗状蛋白质，它是如何设法避免被“堵塞”从而立即失去活性的？虽然这些悖论是由定义未解决的，我在这里提供我的个人见解和知情的推测的基础上二十年的生物学和药理学的IDE工作，并提出具体的实验策略，以解决这些难题。我还提供了我认为是特别富有成效的途径，使新技术和IDE特异性试剂的发展成为可能的调查。我希望这些想法将有助于继续阐明这一重要肽酶的生理学和病理生理学。
More than seven decades have passed since the discovery of a proteolytic activity within crude tissue extracts that would become known as insulin-degrading enzyme (IDE). Certainly much has been learned about this atypical zinc-metallopeptidase; at the same time, however, many quite fundamental gaps in our understanding remain. Herein, I outline what I consider to be among the most critical unresolved questions within the field, many presenting as intriguing paradoxes. For instance, where does IDE, a predominantly cytosolic protein with no signal peptide or clearly identified secretion mechanism, interact with insulin and other extracellular substrates? Where precisely is IDE localized within the cell, and what are its functional roles in these compartments? How does IDE, a bowl-shaped protein that completely encapsulates its substrates, manage to avoid getting “clogged” and thus rendered inactive virtually immediately? Although these paradoxes are by definition unresolved, I offer herein my personal insights and informed speculations based on two decades working on the biology and pharmacology of IDE and suggest specific experimental strategies for addressing these conundrums. I also offer what I believe to be especially fruitful avenues for investigation made possible by the development of new technologies and IDE-specific reagents. It is my hope that these thoughts will contribute to continued progress elucidating the physiology and pathophysiology of this important peptidase.
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小分子对胰岛素降解酶的催化位点诱导小鼠葡萄糖不耐症。
影响因子：
16.6
作者：
Deprez-Poulain R;Hennuyer N;Bosc D;Liang WG;Enée E;Marechal X;Charton J;Totobenazara J;Berte G;Jahklal J;Verdelet T;Dumont J;Dassonneville S;Woitrain E;Gauriot M;Paquet C;Duplan I;Hermant P;Cantrelle FX;Sevin E;Culot M;Landry V;Herledan A;Piveteau C;Lippens G;Leroux F;Tang WJ;van Endert P;Staels B;Deprez B
通讯作者：
Deprez B
影响因子：
3.7
作者：
Cabrol C;Huzarska MA;Dinolfo C;Rodriguez MC;Reinstatler L;Ni J;Yeh LA;Cuny GD;Stein RL;Selkoe DJ;Leissring MA
通讯作者：
Leissring MA
影响因子：
2.4
作者：
Suire CN;Brizuela MK;Leissring MA
通讯作者：
Leissring MA
影响因子：
7.7
作者：
GOLDFINE, ID;WILLIAMS, JA;ROTH, RA
通讯作者：
ROTH, RA
DOI：
10.1152/ajpendo.00040.2019
发表时间：
2019-11-01
影响因子：
5.1
作者：
Fernandez-Diaz, Cristina M.;Merino, Beatriz;Cozar-Castellano, Irene
通讯作者：
Cozar-Castellano, Irene