Tyrosine modifications of insulin-degrading enzyme enable favorable control of substrate specificity for both Alzheimer's disease and type-2 diabetes mellitus.

IF 4.5 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Bioorganic Chemistry Pub Date : 2024-12-01 Epub Date: 2024-10-24 DOI:10.1016/j.bioorg.2024.107916

Yusuke Hatakawa, Yuki Takeuchi, Seon Hwa Lee, Tomoyuki Oe

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引用次数: 0

Abstract

Insulin-degrading enzyme (IDE) cleaves amyloid beta (Aβ), insulin, and other bioactive peptides. Because Aβ and insulin are closely related to Alzheimer's disease (AD) and type-2 diabetes mellitus (T2DM), respectively, IDE is a candidate drug target for treating both AD and T2DM. However, the activity of IDE has opposing effects, including decreasing AD risk by degrading Aβ and increasing T2DM risk by degrading insulin. The opposed substrate specificity is associated with the exo- and active sites containing Tyr³¹⁴ and Tyr⁸³¹ residues, the plausible modification targets for controlling substrate specificity. In this study, we used a tyrosine-specific modification regent, Cookson reagent (4-phenyl-1,2,4-triazoline-3,5-dione, PTAD), for IDE and examined the degradation activities on Aβ₄₀ and insulin. Fifteen tyrosine residues, including Tyr³¹⁴ and Tyr⁸³¹, were modified by PTAD. After incubation with PTAD-modified IDE for 3 days, insulin remained intact, whereas Aβ₄₀ was completely degraded. This favorable change of substrate specificity was also observed in the mixture of Aβ₄₀ and insulin, suggesting that tyrosine modification of IDE might be a therapeutic strategy for AD and T2DM.

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对胰岛素降解酶进行酪氨酸修饰，有利于控制阿尔茨海默病和 2 型糖尿病的底物特异性。

胰岛素降解酶（IDE）能裂解淀粉样β（Aβ）、胰岛素和其他生物活性肽。由于 Aβ 和胰岛素分别与阿尔茨海默病（AD）和 2 型糖尿病（T2DM）密切相关，因此 IDE 是治疗 AD 和 T2DM 的候选药物靶点。然而，IDE的活性具有相反的作用，包括通过降解Aβ降低AD风险，以及通过降解胰岛素增加T2DM风险。这种相反的底物特异性与含有 Tyr314 和 Tyr831 残基的外位点和活性位点有关，这两个残基是控制底物特异性的可信修饰靶点。在本研究中，我们使用酪氨酸特异性修饰试剂 Cookson 试剂（4-苯基-1,2,4-三唑啉-3,5-二酮，PTAD）进行 IDE，并检测了 Aβ40 和胰岛素的降解活性。PTAD 修饰了包括 Tyr314 和 Tyr831 在内的 15 个酪氨酸残基。与 PTAD 修饰的 IDE 培养 3 天后，胰岛素保持完整，而 Aβ40 则完全降解。在Aβ40和胰岛素的混合物中也观察到了这种底物特异性的有利变化，这表明对IDE进行酪氨酸修饰可能是治疗AD和T2DM的一种策略。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Bioorganic Chemistry 生物-生化与分子生物学

CiteScore

9.70

自引率

3.90%

发文量

679

审稿时长

31 days

期刊介绍： Bioorganic Chemistry publishes research that addresses biological questions at the molecular level, using organic chemistry and principles of physical organic chemistry. The scope of the journal covers a range of topics at the organic chemistry-biology interface, including: enzyme catalysis, biotransformation and enzyme inhibition; nucleic acids chemistry; medicinal chemistry; natural product chemistry, natural product synthesis and natural product biosynthesis; antimicrobial agents; lipid and peptide chemistry; biophysical chemistry; biological probes; bio-orthogonal chemistry and biomimetic chemistry. For manuscripts dealing with synthetic bioactive compounds, the Journal requires that the molecular target of the compounds described must be known, and must be demonstrated experimentally in the manuscript. For studies involving natural products, if the molecular target is unknown, some data beyond simple cell-based toxicity studies to provide insight into the mechanism of action is required. Studies supported by molecular docking are welcome, but must be supported by experimental data. The Journal does not consider manuscripts that are purely theoretical or computational in nature. The Journal publishes regular articles, short communications and reviews. Reviews are normally invited by Editors or Editorial Board members. Authors of unsolicited reviews should first contact an Editor or Editorial Board member to determine whether the proposed article is within the scope of the Journal.