Abstract:
SIRT1 is an NAD+-dependent protein deacetylase that has been shown to play a significant role in many biological pathways, such as insulin secretion, tumor formation, lipid metabolism, and neurodegeneration. There is great interest in understanding the regulation of SIRT1 to better understand SIRT1-related diseases and to better design therapeutic approaches that target SIRT1. There are many known protein and small molecule activators and inhibitors of SIRT1. One well-studied SIRT1 regulator, resveratrol, has historically been regarded as a SIRT1 activator, however, recent studies have shown that it can also act as an inhibitor depending on the identity of the peptide substrate. The inhibitory nature of resveratrol has yet to be studied in detail. Understanding the mechanism behind this dual behavior is crucial for assessing the potential side effects of STAC-based therapeutics. Here, we investigate the detailed mechanism of substrate-dependent SIRT1 regulation by resveratrol. We demonstrate that resveratrol alters the substrate recognition of SIRT1 by affecting the K M values without significantly impacting the catalytic rate (k cat). Furthermore, resveratrol destabilizes SIRT1 and extends its conformation, but the conformational changes differ between the activation and inhibition scenarios. We propose that resveratrol renders SIRT1 more flexible in the activation scenario, leading to increased activity, while in the inhibition scenario, it unravels the SIRT1 structure, compromising substrate recognition. Our findings highlight the importance of substrate identity in resveratrol-mediated SIRT1 regulation and provide insights into the allosteric control of SIRT1. This knowledge can guide the development of targeted therapeutics for diseases associated with dysregulated SIRT1 activity.
摘要:
SIRT1是一种NAD+依赖性蛋白质去乙酰化酶,已被证明在许多生物学途径中起重要作用。如胰岛素分泌,肿瘤形成,脂质代谢,和神经变性。人们对理解SIRT1的调节有很大的兴趣,以更好地理解SIRT1相关疾病,并更好地设计靶向SIRT1的治疗方法。有许多已知的SIRT1的蛋白质和小分子活化剂和抑制剂。一个经过充分研究的SIRT1调节剂,白藜芦醇,历史上一直被认为是SIRT1激活剂,然而,最近的研究表明,根据肽底物的特性,它也可以作为抑制剂。白藜芦醇的抑制性质尚未详细研究。了解这种双重行为背后的机制对于评估基于STAC的疗法的潜在副作用至关重要。这里,我们研究了白藜芦醇对底物依赖性SIRT1调节的详细机制。我们证明白藜芦醇通过影响KM值而不会显着影响催化速率(kcat)来改变SIRT1的底物识别。此外,白藜芦醇使SIRT1不稳定并扩展其构象,但是激活和抑制方案之间的构象变化不同。我们建议白藜芦醇使SIRT1在激活场景中更灵活,导致活动增加,而在抑制场景中,它解开了SIRT1结构,损害底物识别。我们的发现强调了底物身份在白藜芦醇介导的SIRT1调控中的重要性,并提供了对SIRT1变构控制的见解。这些知识可以指导与SIRT1活性失调相关的疾病的靶向治疗方法的开发。