Kumar Ashutosh, Zhang Kam Y J
Structural Bioinformatics Team, Division of Structural and Synthetic Biology, Center for Life Science Technologies, RIKEN, 1-7-22 Suehiro, Yokohama, Kanagawa 230-0045, Japan.
Comput Struct Biotechnol J. 2015 Mar 24;13:204-11. doi: 10.1016/j.csbj.2015.03.001. eCollection 2015.
Sumoylation is a reversible post-translational modification that involves the covalent attachment of small ubiquitin-like modifier (SUMO) proteins to their substrate proteins. Prior to their conjugation, SUMO proteins need to be proteolytically processed from its precursor form to mature or active form. SUMO specific proteases (SENPs) are cysteine proteases that cleave the pro or inactive form of SUMO at C-terminus using its hydrolase activity to expose two glycine residues. SENPs also catalyze the de-conjugation of SUMO proteins using their isopeptidase activity, which is crucial for recycling of SUMO from substrate proteins. SENPs are important for maintaining the balance between sumoylated and unsumoylated proteins required for normal cellular physiology. Several studies reported the overexpression of SENPs in disease conditions and highlighted their role in the development of various diseases, especially cancer. In this review, we will address the current biological understanding of various SENP isoforms and their role in the pathogenesis of different cancers and other diseases. We will then discuss the advances in the development of protein-based, peptidyl and small molecule inhibitors of various SENP isoforms. Finally, we will summarize successful examples of computational screening that allowed the identification of SENP inhibitors with therapeutic potential.
SUMO化是一种可逆的翻译后修饰，涉及小泛素样修饰物（SUMO）蛋白与其底物蛋白的共价连接。在它们结合之前，SUMO蛋白需要从其前体形式进行蛋白水解加工成成熟或活性形式。SUMO特异性蛋白酶（SENP）是半胱氨酸蛋白酶，利用其水解酶活性在C末端切割SUMO的前体或无活性形式，以暴露两个甘氨酸残基。SENP还利用其异肽酶活性催化SUMO蛋白的去结合，这对于SUMO从底物蛋白的循环利用至关重要。SENP对于维持正常细胞生理所需的SUMO化和非SUMO化蛋白之间的平衡很重要。几项研究报道了疾病状态下SENP的过表达，并强调了它们在各种疾病，尤其是癌症发展中的作用。在这篇综述中，我们将阐述目前对各种SENP亚型的生物学理解及其在不同癌症和其他疾病发病机制中的作用。然后，我们将讨论各种SENP亚型的基于蛋白质、肽基和小分子抑制剂开发方面的进展。最后，我们将总结计算筛选的成功实例，这些实例有助于鉴定具有治疗潜力的SENP抑制剂。
