Inhibitors of the sphingomyelin cycle: Sphingomyelin synthases and sphingomyelinases
Inhibitors of the sphingomyelin cycle: Sphingomyelin synthases and sphingomyelinases
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DOI：
10.1016/j.chemphyslip.2015.07.008
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发表时间：
2016-05-01
影响因子：
3.4
通讯作者：
Canals, Daniel
中科院分区：
文献类型：
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作者：
Adada, Mohamad;Luberto, Chiara;Canals, Daniel
鞘磷脂是一类具有生物活性的脂类，是细胞周期、细胞凋亡、血管生成、应激和炎症反应等多种生理和病理生理过程的关键调节因子。鞘磷脂是生物膜的重要结构成分，也是合成鞘磷脂的终点之一。鞘磷脂主要是在高尔基体中合成的，它被运输到所有其他生物膜上。在刺激条件下，5种不同的鞘磷脂酶可将其分解为神经酰胺。神经酰胺的多样性和细胞拓扑结构使其具有多种生物学功能。此外，神经酰胺可以被代谢成许多其他生物活性的鞘磷脂。神经酰胺来源于鞘磷脂或其他复杂的鞘磷脂，可以被水解为鞘氨醇，这很容易改变细胞的定位。反过来，鞘氨醇可以在内质网上循环为神经酰胺和神经鞘磷脂，完成神经鞘磷脂循环。我们对不同鞘脂在调节不同细胞过程中的作用的理解来自于对调节这些鞘脂的酶及其操作的研究。药物抑制剂的使用对他们的研究至关重要，也是治疗疾病的有希望的子弹。其中一些涉及鞘磷脂周期的疾病包括癌症、炎症、动脉粥样硬化、糖尿病和一些罕见的疾病，如尼曼-皮克病。这篇综述将集中在神经鞘磷脂周期中的酶，它们的历史以及它们在病理生理过程中的作用。最后，它将详细描述所有用于抑制这些酶的小分子及其在治疗学中的用途。(C)2015爱思唯尔爱尔兰有限公司。保留所有权利。
Sphingolipids are a class of bioactive lipids, which are key modulators of an increasing number of physiologic and pathophysiologic processes that include cell cycle, apoptosis, angiogenesis, stress and inflammatory responses. Sphingomyelin is an important structural component of biological membranes, and one of the end-points in the synthesis of sphingolipids. Mainly synthetized in the Golgi apparatus, sphingomyelin is transported to all other biological membranes. Upon stimulation, sphingomyelin can be hydrolyzed to ceramide by 5 different sphingomyelinases. The diversity and cellular topology of ceramide allow it to exert multiple biologies. Furthermore, ceramide can be metabolized to many other bioactive sphingolipids. Ceramide, coming from sphingomyelin or other complex sphingolipids, can be hydrolyzed to sphingosine, which can easily change cellular localization. In turn, sphingosine can be recycled to ceramide and to sphingomyelin in the endoplasmic reticulum, completing the sphingomyelin cycle. Our understanding of the roles of various sphingolipids in the regulation of different cellular processes has come from studying the enzymes that regulate these sphingolipids, and their manipulation. The use of pharmacologic inhibitors has been critical for their study, as well as being promising bullets for disease treatment. Some of these diseases involving the sphingomyelin cycle include cancer, inflammation, atherosclerosis, diabetes and some rare diseases such as Niemann-Pick disease. This review will focus on the enzymes involved in the sphingomyelin cycle, their history, and their involvement in pathophysiological processes. Finally, it will describe in details all the small molecules that are being used to inhibit these enzymes and their use in therapeutics. (C) 2015 Elsevier Ireland Ltd. All rights reserved.