An overview of sphingolipid metabolism: from synthesis to breakdown.
An overview of sphingolipid metabolism: from synthesis to breakdown.
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DOI：
10.1007/978-1-4419-6741-1_1
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发表时间：
2010
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鞘脂构成一类由其十八碳氨基醇主链定义的脂质，所述十八碳氨基醇主链在ER中由非鞘脂前体合成。这种基本结构的修饰产生了鞘脂的大家族，其在膜生物学中发挥重要作用，并提供许多调节细胞功能的生物活性代谢物。尽管鞘脂的结构和功能的多样性，它们的产生和破坏由共同的合成和分解代谢途径控制。在这方面，鞘脂代谢可以被想象为一系列相互连接的网络，这些网络从一个共同的入口点分叉，并汇聚成一个共同的分解途径。在其最简单的形式中，鞘氨醇、植物鞘氨醇和二氢鞘氨醇充当主链，在其上实现进一步的复杂性。例如，C1羟基的磷酸化分别产生最终分解产物和/或重要的信号分子鞘氨醇-1-磷酸、植物鞘氨醇-1-磷酸和二氢鞘氨醇-1-磷酸。另一方面，鞘氨醇、植物鞘氨醇或二氢鞘氨醇与几种可能的酰基CoA分子之一通过不同的神经酰胺脱氢酶的作用酰化产生定义为神经酰胺、植物神经酰胺或二氢神经酰胺的分子。神经酰胺，由于可用于产生它的不同酰基辅酶A，在技术上是一类分子而不是单个分子，因此可能具有不同的生物学功能，这取决于其组成的酰基链。最复杂的是被称为鞘糖脂（GSL）的脂质组，其包含数十种不同的鞘脂种类，这些鞘脂种类因连接到其头基的糖残基的顺序和类型而不同。由于这些分子是由神经酰胺前体产生的，它们的酰基链组成也可能存在差异，从而揭示了另一层变异。鞘糖脂大致分为两类：鞘糖脂和鞘半乳糖脂。鞘糖脂最初依赖于葡萄糖神经酰胺合酶（GCS），该酶将葡萄糖作为第一个残基连接到C1羟基位置。另一方面，半乳糖鞘脂由半乳糖神经酰胺合酶（GalCerS）产生，这是一种与GCS进化上不同的酶。鞘糖脂基于通过各种糖基转移酶的进一步修饰而进一步划分，所述糖基转移酶使脂质种类的潜在变化增加数倍。更丰富的是鞘磷脂种类，其与鞘糖脂平行产生，但是它们由磷酸胆碱头基而不是糖残基的添加来定义。虽然鞘磷脂种类都具有共同的头基，但它们也是由各种神经酰胺种类产生的，因此可以具有连接到其C-2氨基的不同酰基链。SM中不同的酰基链长度是否决定了独特的功能或重要的生物物理特性尚未确定。了解所有现有的鞘糖脂和鞘磷脂种类的功能将是未来的一项重大任务，因为研究和测量这些种类的工具才刚刚开始开发。简单的鞘脂既是更复杂鞘脂的前体，也是其分解产物。重要的是，近几十年来，这些简单的鞘脂因在细胞内具有重要的信号传导和调节作用而受到关注。此外，已经出现了许多工具来测量简单鞘脂的水平，因此近年来已成为更深入研究的焦点。考虑到这一点，本章将致力于复杂的鞘脂，但重点是简单的鞘脂代谢的调节。
Sphingolipids constitute a class of lipids defined by their eighteen carbon amino-alcohol backbones which are synthesized in the ER from nonsphingolipid precursors. Modification of this basic structure is what gives rise to the vast family of sphingolipids that play significant roles in membrane biology and provide many bioactive metabolites that regulate cell function. Despite the diversity of structure and function of sphingolipids, their creation and destruction are governed by common synthetic and catabolic pathways. In this regard, sphingolipid metabolism can be imagined as an array of interconnected networks that diverge from a single common entry point and converge into a single common breakdown pathway. In their simplest forms, sphingosine, phytosphingosine and dihydrosphingosine serve as the backbones upon which further complexity is achieved. For example, phosphorylation of the C1 hydroxyl group yields the final breakdown products and/or the important signaling molecules sphingosine-1-phosphate, phytosphingosine-1-phosphate and dihydrosphingosine-1-phosphate, respectively. On the other hand, acylation of sphingosine, phytosphingosine, or dihydrosphingosine with one of several possible acyl CoA molecules through the action of distinct ceramide synthases produces the molecules defined as ceramide, phytoceramide, or dihydroceramide. Ceramide, due to the differing acyl CoAs that can be used to produce it, is technically a class of molecules rather than a single molecule and therefore may have different biological functions depending on the acyl chain it is composed of. At the apex of complexity is the group of lipids known as glycosphingolipids (GSL) which contain dozens of different sphingolipid species differing by both the order and type of sugar residues attached to their headgroups. Since these molecules are produced from ceramide precursors, they too may have differences in their acyl chain composition, revealing an additional layer of variation. The glycosphingolipids are divided broadly into two categories: glucosphingolipids and galactosphingolipids. The glucosphingolipids depend initially on the enzyme glucosylceramide synthase (GCS) which attaches glucose as the first residue to the C1 hydroxyl position. Galactosphingolipids, on the other hand, are generated from galactosylceramide synthase (GalCerS), an evolutionarily dissimilar enzyme from GCS. Glycosphingolipids are further divided based upon further modification by various glycosyltransferases which increases the potential variation in lipid species by several fold. Far more abundant are the sphingomyelin species which are produced in parallel with glycosphingolipids, however they are defined by a phosphocholine headgroup rather than the addition of sugar residues. Although sphingomyelin species all share a common headgroup, they too are produced from a variety of ceramide species and therefore can have differing acyl chains attached to their C-2 amino groups. Whether or not the differing acyl chain lengths in SMs dictate unique functions or important biophysical distinctions has not yet been established. Understanding the function of all the existing glycosphingolipids and sphingomyelin species will be a major undertaking in the future since the tools to study and measure these species are only beginning to be developed. The simple sphingolipids serve both as the precursors and the breakdown products of the more complex ones. Importantly, in recent decades, these simple sphingolipids have gained attention for having significant signaling and regulatory roles within cells. In addition, many tools have emerged to measure the levels of simple sphingolipids and therefore have become the focus of even more intense study in recent years. With this thought in mind, this chapter will pay tribute to the complex sphingolipids, but focus on the regulation of simple sphingolipid metabolism.