EaStCHEM, School of Chemistry, University of Edinburgh, Edinburgh, Scotland, U.K.
Biochem Soc Trans. 2012 Jun 1;40(3):547-54. doi: 10.1042/BST20110769.
SLs (sphingolipids) are composed of fatty acids and a polar head group derived from L-serine. SLs are essential components of all eukaryotic and many prokaryotic membranes but S1P (sphingosine 1-phosphate) is also a potent signalling molecule. Recent efforts have sought to inventory the large and chemically complex family of SLs (LIPID MAPS Consortium). Detailed understanding of SL metabolism may lead to therapeutic agents specifically directed at SL targets. We have studied the enzymes involved in SL biosynthesis; later stages are species-specific, but all core SLs are synthesized from the condensation of L-serine and a fatty acid thioester such as palmitoyl-CoA that is catalysed by SPT (serine palmitoyltransferase). SPT is a PLP (pyridoxal 5'-phosphate)-dependent enzyme that forms 3-KDS (3-ketodihydrosphingosine) through a decarboxylative Claisen-like condensation reaction. Eukaryotic SPTs are membrane-bound multi-subunit enzymes, whereas bacterial enzymes are cytoplasmic homodimers. We use bacterial SPTs (e.g. from Sphingomonas) to probe their structure and mechanism. Mutations in human SPT cause a neuropathy [HSAN1 (hereditary sensory and autonomic neuropathy type 1)], a rare SL metabolic disease. How these mutations perturb SPT activity is subtle and bacterial SPT mimics of HSAN1 mutants affect the enzyme activity and structure of the SPT dimer. We have also explored SPT inhibition using various inhibitors (e.g. cycloserine). A number of new subunits and regulatory proteins that have a direct impact on the activity of eukaryotic SPTs have recently been discovered. Knowledge gained from bacterial SPTs sheds some light on the more complex mammalian systems. In the present paper, we review historical aspects of the area and highlight recent key developments.
鞘脂由脂肪酸和来源于 L-丝氨酸的极性头基组成。鞘脂是所有真核生物和许多原核生物膜的基本组成部分，但 S1P（鞘氨醇 1-磷酸）也是一种有效的信号分子。最近的研究工作试图对鞘脂（脂质图谱联盟）这个庞大而复杂的家族进行编目。对鞘脂代谢的详细了解可能会导致专门针对鞘脂靶点的治疗药物的产生。我们已经研究了参与鞘脂生物合成的酶；后期阶段因物种而异，但所有核心鞘脂都是由 L-丝氨酸和脂肪酸硫酯（如棕榈酰 CoA）缩合而成，这一过程由 SPT（丝氨酸棕榈酰转移酶）催化。SPT 是一种依赖 PLP（吡哆醛 5'-磷酸）的酶，通过脱羧克莱森缩合反应形成 3-KDS（3-酮二氢鞘氨醇）。真核 SPT 是膜结合的多亚基酶，而细菌酶是细胞质同二聚体。我们使用细菌 SPT（例如来自鞘氨醇单胞菌）来探测其结构和机制。人类 SPT 的突变导致一种神经病[HSAN1（遗传性感觉和自主神经病 1）]，这是一种罕见的鞘脂代谢疾病。这些突变如何扰乱 SPT 活性是微妙的，HSAN1 突变体的细菌 SPT 模拟物会影响 SPT 二聚体的酶活性和结构。我们还使用各种抑制剂（例如环丝氨酸）探索了 SPT 抑制作用。最近发现了一些对真核 SPT 活性有直接影响的新亚基和调节蛋白。从细菌 SPT 获得的知识为更复杂的哺乳动物系统提供了一些启示。在本文中，我们回顾了该领域的历史方面，并强调了最近的关键进展。
