Fungal metabolite sulfamisterin suppresses sphingolipid synthesis through inhibition of serine palmitoyltransferase.
Fungal metabolite sulfamisterin suppresses sphingolipid synthesis through inhibition of serine palmitoyltransferase.
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DOI：
10.1021/bi048605l
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发表时间：
2005-01
期刊：
影响因子：
2.9
通讯作者：
A. Yamaji-Hasegawa;A. Takahashi;Y. Tetsuka;Yukiko Senoh;Toshihide Kobayashi
中科院分区：
文献类型：
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作者：
A. Yamaji-Hasegawa;A. Takahashi;Y. Tetsuka;Yukiko Senoh;Toshihide Kobayashi
已知鞘脂及其代谢物调节各种细胞事件，包括增殖、分化和凋亡。丝氨酸棕榈酰转移酶（SPT）是催化所有鞘脂生物合成的第一步的酶。在这里，我们报告说，一种新发现的抗生素，磺胺，来自真菌Pycnidiella sp.，是SPT的特异性抑制剂。磺胺醋酰的化学结构类似于鞘氨醇以及SPT的有效抑制剂ISP-1（多球菌素）。在从中国仓鼠卵巢（CHO）成纤维细胞制备的无细胞裂解物中，磺胺醋酰抑制SPT活性，IC（50）= 3 nM。通过放射性前体监测，磺胺醋酰显著抑制活CHO细胞和酵母酿酒酵母中鞘脂的生物合成。与无细胞实验不同，在完整细胞中完全抑制鞘脂生物合成需要10 μ M的磺酰胺。我们还合成了一系列的结构类似物的磺胺，并研究了它们的活动，无论是在无细胞和活细胞系统。
Sphingolipids and their metabolites are known to modulate various cellular events including proliferation, differentiation, and apoptosis. Serine palmitoyltransferase (SPT) is the enzyme that catalyzes the first step of the biosynthesis of all sphingolipids. Here, we report that a newly identified antibiotic, sulfamisterin, derived from the fungus Pycnidiella sp., is a specific inhibitor of SPT. The chemical structure of sulfamisterin resembles both that of sphingosine as well as a potent inhibitor of SPT, ISP-1 (myriocin). Sulfamisterin inhibited SPT activity with IC(50) = 3 nM in a cell-free lysate prepared from Chinese hamster ovary (CHO) fibroblasts. Sulfamisterin markedly inhibited the biosynthesis of sphingolipids in living CHO cells and in yeast Saccharomyces cerevisiae as monitored by radioactive precursors. Unlike the cell-free experiments, 10 microM sulfamisterin was required for complete inhibition of sphingolipid biosynthesis in intact cells. We also synthesized a series of structural analogues of sulfamisterin and examined their activities both in cell-free and in living cell systems.