Fungal Metabolite Sulfamisterin Suppresses Sphingolipid Synthesis through Inhibition of Serine Palmitoyltransferase

Abstract

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.