Combined Omics Approach Identifies Gambogic Acid and Related Xanthones as Covalent Inhibitors of the Serine Palmitoyltransferase Complex. Issue 5 (21st May 2020)

• Record Type: Journal Article
• Authors: Hoch, Dominic G.; Abegg, Daniel; Hannich, J. Thomas; Pechalrieu, Dany; Shuster, Anton; Dwyer, Brendan G.; Wang, Chao; Zhang, Xiaojin; You, Qidong; Riezman, Howard; Adibekian, Alexander
• Is Part Of: Cell chemical biology. Volume 27:Issue 5(2020)
• Page Start: 586
• Page End: 597.e12
• Publication Date: 2020-05-21
• Subjects: chemical proteomics -- target identification -- natural products -- mass spectrometry -- sphingosine-1-phosphate; Biochemistry -- Periodicals; 572.05
• DOI: 10.1016/j.chembiol.2020.03.008
• Languages: English
• ISSNs: 2451-9456

Abstract

Summary: In this study, we identify the natural product gambogic acid as well as structurally related synthetic xanthones as first-in-class covalent inhibitors of the de novo sphingolipid biosynthesis. We apply chemoproteomics to determine that gambogic acid binds to the regulatory small subunit B of the serine palmitoyltransferase complex (SPTSSB). We then test structurally related synthetic xanthones to identify 18 as an equally potent but more selective binder of SPTSSB and show that 18 reduces sphingolipid levels in situ and in vivo . Finally, using various biological methods, we demonstrate that 18 induces cellular responses characteristic for diminished sphingosine-1-phosphate (S1P) signaling. This study demonstrates that SPTSSB may become a viable therapeutic target in various diseases with pathological S1P signaling. Furthermore, we believe that our compound will become a valuable tool for studying the sphingolipid metabolism and serve as a blueprint for the development of a new generation of sphingolipid biosynthesis inhibitors. Graphical Abstract: Highlights: Gambogic acid causes reduction of S1P levels through binding to SPTSSB Structurally related xanthone 18 is a more selective SPTSSB binder SPTSSB engagement by xanthone 18 leads to a decrease in S1P levels in cells and mice Xanthone 18 induces cellular responses characteristic for diminished S1P signaling Abstract : In this study, Hoch et al. discovered that the natural product gambogic acid and related synthetic xanthones bind to the regulatory small subunit B of the serine palmitoyltransferase complex, leading to a decrease in sphingolipids, including sphingosine-1-phosphate, in cells and mice.