Combined Omics Approach Identifies Gambogic Acid and Related Xanthones as Covalent Inhibitors of the Serine Palmitoyltransferase Complex
| Autor: | Dominic Gregor Hoch, Xiaojin Zhang, Howard Riezman, Dany Pechalrieu, Alexander Adibekian, J. Thomas Hannich, Chao Wang, Anton Shuster, Daniel Abegg, Qidong You, Brendan G. Dwyer |
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| Rok vydání: | 2020 |
| Předmět: |
Proteomics
Xanthones Clinical Biochemistry Serine C-Palmitoyltransferase Biology 01 natural sciences Biochemistry Covalent inhibitors Mice chemistry.chemical_compound Then test Sphingosine Drug Discovery Animals Humans Chemoproteomics Sphingosine-1-phosphate Enzyme Inhibitors Molecular Biology Pharmacology Mice Inbred ICR Sphingolipids Natural product 010405 organic chemistry Gambogic acid Serine C-palmitoyltransferase Sphingolipid 0104 chemical sciences HEK293 Cells chemistry Covalent bond ddc:540 Lipidomics MCF-7 Cells Molecular Medicine lipids (amino acids peptides and proteins) Lysophospholipids |
| Zdroj: | Cell Chemical Biology, Vol. 27, No 5 (2020) pp. 586-597.e12 |
| ISSN: | 2451-9456 2451-9448 |
| DOI: | 10.1016/j.chembiol.2020.03.008 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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