Major Advance in Understanding the Regulation of Sphingolipid Biosynthesis
The enzyme responsible for sphingolipid biosynthesis, serine palmitoyl transferase (SPT) which condenses serine and palmitic acid to generate sphingosine. This enzyme is inhibited by ceramide and this ceramide-mediated regulation is mediated by ORMDL proteins. While this has been known for some time, the mechanisms of SPT-mediated sphingosine biosynthesis and its regulation by ORMDLs have remained unresolved. Two back-to-back papers in Nature Structural and Molecular Biology by Wang et al and Li et. al. present cyro-EM structures of human serine palmitoyl transferase (SPT) in a complex with its ORMDL3 regulator. This exciting research, which garnered a News and Views comment (https://www.nature.com/articles/s41594-021-00562-0) provides a molecular and mechanistic understanding of the synthesis and regulation of sphingolipids. They show the organization of the ORMDL3 complex with the SPT and how this organization affects sphingolipid biosynthesis. These articles are sure to attract a great deal of attention and will have a major impact on our understanding of sphingolipid biochemistry and biology. (Note: an ASBMB Lipid News article highlighting this paper is scheduled to appear in the October, 2021 issue of A-Today).
Structural insights into the regulation of human serine palmitoyltransferase complexes Wang et al.
Structural insights into the assembly and substrate selectivity of human SPT–ORMDL3 complex Li et al
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