Sphingomyelin synthase

In enzymology, a sphingomyelin synthase (EC 2.7.8.27) is an enzyme that catalyzes the chemical reaction

SMSr-ceramide
The cryo-EM structure of human sphingomyelin synthase-related protein in complex with ceramide. PDB 8IJQ
Identifiers
EC no.2.7.8.27
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IntEnzIntEnz view
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MetaCycmetabolic pathway
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a ceramide + a phosphatidylcholine a sphingomyelin + a 1,2-diacyl-sn-glycerol

or the reaction using phosphatidylethanolamine instead of phosphatidylcholine to generate ceramide phosphoethanolamine (CPE), a sphingomyelin analog rich in invertebrates, such as insects.

Thus, the two substrates of this enzyme are ceramide and phosphatidylcholine, whereas its two products are sphingomyelin and 1,2-diacyl-sn-glycerol.

This enzyme belongs to the family of transferases, specifically those transferring non-standard substituted phosphate groups. The systematic name of this enzyme class is ceramide:phosphatidylcholine cholinephosphotransferase. Other names in common use include SM synthase, SMS1, and SMS2. SM synthase family also includes the enzyme catalyzing CPE synthesis, named SMSr (SMS-related).

Structure of SM synthases

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The high sequence identities shared among the three members of the Sphingomyelin Synthase (SMS) family have intrigued researchers for years. Recent cryo-electron microscopic studies have unveiled a fascinating hexameric organization specifically for SMSr,[1] while biochemical investigations have highlighted the formation of stable dimers by SMS1 and SMS2.[2] Within this hexameric structure, each monomeric unit of SMSr functions as an independent catalytic entity, characterized by six transmembrane helices.

The structural analysis has revealed the presence of a sizable chamber within the helical bundle of SMSr. This chamber serves as the site for catalytic activity, with researchers pinpointing a catalytic pentad, denoted as E-H/D-H-D, strategically positioned at the interface between the lipophilic and hydrophilic segments of the reaction chamber. Furthermore, the elucidation of SMSr's catalytic mechanism has uncovered an intricate two-step synthesis process for SM synthesis. Initially, phosphoethanolamine (or phosphatidylcholine in case of SMS1/2) is hydrolyzed from phosphatidylethanolamine (PE-PLC hydrolysis), followed by the subsequent transfer of the phosphoethanolamine moiety to ceramide.

References

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  1. ^ Hu K, Zhang Q, Chen Y, Yang J, Xia Y, Rao B, et al. (2024). "Cryo-EM structure of human sphingomyelin synthase and its mechanistic implications for sphingomyelin synthesis". Nat Struct Mol Biol: 1–12. doi:10.1038/s41594-024-01237-2.
  2. ^ Hayashi Y, Nemoto-Sasaki Y, Matsumoto N, Tanikawa T, Oka S, Tanaka Y, et al. (January 2017). "Carboxyl-terminal Tail-mediated Homodimerizations of Sphingomyelin Synthases Are Responsible for Efficient Export from the Endoplasmic Reticulum". Journal of Biological Chemistry. 292 (3): 1122–1141. doi:10.1074/jbc.M116.746602. PMC 5247646. PMID 27927984.