Sphingomyelin synthase

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

a ceramide + a phosphatidylcholine ${\displaystyle \rightleftharpoons }$ 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

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

• Ullman MD, Radin NS (1974). "The enzymatic formation of sphingomyelin from ceramide and lecithin in mouse liver". J. Biol. Chem. 249 (5): 1506–12. doi:10.1016/S0021-9258(19)42911-6. PMID 4817756.
• Voelker DR, Kennedy EP (1982). "Cellular and enzymic synthesis of sphingomyelin". Biochemistry. 21 (11): 2753–9. doi:10.1021/bi00540a027. PMID 7093220.
• Huitema K, van den Dikkenberg J, Brouwers JF, Holthuis JC (2004). "Identification of a family of animal sphingomyelin synthases". EMBO J. 23 (1): 33–44. doi:10.1038/sj.emboj.7600034. PMC 1271672. PMID 14685263.
• Tafesse FG, Ternes P, Holthuis JC (2006). "The multigenic sphingomyelin synthase family". J. Biol. Chem. 281 (40): 29421–5. doi:10.1074/jbc.R600021200. PMID 16905542.
• Yamaoka S, Miyaji M, Kitano T, Umehara H, Okazaki T (2004). "Expression cloning of a human cDNA restoring sphingomyelin synthesis and cell growth in sphingomyelin synthase-defective lymphoid cells". J. Biol. Chem. 279 (18): 18688–93. doi:10.1074/jbc.M401205200. PMID 14976195.