Identification of a family of animal sphingomyelin synthases

Abstract

Sphingomyelin (SM) is a major component of animal plasma membranes. Its production involves the transfer of phosphocholine from phosphatidylcholine onto ceramide, yielding diacylglycerol as a side product. This reaction is catalysed by SM synthase, an enzyme whose biological potential can be judged from the roles of diacylglycerol and ceramide as anti-and proapoptotic stimuli, respectively. SM synthesis occurs in the lumen of the Golgi as well as on the cell surface. As no gene for SM synthase has been cloned so far, it is unclear whether different enzymes are present at these locations. Using a functional cloning strategy in yeast, we identified a novel family of integral membrane proteins exhibiting all enzymatic features previously attributed to animal SM synthase. Strikingly, human, mouse and Caenorhabditis elegans genomes each contain at least two different SM synthase (SMS) genes. Whereas human SMS1 is localised to the Golgi, SMS2 resides primarily at the plasma membrane. Collectively, these findings open up important new avenues for studying sphingolipid function in animals.

Tales and Mysteries of the Enigmatic Sphingomyelin Synthase Family

“…CPI production requires the product of the AUR1 gene, 45 a protein containing the C2 and C3 active site motifs characteristic for members of the lipid phosphate phosphatase (LPP) superfamily. 57 A database search for novel sequences encoding integral membrane proteins containing the C2 and C3 domains common to Aur1p and LPPs identified three families of candidate SM synthase ( y CSS) genes with homologues in multiple animal species 58 (Fig. 3).…”

“…57,58 Both groups of enzymes contain a six times membrane-spanning core domain with the termini facing the cytosol and the putative C2 and C3 active site residues facing the exoplasmic leaflet (Fig. 4).…”

The natural marine anhydrophytosphingosine, Jaspine B, induces apoptosis in melanoma cells by interfering with ceramide metabolism

“…Holthuis (Utrecht, The Netherlands) [19]. Cells were grown in a humidified M a n u s c r i p t 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 Salma et al BCP-D-09-00334rev 7 5% CO 2 atmosphere at 37°C in DMEM medium containing Glutamax (2 mM), and heat-inactivated FCS (10%).…”

“…The biosynthesis of SM is catalyzed by SMS, an enzyme that transfers the phosphocholine moiety from phosphatidylcholine onto the primary hydroxyl group of ceramide generating SM and diacylglycerol [37]. There are two isoforms of mammalian SMS genes [19,38]. The corresponding proteins, SMS1 and SMS2, are located in the cis-, medial-Golgi and at the plasma membrane, respectively.…”

Lipid pickup and delivery

“…Recent work identifying the elusive sphingomyelin synthase has now provided an answer to this question. Huitema and colleagues 15 have identified two human sphingomyelin synthases (SMSs), of which SMS1 fulfills many criteria to be the common Golgi sphingomyelin synthase. SMS1 is a Golgi protein with a relative molecular mass (M r ) of 49,000.…”