**5. Sphingomyelin Synthase**

Sphingomyelin Synthase (SMS) is responsible for generating SM and diacylglycerol (DAG) by transferring the phosphocholine from phosphatidylcholine onto the primary hydroxyl group of Cer [81,82]. Thus, SMS is also biologically important as it regulates the levels of Cer and DAGs, resulting in bioactive lipids [83]. In the de novo synthesis pathway, Cer biosynthesis starts with L-serine and palmitoyl CoA to give 3-Ketosphinganine, which then undergoes a series of enzymatic reactions to yield Cer on the cytoplasmic side of the endoplasmic reticulum (ER) membrane. Cer is then transferred to the Golgi compartment in a non-vesicle way by the Cer transfer protein (CERT). There, SMS transfers the phosphocholine headgroup from phosphatidylcholine to Cer, yielding SM and DAG. The SM produced in this step is then sorted into cell membranes by either vesicle traffic or protein-facilitated transportation [84]. It is noteworthy that SM is the basic component of lipid rafts. Lipid rafts are important microdomains of cell membranes that provide a platform for many receptors and transport proteins. The SMS gene family consists of three members—sphingomyelin synthase 1 (*SGMS1*), sphingomyelin synthase 2 (*SGMS2*), and sterile alpha motif domain containing 8 (*SAMD8*), which encode their respective proteins: SMS1, SMS2, and SMS-related protein (SMSr). Even though SMSr displays high homology with SMS1 and SMS2, it does not have any SM synthase activity [82]. SMS1 and SMS2 are localized in the trans-Golgi network, where SM is synthesized from Cer, which is transported from the ER to the Golgi by the CERT [1]. SMSs are present in all tissues, and SMS1 is the principal contributor to the SMS activity in most cells. Both isoforms share 57% of sequential identity and are conserved in mammals [82]. In SMS1, a sterile alpha motif (SAM) is present, which takes part in protein–protein interactions, and which is not present in SMS2. SMSs contain six transmembrane regions with both N- and C-termini exposed into the cytosol.

#### *Biological Significance of Sphingomyelin Synthase*

The formation of SM is essential for cell growth and survival. In a mouse lymphoid cell line deficient in SM synthase activity, loss of SMS activity halted cell growth in serumfree conditions, which could, however, be restored by supplemental exogenous SM or heterologous expression of SMS1 [85]. Different studies have correlated the up- and downregulation of SM synthase activity to mitogenic and proapoptotic signaling in different mammalian cell types [86–88]. Although the cellular pathway for the effects of SMS is unclear, it can exert its effect through the following mechanisms: (1) SM accumulation in the plasma membrane, and its affinity for sterols, contributes to the rigidity of the cell membrane; and (2) SM accumulation in the plasma membrane acts as a source of a number of other SLs, which are catalyzed by acidic or neutral sphingomyelinases (SMases) [89,90]. Cer, sphingosine, and sphingosine 1-phosphate are all potential SM metabolites and have proven to be significant regulators of cellular functions like cell proliferation, differentiation, and apoptosis [2,91,92]. The microdomain formation of SM in the Golgi apparatus plays a role in the sorting process of different SLs [93]. SM synthesis can act as a source of DAG in the trans-Golgi network, thus facilitating the protein kinase D recruitment leading to the formation of transport carrier proteins [94]. SM synthesis regulates the cellular levels of both the proapoptotic factor Cer and the mitogenic factor DAG, directly impacting cell proliferation [88,95]. Some of the SMS inhibitors are natural products which originate from the marine environment; these molecules and their synthetic analogs resemble SMS substrates and are depicted in Figure 7.

**Figure 7.** Sphingomyelin Synthase inhibitors.
