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. 2019 Mar 19;133(6):763–776. doi: 10.1042/CS20180911

Figure 1. Sphingolipid biosynthesis and sphingolipid-centric theraputics.

Figure 1

(1) De novo sphingolipid synthesis starts in the ER with the decarboxylation of a serine residue and condensation with a palmitoyl-CoA catalyzed by SPT. Sequential reactions lead to the production of ceramides, which are precursors for the biosynthesis of sphingomyelins and glycosphingolipids. In the ER, ceramides can be deacylated by CDase to form sphingosine. Sphingosine can be phosphorylated to form sphingosine-1-phosphate (S1P) by SphK1/2. In the Golgi, ceramides transferred by CERT are predestined to synthesize sphingomyelins by the addition of phosphocholine head group or be phosphorylated to form ceramide-1-phosphate. Ceramides transferred by vesicular transport can be glycosylated to form glucosylceramides or galactosylceramides. FAPP2 can transfer glucosylceramides from the cis-Golgi to the trans-Golgi, where they are converted into lactosylceramides. (2) Bidirectionally, in the plasma membrane, lysosome, mitochondria, and Golgi, sphingomyelins can be converted into ceramides by SMSases. Similarly, ceramide-1-phosphate and glycosphingolipids can be hydrolyzed to form ceramides (not shown). (3) Sphingosine can be recycled to generate ceramides by CerSs. Myriocin is a SPT inhibitor; Fenretinide plays a role in DES1 inhibition; Adiponectin exerts its metabolic improvement functions through CDase signaling; FTY720 and CYM5442 are S1P analogs; D609 and D2-series are SMS inhibitors; Desipramine and SMA-7 et al. are inhibitors of SMase. D-PDMP inhibits both GCS and LCS; AMP-DNM and EtDO-P4 are specific GCS inhibitors. Abbreviations: AMP-DNM, N-(5-adamantane-1-yl-methoxy)-pentyl-1-deoxynoijirimycin; CDase, ceramidase; CERK, ceramide kinase; CerS1-6, ceramide synthase1-6; CERT, ceramide transfer protein; DES1/2, dihydroceramide desaturase1/2; D-PDMP, d-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol; EtDO-P4, d-threo-1-ethylendioxyphenyl-2-palmitoylamino-3-pyrrolidino-propanol; FAPP2, four-phosphate adaptor protein 2; FTY720, 2-amino-2-[2-(4-octylphenyl)ethyl] propane-1, 3-diolhydrochloride; GalCerS, galactosylceramide synthase; GCS, glucosylceramide synthase; KSR, 3-ketosphinganine reductase; LCS, lactose CerS; SMS, sphingomyelin synthase; SphK1/2, sphingosine kinase1/2; SPP1/2, S1P phosphatase1/2; SPL, S1P lyase.