Inhibits de novo sphingolipid biosynthesis.

A specific haplotype increasing the biosynthesis of long-chain omega-3 and omega-6 fatty acids was discovered and its importance in the development of modern pathologies is demonstrated ().

inhibitor of sphingolipid biosynthesis ..

First suggestion that sphingolipid-derived metabolitescould function as second messengers.

inhibitors of sphingolipid biosynthesis…

Sphingolipids are essential membrane components of virtually all eukaryotic cells. An important step in the sphingolipid biosynthesis pathways is the glucosylation of ceramide mediated by glucosylceramide (GlcCer) synthase, whose activity can be modulated by pharmacological inhibitors, including PPMP (-threo-1-phenyl-2-palmitoylamino-3-morpholino-1-pro- panol) (, ). In the present study, we examined the sphingolipid biosynthetic pathways as a potential target for anti-G. lamblia drugs. Previous studies of G. lamblia lipid metabolism revealed that the parasite has only a limited capability for de novo lipid synthesis but that it is capable of taking up lipids from the environment (), including gangliosides () and ceramide (). However, data about G. lamblia lipid requirements and lipid biosynthesis pathways are still scarce.

Inhibits de novo sphingolipid biosynthesis ..

An in vitro model of Gaucher's disease in murine neuroblastoma X rat glioma NG108-15 cells was used to investigate the physiological effects of two specific inhibitors of glucosylceramide synthase, d,l-threo-1-phenyl-2- decanoylamino-3-morpholino-1-propanol (d,l-PDMP) and N-butyldeoxynojirimycin (NB-DNJ), which have been suggested as agents for treatment of glycolipid storage disorders. Incubation of NG108-15 cells with conduritol-B-epoxide, a covalent inhibitor of glucosylceramidase, raised the intracellular concentration of glucosylceramide (GC) by more than fourfold, indicating a glycolipid composition equivalent to that of Gaucher's cells. The level of GC was decreased, and the cells were depleted of gangliosides by postincubation with d,l-PDMP or NB-DNJ. Treatment with d,l-PDMP, but not with NB-DNJ, resulted in a dose-dependent reduction of the growth rate and eventually caused cell death in NG108-15 cells on reaching confluency. An in situ detection assay using terminal nucleotidyltransferase indicated that cell degeneration was accompanied by apoptosis. Lipid analysis by high-performance TLC revealed that on incubation with d,l-PDMP, but not with NB-DNJ, the concentration of endogenous ceramide was elevated by threefold. Ceramide elevation and apoptosis were also observed when NG108-15 cells were incubated with daunorubicin, which was previously reported to induce programmed cell death by stimulation of ceramide synthesis. Structural characterization by HPLC and subsequent laser desorption mass spectrometry revealed that the endogenous ceramide contained fatty acids with chain lengths ranging from C14:0 to C24:0. The results indicate that elevation of levels of these ceramide species by incubation with d,l-PDMP or daunorubicin induces programmed cell death in NG108-15 cells. Because ceramide accumulation and cell death were not observed on incubation with NB-DNJ, its use is suggested to be less toxic than that of d,l-PDMP for treatment of Gaucher's disease and other sphingolipid storage disorders.

T1 - Differential effects of glycolipid biosynthesis inhibitors on ceramide- induced cell death in neuroblastoma cells
Conculsions: These results suggest that sphingolipid metabolism may be associated with cholesterol gallstone formation in C57BL/6J mice.

Up-regulation of de novo sphingolipid biosynthesis …

29-70).

The first component protein of an enzyme of fatty acid biosynthesis, fatty acidsynthase, was purified ().

Polyprenol diphosphates were shown to be involved in the biosynthesis ofpolysaccharides in () and in the biosynthesis of peptidoglycans in ().

The structure of juvenile hormone of insects was elucidated by Roller H ().

The first total synthesis of the sphingolipid biosynthesis inhibitor fumonisin B1 has been achieved

Inhibition of sphingolipid biosynthesis by fumonisins.

showed that it is formed from acetateduring the normal course of cholesterol biosynthesis in rat liver homogenates (, J Biol Chem 1981, 256, 1067).

First description of the possibility of curing neuropsychiatric disorders with adiet enriched in linolenic acid (flaxseed oil) ().

Eberhard A et al.

We find that niltubacin is inactive in the inhibition of sphingolipid biosynthesis, ..

Khafrefungin, a Novel Inhibitor of Sphingolipid Synthesis



Fatty acid oxidationFatty acid oxidation is a set of cyclical series of long-chain fatty acids oxidations that occur in the mitochondria resulting in production of short-chain fatty acids, generating NADH, FADH2 and acetyl-CoA for biosynthetic pathways and produce ATP.