Disease relevance of Myriocin

• Myriocin is an inhibitor of SPT and suppresses replication of the hepatitis C virus (HCV) replicon [1].
• Male Balb/c mice, weighing 22 g were injected intraperitoneally with myriocin at 0, 0.1, 0.3, and 1.0 mg kg(-1) body weight daily for 5 days [2].
• Results suggest that the mechanisms by which myriocin and silymarin protect renal cells are different, and silymarin potentially prevents fumonisin B1-induced toxicity by modulating TNFalpha expression or signals downstream of the inhibition of ceramide synthase [3].
• FTY720, a synthetic myriocin analogue derived from culture filtrates of Isaria sinclairii, is a novel immunosuppressant that in experimental animals and nonhuman primates produces lymphocytopenia and prolongs allograft survival in dose-dependent fashion [4].

High impact information on Myriocin

• [3H]DHS incorporation is greatly enhanced if endogenous synthesis of DHS is inhibited by myriocin [5].
• Inhibition of ceramide synthesis by a fungal metabolite, myriocin, leads to a rapid and specific reduction in the rate of transport of glycosylphosphatidylinositol (GPI)-anchored proteins to the Golgi apparatus without affecting transport of soluble or transmembrane proteins [6].
• We employed myriocin, a specific inhibitor of serine palmitoyl-CoA transferase that mediates the first commitment step in sphingolipid synthesis [7].
• We found that myriocin could effectively block AICD in T-cell hybridomas and T-cell blasts [7].
• Following the present concepts, the synthetic sphingosine analog of myriocin FTY720 alters migration and homing of lymphocytes via sphingosine 1-phosphate receptors [8].

Biological context of Myriocin

• 1-Phenyl-2-decanoylamino-3-morpholino-1-propanol, tamoxifen, and C(2)-ceramide stimulated the expression of beclin 1, whereas myriocin antagonized the tamoxifen-dependent up-regulation [9].
• In contrast, myriocin, an inhibitor of the de novo ceramide synthesis pathway, only partially suppressed the production of ceramides in mitochondria and cannot suppress UV-induced apoptosis [10].
• Furthermore, cell death could in part be reversed by myriocin, indicating, for the first time, that endogenous ceramide generation by this agent contributes towards its biological activity [11].
• The interaction of SPT with myriocin suggested that such product-related compounds would strongly and competitively inhibit enzyme activity by forming an external aldimine in the active site of the enzyme [12].
• We investigated the anti-HCV effect of myriocin against intact HCV using chimeric mice with humanized liver infected with HCV genotype 1a or 1b [1].

Anatomical context of Myriocin

• ISP-1/myriocin is a potent inhibitor of sphingolipid biosynthesis and induces severe growth defects in eukaryotic cells because of the sphingolipid deprivation [13].
• In L6 skeletal myoblasts induced to differentiate by Arg8-vasopressin treatment, a short-lived lowering of ceramide levels was observed, followed by a long-lasting elevation that was prevented by inhibitors of the de novo synthesis pathway, fumonisin B1 and myriocin [14].
• BACKGROUND: Myriocin is a natural product that potently induces apoptosis of a murine cytotoxic T lymphocyte cell line (CTLL-2) and inhibits a serine palmitoyltransferase (SPT) activity that has been detected in cell extracts and is thought to initiate sphingolipid biosynthesis [15].
• In Jurkat cells PDT-induced intracellular sphinganine accumulation, DEVDase activation, PARP cleavage, and apoptosis were suppressed by the de novo sphingolipid synthesis inhibitor ISP-1 (Myriocin) [16].
• Finally, treatment of L. mexicana promastigotes with myriocin, an inhibitor of sphingolipid biosynthesis, demonstrated that ongoing sphingolipid biosynthesis is not required for the plasma-membrane transport of either gp63 or the GIPLs and that DRMs persist even when cellular levels of the major sphingolipid are depleted by 70% [17].

Associations of Myriocin with other chemical compounds

• The results demonstrated that (3)H label was incorporated into newly synthesized long chain ceramides, which was inhibited by FB1 and not by MYR [18].
• Tamoxifen and C(2)-ceramide interfere with the activation of protein kinase B, whereas myriocin relieved the inhibitory effect of tamoxifen [9].
• On a chow diet, myriocin treatment caused a significant decrease (50%) in liver SPT activity (p < 0.001), significant decreases in plasma sphingomyelin, ceramide, and sphingosine-1-phosphate levels (54, 32, and 73%, respectively) (p < 0.0001), and a significant increase in plasma phosphatidylcholine levels (91%) (p < 0.0001) [19].
• The 4-HPR-induced increase in ceramide was suppressed by inhibitors of ceramide synthesis, fumonisin B(1), myriocin, and l-cycloserine, and 4-HPR transiently activated serine palmitoyltransferase, demonstrating that 4-HPR induced de novo ceramide synthesis [20].
• Uninephrectomized Sprague-Dawley rats were fed a folate-free diet for 8 weeks to produce hHcys and the de novo ceramide synthesis inhibitor myriocin or the NAD(P)H oxidase inhibitor apocynin was administrated [21].

Gene context of Myriocin

• RESULTS: Myriocin derivatives were synthesized and evaluated using CTLL-2 proliferation and SPT activity assays [15].
• In addition, the modulation of telomerase activity by ATRA correlated with the induction of morphologic differentiation, which was also blocked by myriocin, as determined by extension of neurites using phase-contrast microscopy [22].
• Blockade of the de novo ceramide production pathway by fumonisin B(1) or myriocin inhibited the ceramide responses, but did not prevent aromatase inhibition by 15-dPGJ(2) or 4HPR [23].
• Inhibition of serine palmitoyltransferase by myriocin, a natural mycotoxin, causes induction of c-myc in mouse liver [2].
• Inhibition of de novo sphingolipid biosynthesis with myriocin significantly attenuated Bax oligomerization and downstream caspase activation after SK1 loss [24].

Analytical, diagnostic and therapeutic context of Myriocin

• Guided by these results, affinity chromatography matrices were prepared and two specific myriocin-binding proteins were isolated from CTLL-2 lysates [15].
• To further test the ability of MALDI TOF-MS to quantify changes in phospholipid (PL) metabolic pathways, myriocin, an inhibitor of SM synthesis, was added to the cells [25].
• Myriocin treatment resulted in significant reductions in both plasma SM and GSL concentration of 42% and 25%, as assessed by enzymatic and HPLC methods, respectively [26].
• Immunosuppressive activities of those myriocin analogs on mouse allogeneic mixed lymphocyte reaction were examined, and Z-14-deoxomyriocin was found to show the most potent activity among them [27].
• The mice were pretreated daily with intraperitoneal injection of 1.0 mg/kg myriocin 30 min before subcutaneous injections of 2.25 mg/kg of FB(1) for 3 days [28].

References