Glycosphingolipidoses: Beyond the enzymatic defect

Raas‐Rothschild, Annick; Pankova-Kholmyansky, Irene; Kacher, Yaacov; Futerman, Anthony H.

doi:10.1023/b:glyc.0000046272.38480.ef

Cited by 43 publications

(27 citation statements)

References 36 publications

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“…Although mammalian cells must turn over or break down complex sphingolipids to survive and prevent the accumulation of toxic molecules that cause debilitating human diseases termed sphingolipidoses (51), it has only fairly recently become apparent that S. cerevisiae cells even break down complex sphingolipids, let alone that the breakdown plays any observable physiological role. Complex sphingolipids in yeast constitute ?30% of the phosphorylated membrane lipids and nearly 7% of the mass of the plasma membrane (52).…”

Section: Sphingolipid Metabolismmentioning

confidence: 99%

Thematic Review Series: Sphingolipids. New insights into sphingolipid metabolism and function in budding yeast

Dickson

2008

Journal of Lipid Research

206

215

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Our understanding of sphingolipid metabolism and functions in the baker's yeast Saccharomyces cerevisiae has progressed substantially in the past 2 years. Yeast sphingolipids contain a C 26 -acyl moiety, all of the genes necessary to make these long-chain fatty acids have been identified, and a mechanism for how chain length is determined has been proposed. Advances in understanding how the de novo synthesis of ceramide and complex sphingolipids is regulated have been made, and they demonstrate that the Target Of Rapamycin Complex 2 (TORC2) controls ceramide synthase activity. Other work shows that TORC2 regulates the level of complex sphingolipids in a pathway using the Slm1 and Slm2 proteins to control the protein phosphatase calcineurin, which regulates the breakdown of complex sphingolipids. The activity of Slm1 and Slm2 has also been shown to be regulated during heat stress by phosphoinositides and TORC2, along with sphingoid long-chain bases and the Pkh1 and Pkh2 protein kinases, to control the actin cytoskeleton, the trafficking of nutrient transporters, and cell viability.Together, these results provide the first molecular insights into understanding previous genetic interaction data that indicated a connection between sphingolipids and the TORC2 and phosphoinositide signaling networks. This new knowledge provides a foundation for greatly advancing our understanding of sphingolipid biology in yeast.-Dickson, R. C. New insights into sphingolipid metabolism and function in budding yeast. J. Lipid Res. 2008. 49: 909-921.

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Section: Sphingolipid Metabolismmentioning

confidence: 99%

Thematic Review Series: Sphingolipids. New insights into sphingolipid metabolism and function in budding yeast

Dickson

2008

Journal of Lipid Research

206

215

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“…1), ceramide can be regarded as the central hub and is synthesized de novo from serine and palmitate through the action of serine palmitoyl transferase [4,5] and ceramide synthase [6]. Ceramide can be converted to SM [7] or glycosphingolipids (GSLs) [8] as membrane compartment and, as necessary, be generated from SM and GSL by several sphingomyelinases [9] and glycosylceramidases [10,11], respectively. Ceramide is also converted to sphingosine by one of many ceramidases [12,13], which in turn is phosphorylated to form S1P by SphKs including SphK1 and SphK2 [14].…”

Section: Introductionmentioning

confidence: 99%

Sphingolipids in cancer

Furuya

Shimizu

Kawamori

2011

Cancer Metastasis Rev

113

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The bioactive sphingolipids including, ceramide, sphingosine, and sphingosine-1-phosphate (S1P) have important roles in several types of signaling and regulation of many cellular processes including cell proliferation, apoptosis, senescence, angiogenesis, and transformation. Recent accumulating evidence suggests that ceramide- and S1P-mediated pathways have been implicated in cancer development, progression, and chemotherapy. Ceramide mediates numerous cell-stress responses, such as induction of apoptosis and cell senescence, whereas S1P plays pivotal roles in cell survival, migration, and inflammation. These sphingolipids with opposing roles can be interconverted within cells, suggesting that the balance between them is related to cell fate. Importantly, these sphingolipids are metabolically related through actions of enzymes including ceramidases, ceramide synthases, sphingosine kinases, and S1P phosphatases thereby forming a network of metabolically interrelated bioactive lipid mediators whose importance in normal cellular function and diseases is gaining appreciation. In this review, we summarize involvement of sphingolipids and their related enzymes in pathogenesis and therapy of cancer and discuss future directions of sphingolipid field in cancer research.

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“…LSDs form a group of about 50 diseases (Wraith 2002) with an estimated incidence of 1:7,000 live births (Meikle et al 1999b;Poorthuis et al 1999). LSDs are classified according to the substrate stored: sphingolipidoses, such as Gaucher disease (GD) or Fabry disease (FD); mucopolysaccharidoses (MPS); glycoproteinoses; and others (Gieselmann 1995;Raas-Rothschild et al 2004). Enzyme administration of the recombinant form of the enzyme that is deficient in LSD patients is known as enzyme replacement therapy (ERT).…”

Section: Introductionmentioning

confidence: 99%

Quality of Life of Brazilian Patients with Gaucher Disease and Fabry Disease

et al. 2012

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Summary Objective: To evaluate QoL in a sample of Brazilian patients with Gaucher (GD) and Fabry (FD) disease using the SF-36 survey.Method: Observational cross-sectional study. The SF-36 survey was administered to cognitively able patients 12 years or older, who were seen in the Medical Genetics Service of Hospital de Clínicas de Porto Alegre, Brazil.Results: Thirty-five patients were included in the study (GD ¼ 21, FD ¼ 14), mean age was 29.8 AE 14. Discussion and Conclusion: Although limited because of the small number of patients included, findings suggest that patients with GD receiving ERT have a better QoL than patients with FD or with GD not receiving ERT. Imiglucerase has a beneficial effect against pain for patients with GD. Further studies should be conducted to confirm our findings.

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Glycosphingolipidoses: Beyond the enzymatic defect

Cited by 43 publications

References 36 publications

Thematic Review Series: Sphingolipids. New insights into sphingolipid metabolism and function in budding yeast

Thematic Review Series: Sphingolipids. New insights into sphingolipid metabolism and function in budding yeast

Sphingolipids in cancer

Quality of Life of Brazilian Patients with Gaucher Disease and Fabry Disease

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