Simulation and validation of modelled sphingolipid metabolism in Saccharomyces cerevisiae

Alvarez‐Vasquez, Fernando; Sims, Kellie J.; Cowart, L. Ashley; Okamoto, Yasuo; Voit, Eberhard O.; Hannun, Yusuf A.

doi:10.1038/nature03232

Cited by 146 publications

(136 citation statements)

References 21 publications

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“…By monitoring the absolute abundance of individual lipid species we demonstrated that differences in growth temperature and defects in the lipid biosynthesis machinery produced alterations throughout the entire yeast lipidome. These ripple effects could not have been predicted from known activities of lipid biosynthesis enzymes (32). We also note that phenotypes seen upon deletion of genes expected to affect a specific lipid class might derive from seemingly unrelated compensatory changes within the lipidome that can only be assessed by global lipid analysis.…”

Section: Discussionmentioning

confidence: 99%

Global analysis of the yeast lipidome by quantitative shotgun mass spectrometry

Ejsing

Sampaio

Surendranath

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

981

1,064

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Although the transcriptome, proteome, and interactome of several eukaryotic model organisms have been described in detail, lipidomes remain relatively uncharacterized. Using Saccharomyces cerevisiae as an example, we demonstrate that automated shotgun lipidomics analysis enabled lipidome-wide absolute quantification of individual molecular lipid species by streamlined processing of a single sample of only 2 million yeast cells. By comparative lipidomics, we achieved the absolute quantification of 250 molecular lipid species covering 21 major lipid classes. This analysis provided Ϸ95% coverage of the yeast lipidome achieved with 125-fold improvement in sensitivity compared with previous approaches. Comparative lipidomics demonstrated that growth temperature and defects in lipid biosynthesis induce ripple effects throughout the molecular composition of the yeast lipidome. This work serves as a resource for molecular characterization of eukaryotic lipidomes, and establishes shotgun lipidomics as a powerful platform for complementing biochemical studies and other systems-level approaches.fatty acid elongation ͉ S. cerevisiae ͉ shotgun lipidomics T he lipidome of eukaryotic cells consists of hundreds to thousands of individual lipid species that constitute membranes, store metabolic energy and function as bioactive molecules (1-3). Despite the extensive characterization of proteins, their association into complexes and activities (4-6), it is still difficult to assess how perturbations within the lipid metabolic network affect the full lipidome of cells. This work shows that lipidome-wide quantification of individual molecular lipid species (molecules with defined chemical structure) by absolute quantification (expressed in mol or mol%) provides a new approach to relate lipidomics and functional genomics studies.The yeast Saccharomyces cerevisiae serves as a prime model organism for studying the molecular organization and regulatory circuitry of eukaryotic lipidomes (7-9). It uses a relatively simple and conserved network of lipid metabolic pathways (Fig. 1) that synthesize a few hundred molecular lipid species constituting its full lipidome (3). The lipidome diversity is primarily determined by the fatty acid synthase (10), the ⌬-9 desaturase (11) and the fatty acid elongation complex (12) that produce only saturated or mono-unsaturated fatty acids having 10 to 26 carbon atoms for the biosynthesis of glycerolipids, glycerophospholipids, and sphingolipids. Importantly, several metabolic conversions interlink sphingolipid, glycerophospholipid, and glycerolipid metabolism such that any perturbation within the metabolic network is prone to induce lipidome-wide ripple effects. Remarkably, numerous genes involved in lipid metabolism and trafficking can be mutated or deleted without apparent physiological consequences (Fig. 1).Despite remarkable methodological advances, lipidomics seldom complements functional genomics efforts owing to three major factors. First, analysis of glycerophospholipids and sphingolipids requires ...

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Section: Discussionmentioning

confidence: 99%

Global analysis of the yeast lipidome by quantitative shotgun mass spectrometry

Ejsing

Sampaio

Surendranath

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

981

1,064

View full text Add to dashboard Cite

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“…It has long been known that inositol-containing sphingolipid synthesis is reduced during inositol starvation (13,(53)(54)(55). It has also been shown that treating cells with AbA (56) inhibits inositol phosphorylceramide synthase activity leading to a reduction in inositol-containing sphingolipid synthesis (57).…”

Section: Discussionmentioning

confidence: 99%

Activation of Protein Kinase C-Mitogen-activated Protein Kinase Signaling in Response to Inositol Starvation Triggers Sir2p-dependent Telomeric Silencing in Yeast

Lee¹,

Gaspar²,

Aregullin

et al. 2013

Journal of Biological Chemistry

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Background: Inhibition of complex sphingolipid synthesis by inositol starvation activates the PKC-MAPK signaling pathway. Results: Sir2p-dependent telomeric silencing is activated by interrupting sphingolipid synthesis and requires the MAPK, Slt2p. Conclusion: Telomeric silencing is regulated by PKC-MAPK signaling in response to interruption of sphingolipid synthesis. Significance: Sphingolipid metabolism plays an important role in regulating silencing and chronological life span.

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“…The signals, which result from inositol and/or lipid metabolism and control the responses of genes other than those containing the UAS INO element (2), remain to be elucidated. In yeast, PI also serves as a precursor to the inositol-containing sphingolipids, which have also been shown to undergo changes in metabolism following inositol addition (47). In yeast, PI also serves as precursor to phosphoinositides, as well as a variety of inositol phosphates, many of which play roles in transcriptional regulation signaling processes and membrane trafficking (36).…”

Section: Discussionmentioning

confidence: 99%

Inositol Induces a Profound Alteration in the Pattern and Rate of Synthesis and Turnover of Membrane Lipids in Saccharomyces cerevisiae

Gaspar

Aregullin

Jesch

et al. 2006

Journal of Biological Chemistry

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The addition of inositol to actively growing yeast cultures causes a rapid increase in the rate of synthesis of phosphatidylinositol and, simultaneously, triggers changes in the expression of hundreds of genes. We now demonstrate that the addition of inositol to yeast cells growing in the presence of choline leads to a dramatic reprogramming of cellular lipid synthesis and turnover. The response to inositol includes a 5-6-fold increase in cellular phosphatidylinositol content within a period of 30 min. The increase in phosphatidylinositol content appears to be dependent upon fatty acid synthesis. Phosphatidylcholine turnover increased rapidly following inositol addition, a response that requires the participation of Nte1p, an endoplasmic reticulum-localized phospholipase B. Mass spectrometry revealed that the acyl species composition of phosphatidylinositol is relatively constant regardless of supplementation with inositol or choline, whereas phosphatidylcholine acyl species composition is influenced by both inositol and choline. In medium containing inositol, but lacking choline, high levels of dimyristoylphosphatidylcholine were detected. Within 60 min following the addition of inositol, dimyristoylphosphatidylcholine levels had decreased from ϳ40% of total phosphatidylcholine to a basal level of less than 5%. nte1⌬ cells grown in the absence of inositol and in the presence of choline exhibited lower levels of dimyristoylphosphatidylcholine than wild type cells grown under these same conditions, but these levels remained largely constant after the addition of inositol. These results are discussed in relationship to transcriptional regulation known to be linked to lipid metabolism in yeast.

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Simulation and validation of modelled sphingolipid metabolism in Saccharomyces cerevisiae

Cited by 146 publications

References 21 publications

Global analysis of the yeast lipidome by quantitative shotgun mass spectrometry

Global analysis of the yeast lipidome by quantitative shotgun mass spectrometry

Activation of Protein Kinase C-Mitogen-activated Protein Kinase Signaling in Response to Inositol Starvation Triggers Sir2p-dependent Telomeric Silencing in Yeast

Inositol Induces a Profound Alteration in the Pattern and Rate of Synthesis and Turnover of Membrane Lipids in Saccharomyces cerevisiae

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