Metabolism and Regulation of Glycerolipids in Yeast
Bilayer-forming phospholipids and storage lipids like triacylglycerol are all part of the lipid class known as glycerolipids. Research conducted in the model organism Saccharomyces cerevisiae has been at the forefront of the identification of the enzymes involved in the metabolism of glycerolipids and its regulation. The initial two sequential acylations of glycerol 3-phosphate using acyl-CoA as acyl donor to produce phosphatidic acid (PA) are common steps in the de novo synthesis of glycerolipids. PA represents a critical branching point in this pathway as it can either be (1) dephosphorylated to produce diacylglycerol (DAG) for the synthesis of triacylglycerol or phospholipids through the Kennedy pathways or (2) be converted to CDP-DAG for the synthesis of phospholipids. PA has surfaced as not only the precursor for all glycerolipids but also as a potent signalling lipid able to integrate cellular cues to balance synthesis of phospholipids for membrane expansion versus storage in the form of triacylglycerol. The PA-dependent regulatory circuit Ino2-Ino4-Opi1 that controls expression of enzymes involved in glycerolipid synthesis downstream of the PA branching point has been very well characterized in yeast. Less is known about the regulation of the upstream initial steps leading to PA synthesis. Emerging research points to the production of different pools of PA by the acyltransferases in charge of the initial acylation steps in concert with other pathways that produce and use acyl-CoAs. In addition, recent discoveries on the movement of PA between organelles further indicate these pools are mobile. Although elucidation of lipid pool partitioning remains a major challenge in the field, current technology combined with the tractability of yeast warrant future progress on this topic.
This work was supported by an NSERC Discovery grant and NSERC Discovery Accelerator Supplement to VZ; an Eyes High International Doctoral Scholarship to SG and, an NSERC-CGSM award to BNS.
- Ghosh AK, Ramakrishnan G, Rajasekharan R (2008) YLR099C (ICT1) encodes a soluble acyl-CoA-dependent lysophosphatidic acid acyltransferase responsible for enhanced phospholipid synthesis on organic solvent stress in Saccharomyces cerevisiae. J Biol Chem 283:9768–9775. https://doi.org/10.1074/jbc.M708418200CrossRefPubMedPubMedCentralGoogle Scholar
- Kopec KO, Alva V, Lupas AN (2010) Homology of SMP domains to the TULIP superfamily of lipid-binding proteins provides a structural basis for lipid exchange between ER and mitochondria. Bioinformatics 26:1927–1931. https://doi.org/10.1093/bioinformatics/btq326CrossRefPubMedPubMedCentralGoogle Scholar
- Marr N, Foglia J, Terebiznik M et al (2012) Controlling lipid fluxes at glycerol-3-phosphate acyltransferase step in yeast: unique contribution of Gat1p to oleic acid-induced lipid particle formation. J Biol Chem 287:10251–10264. https://doi.org/10.1074/jbc.M111.314112CrossRefPubMedPubMedCentralGoogle Scholar
- Pagac M, de la Mora HV, Duperrex C et al (2011) Topology of 1-acyl-sn-glycerol-3-phosphate acyltransferases SLC1 and ALE1 and related membrane-bound O-acyltransferases (MBOATs) of Saccharomyces cerevisiae. J Biol Chem 286:36438–36447. https://doi.org/10.1074/jbc.M111.256511CrossRefPubMedPubMedCentralGoogle Scholar
- Smart HC, Mast FD, Chilije MFJ et al (2014) Phylogenetic analysis of glycerol 3-phosphate acyltransferases in opisthokonts reveals unexpected ancestral complexity and novel modern biosynthetic components. PLoS One 9:e110684. https://doi.org/10.1371/journal.pone.0110684CrossRefPubMedPubMedCentralGoogle Scholar
- Su W-M, Han G-S, Casciano J, Carman GM (2012) Protein kinase A-mediated phosphorylation of Pah1p phosphatidate phosphatase functions in conjunction with the Pho85p-Pho80p and Cdc28p-Cyclin B kinases to regulate lipid synthesis in yeast. J Biol Chem 287:33364–33376. https://doi.org/10.1074/jbc.M112.402339CrossRefPubMedPubMedCentralGoogle Scholar
- Su W-M, Han G-S, Carman GM (2014a) Cross-talk phosphorylations by protein kinase C and Pho85p-Pho80p protein kinase regulate Pah1p phosphatidate phosphatase abundance in Saccharomyces cerevisiae. J Biol Chem 289:18818–18830. https://doi.org/10.1074/jbc.M114.581462CrossRefPubMedPubMedCentralGoogle Scholar
- Tamura Y, Onguka O, Itoh K et al (2012b) Phosphatidylethanolamine biosynthesis in mitochondria: phosphatidylserine (PS) trafficking is independent of a PS decarboxylase and intermembrane space proteins Ups1p and Ups2p. J Biol Chem 287:43961–43971. https://doi.org/10.1074/jbc.M112.390997CrossRefPubMedPubMedCentralGoogle Scholar
- Vionnet C, Roubaty C, Ejsing CS et al (2011) Yeast cells lacking all known ceramide synthases continue to make complex sphingolipids and to incorporate ceramides into glycosylphosphatidylinositol (GPI) anchors. J Biol Chem 286:6769–6779. https://doi.org/10.1074/jbc.M110.176875CrossRefPubMedGoogle Scholar
- Zaremberg V, McMaster CR (2002) Differential partitioning of lipids metabolized by separate yeast glycerol-3-phosphate acyltransferases reveals that phospholipase D generation of phosphatidic acid mediates sensitivity to choline-containing lysolipids and drugs. J Biol Chem 277:39035–39044. https://doi.org/10.1074/jbc.M207753200CrossRefPubMedGoogle Scholar