Phospholipid synthesis in yeast: regulation by phosphorylation.

The yeast Saccharomyces cerevisiae is a model eukaryotic organism for the study of the regulation of phospholipid synthesis. The major phospholipids (phosphatidylcholine, phosphatidylethanolamine, phosphatidylinositol, and phosphatidylserine) are synthesized by complementary (CDP-diacylglycerol and Kennedy) pathways. The regulation of these pathways is complex and is controlled by genetic and biochemical mechanisms. Inositol plays a major role in the regulation of phospholipid synthesis. Inositol-mediated regulation involves the expression of genes and the modulation of enzyme activities. Phosphorylation is a major mechanism by which enzymes and transcription factors are regulated, and indeed, key phospholipid biosynthetic enzymes have been identified as targets of phosphorylation. Protein kinase A phosphorylates CTP synthetase, choline kinase, Mg2+-dependent phosphatidate phosphatase, phosphatidylserine synthase, and the transcription factor Opi1p. CTP synthetase and Opi1p are also phosphorylated by protein kinase C. The phosphorylation of these proteins plays a role in regulating their activities and (or) function in phospholipid synthesis.

[1]  M. Murray,et al.  Expression of yeast INM1 encoding inositol monophosphatase is regulated by inositol, carbon source and growth stage and is decreased by lithium and valproate , 2000 .

[2]  E. Schweizer,et al.  DNA binding site of the yeast heteromeric Ino2p/Ino4p basic helix‐loop‐helix transcription factor: structural requirements as defined by saturation mutagenesis , 1995, FEBS letters.

[3]  S. Henry,et al.  Phospholipid biosynthesis in the yeast Saccharomyces cerevisiae and interrelationship with other metabolic processes. , 1999, Progress in lipid research.

[4]  G. Carman,et al.  Phosphorylation of CTP Synthetase on Ser36, Ser330, Ser354, and Ser454 Regulates the Levels of CTP and Phosphatidylcholine Synthesis in Saccharomyces cerevisiae* , 2003, Journal of Biological Chemistry.

[5]  E. P. Kennedy,et al.  Enzymatic synthesis of cytidine diphosphate diglyceride. , 1966, Journal of lipid research.

[6]  F. Klein,et al.  YDL142c encodes cardiolipin synthase (Cls1p) and is non‐essential for aerobic growth of Saccharomyces cerevisiae , 1998, FEBS letters.

[7]  G M Carman,et al.  Coordinate regulation of phospholipid biosynthesis in Saccharomyces cerevisiae: pleiotropically constitutive opi1 mutant , 1985, Journal of bacteriology.

[8]  M. Hohenegger,et al.  Gsalpha-selective G protein antagonists. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[9]  G. Daum,et al.  Biogenesis and cellular dynamics of aminoglycerophospholipids. , 2003, International review of cytology.

[10]  J. Zou,et al.  The Initial Step of the Glycerolipid Pathway , 2001, The Journal of Biological Chemistry.

[11]  Fritz Paltauf,et al.  8 Regulation and Compartmentalization of Lipid Synthesis in Yeast , 1992 .

[12]  G. Carman,et al.  Isolation and Characterization of the Saccharomyces cerevisiae EKI1 Gene Encoding Ethanolamine Kinase* , 1999, The Journal of Biological Chemistry.

[13]  E. P. Kennedy,et al.  METABOLISM AND FUNCTION OF BACTERIAL LIPIDS. II. BIOSYNTHESIS OF PHOSPHOLIPIDS IN ESCHERICHIA COLI. , 1964, The Journal of biological chemistry.

[14]  S. Henry,et al.  The Saccharomyces cerevisiae INO4 gene encodes a small, highly basic protein required for derepression of phospholipid biosynthetic enzymes. , 1990, The Journal of biological chemistry.

[15]  M. Frohman,et al.  Phospholipase D signaling is essential for meiosis. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[16]  S. Henry,et al.  Isolation of the yeast structural gene for the membrane-associated enzyme phosphatidylserine synthase. , 1983, Proceedings of the National Academy of Sciences of the United States of America.

[17]  J. A. Gorman,et al.  Effect of CTP Synthetase Regulation by CTP on Phospholipid Synthesis in Saccharomyces cerevisiae * , 1998, The Journal of Biological Chemistry.

[18]  J. Broach,et al.  The function of ras genes in Saccharomyces cerevisiae. , 1990, Advances in cancer research.

[19]  J. Nikawa,et al.  Molecular cloning of the gene encoding CDPdiacylglycerol-inositol 3-phosphatidyl transferase in Saccharomyces cerevisiae. , 1984, European journal of biochemistry.

[20]  J. Thevelein Signal transduction in yeast , 1994, Yeast.

[21]  G. Carman,et al.  Phosphorylation of Saccharomyces cerevisiae CTP Synthetase at Ser424 by Protein Kinases A and C Regulates Phosphatidylcholine Synthesis by the CDP-choline Pathway* , 2003, Journal of Biological Chemistry.

[22]  A. Kinney,et al.  Phosphorylation of yeast phosphatidylserine synthase in vivo and in vitro by cyclic AMP-dependent protein kinase. , 1988, Proceedings of the National Academy of Sciences of the United States of America.

[23]  A. Breitkreutz,et al.  Characterization of the basal and pheromone-stimulated phosphorylation states of Ste12p. , 1997, European journal of biochemistry.

[24]  T. Hunter,et al.  Transcriptional control by protein phosphorylation: signal transmission from the cell surface to the nucleus , 1995, Current Biology.

[25]  G. Carman,et al.  Purification and characterization of CTP synthetase, the product of the URA7 gene in Saccharomyces cerevisiae. , 1994, Biochemistry.

[26]  E. Schweizer,et al.  Yeast transcriptional activator INO2 interacts as an Ino2p/Ino4p basic helix-loop-helix heteromeric complex with the inositol/choline-responsive element necessary for expression of phospholipid biosynthetic genes in Saccharomyces cerevisiae. , 1995, Nucleic acids research.

[27]  G. Carman,et al.  Purification and characterization of phosphatidate phosphatase from Saccharomyces cerevisiae. , 1989, The Journal of biological chemistry.

[28]  W. Wilkison,et al.  Altered growth regulation and enhanced tumorigenicity of NIH 3T3 fibroblasts transfected with protein kinase C-I cDNA , 1988, Cell.

[29]  G. Carman,et al.  Phosphatidate phosphatase from Saccharomyces cerevisiae. Isolation of 45- and 104-kDa forms of the enzyme that are differentially regulated by inositol. , 1991, The Journal of biological chemistry.

[30]  S. Henry,et al.  Saccharomyces cerevisiae cho2 mutants are deficient in phospholipid methylation and cross-pathway regulation of inositol synthesis. , 1988, Genetics.

[31]  S. Henry,et al.  Phosphorylation of the Yeast Phospholipid Synthesis Regulatory Protein Opi1p by Protein Kinase C * , 2001, The Journal of Biological Chemistry.

[32]  S. Henry,et al.  The OPI1 gene of Saccharomyces cerevisiae, a negative regulator of phospholipid biosynthesis, encodes a protein containing polyglutamine tracts and a leucine zipper. , 1991, The Journal of biological chemistry.

[33]  F. Fasiolo,et al.  Cloning, sequencing and characterization of the Saccharomyces cerevisiae URA7 gene encoding CTP synthetase , 1991, Molecular and General Genetics MGG.

[34]  J. Nikawa,et al.  Functional analysis of the regulatory region of the yeast phosphatidylserine synthase gene, PSS , 1991, Journal of bacteriology.

[35]  D. Voelker,et al.  Identification of a Non-mitochondrial Phosphatidylserine Decarboxylase Activity (PSD2) in the Yeast Saccharomyces cerevisiae(*) , 1995, The Journal of Biological Chemistry.

[36]  R. Bell,et al.  sn-1,2-diacylglycerol choline- and ethanolaminephosphotransferases in Saccharomyces cerevisiae. Nucleotide sequence of the EPT1 gene and comparison of the CPT1 and EPT1 gene products. , 1991, The Journal of biological chemistry.

[37]  Z. Xie,et al.  Phospholipase D activity is required for suppression of yeast phosphatidylinositol transfer protein defects. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[38]  Carissa A. Sanchez,et al.  Comparative genomic analysis of tumors: detection of DNA losses and amplification. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[39]  G. Carman,et al.  Regulation of Yeast CTP Synthetase Activity by Protein Kinase C (*) , 1996, The Journal of Biological Chemistry.

[40]  G. Carman,et al.  Nucleotide-dependent Tetramerization of CTP Synthetase from Saccharomyces cerevisiae * , 1998, The Journal of Biological Chemistry.

[41]  S. Henry,et al.  Phospholipid biosynthesis in yeast. , 1989, Annual review of biochemistry.

[42]  J. Nikawa,et al.  Molecular cloning and characterization of the gene encoding cholinephosphate cytidylyltransferase in Saccharomyces cerevisiae. , 1987, European journal of biochemistry.

[43]  S. Henry,et al.  Isolation of the yeast INO1 gene: located on an autonomously replicating plasmid, the gene is fully regulated. , 1984, Proceedings of the National Academy of Sciences of the United States of America.

[44]  J. Nikawa,et al.  Primary structure and disruption of the phosphatidylinositol synthase gene of Saccharomyces cerevisiae. , 1987, The Journal of biological chemistry.

[45]  G M Carman,et al.  Regulation of Phospholipid Biosynthesis in the Yeast Saccharomyces cerevisiae* , 1996, The Journal of Biological Chemistry.

[46]  E. Rozengurt,et al.  Diacylglycerol stimulates DNA synthesis and cell division in mouse 3T3 cells: role of Ca2+-sensitive phospholipid-dependent protein kinase. , 1984, Proceedings of the National Academy of Sciences of the United States of America.

[47]  A. Kinney,et al.  Regulation of phospholipid biosynthesis in Saccharomyces cerevisiae by cyclic AMP-dependent protein kinase , 1990, Journal of bacteriology.

[48]  S. Henry,et al.  Biosynthesis of inositol in yeast. Primary structure of myo-inositol-1-phosphate synthase (EC 5.5.1.4) and functional analysis of its structural gene, the INO1 locus. , 1989, The Journal of biological chemistry.

[49]  J. Lopes,et al.  Genetic regulation of phospholipid biosynthesis in Saccharomyces cerevisiae , 1996, Microbiological reviews.

[50]  D. Vance Chapter 6 - Glycerolipid biosynthesis in eukaryotes , 1996 .

[51]  J. Ambroziak,et al.  INO2 and INO4 gene products, positive regulators of phospholipid biosynthesis in Saccharomyces cerevisiae, form a complex that binds to the INO1 promoter. , 1994, The Journal of biological chemistry.

[52]  Bruce Stillman,et al.  Cold Spring Harbor Laboratory , 1995, Current Biology.

[53]  T. Kodaki,et al.  Yeast phosphatidylethanolamine methylation pathway. Cloning and characterization of two distinct methyltransferase genes. , 1987, The Journal of biological chemistry.

[54]  S. Henry Membrane Lipids of Yeast: Biochemical and Genetic Studies , 1982 .

[55]  S. Henry,et al.  Genetic regulation of phospholipid metabolism: yeast as a model eukaryote. , 1998, Progress in nucleic acid research and molecular biology.

[56]  J. Gerst,et al.  Identification and Characterization of a Gene Encoding Phospholipase D Activity in Yeast (*) , 1996, The Journal of Biological Chemistry.

[57]  S. Henry,et al.  Yeast mutant defective in phosphatidylserine synthesis. , 1980, The Journal of biological chemistry.

[58]  D. Kidby,et al.  Lipids of yeasts. , 1975, Bacteriological reviews.

[59]  M. Bossie,et al.  Nutritional regulation of yeast delta-9 fatty acid desaturase activity , 1989, Journal of bacteriology.

[60]  S. Henry,et al.  The INO2 and INO4 loci of Saccharomyces cerevisiae are pleiotropic regulatory genes , 1984, Molecular and cellular biology.

[61]  J. Broach,et al.  The 45- and 104-kDa forms of phosphatidate phosphatase from Saccharomyces cerevisiae are regulated differentially by phosphorylation via cAMP-dependent protein kinase. , 1992, Journal of Biological Chemistry.

[62]  T. Kodaki,et al.  Characterization of the methyltransferases in the yeast phosphatidylethanolamine methylation pathway by selective gene disruption. , 1989, European journal of biochemistry.

[63]  Y. Nishizuka,et al.  Protein kinase C and calcium ion in mitogenic response of macrophage-depleted human peripheral lymphocytes. , 1985, The Journal of biological chemistry.

[64]  R. Bell,et al.  Mutants of Saccharomyces cerevisiae defective in sn-1,2-diacylglycerol cholinephosphotransferase. Isolation, characterization, and cloning of the CPT1 gene. , 1987, The Journal of biological chemistry.

[65]  C. Kent,et al.  Interactions among pathways for phosphatidylcholine metabolism, CTP synthesis and secretion through the Golgi apparatus. , 1999, Trends in biochemical sciences.

[66]  G. Carman,et al.  Use of synthetic lethal mutants to clone and characterize a novel CTP synthetase gene in Saccharomyces cerevisiae , 1994, Molecular and General Genetics MGG.

[67]  S. Henry,et al.  Mutations in the Saccharomyces cerevisiae opi3 gene: effects on phospholipid methylation, growth and cross-pathway regulation of inositol synthesis. , 1989, Genetics.

[68]  S. Henry,et al.  The INO2 gene of Saccharomyces cerevisiae encodes a helix-loop-helix protein that is required for activation of phospholipid synthesis. , 1992, Nucleic acids research.

[69]  J. Lopes,et al.  Analysis of sequences in the INO1 promoter that are involved in its regulation by phospholipid precursors. , 1991, Nucleic acids research.

[70]  G. Carman Phosphatidate phosphatases and diacylglycerol pyrophosphate phosphatases in Saccharomyces cerevisiae and Escherichia coli. , 1997, Biochimica et biophysica acta.

[71]  D. Voelker,et al.  Phosphatidylserine decarboxylase from Saccharomyces cerevisiae. Isolation of mutants, cloning of the gene, and creation of a null allele. , 1993, The Journal of biological chemistry.

[72]  C Wagner,et al.  Overproduction of the Opi1 repressor inhibits transcriptional activation of structural genes required for phospholipid biosynthesis in the yeast Saccharomyces cerevisiae , 1999, Yeast.

[73]  M. Poznansky,et al.  Superoxide dismutase (SOD)-catalase conjugates. Role of hydrogen peroxide and the Fenton reaction in SOD toxicity. , 1993, The Journal of biological chemistry.

[74]  D. E. Levin,et al.  Mutants in the S. cerevisiae PKC1 gene display a cell cycle-specific osmotic stability defect , 1992, The Journal of cell biology.

[75]  R. Bell,et al.  The sn-1,2-diacylglycerol cholinephosphotransferase of Saccharomyces cerevisiae. Nucleotide sequence, transcriptional mapping, and gene product analysis of the CPT1 gene. , 1990, The Journal of biological chemistry.

[76]  D. Voelker,et al.  Phosphatidylserine Decarboxylase 2 of Saccharomyces cerevisiáe , 1995, The Journal of Biological Chemistry.

[77]  E. O’Shea,et al.  The receptor Msn5 exports the phosphorylated transcription factor Pho4 out of the nucleus , 1998, Nature.

[78]  T. Kodaki,et al.  Cloning and characterization of the yeast CKI gene encoding choline kinase and its expression in Escherichia coli. , 1989, The Journal of biological chemistry.

[79]  T. Hikiji,et al.  Primary structure and product characterization of the Saccharomyces cerevisiae CHO1 gene that encodes phosphatidylserine synthase. , 1987, Journal of biochemistry.

[80]  S. Henry,et al.  Regulation of the yeast INO1 gene. The products of the INO2, INO4 and OPI1 regulatory genes are not required for repression in response to inositol. , 2000, Genetics.

[81]  G. Carman,et al.  Phosphorylation of Saccharomyces cerevisiae Choline Kinase on Ser30 and Ser85 by Protein Kinase A Regulates Phosphatidylcholine Synthesis by the CDP-choline Pathway* , 2002, The Journal of Biological Chemistry.

[82]  C. McMaster,et al.  Cessation of Growth to Prevent Cell Death Due to Inhibition of Phosphatidylcholine Synthesis Is Impaired at 37 °C inSaccharomyces cerevisiae * , 2002, The Journal of Biological Chemistry.

[83]  C. Martín,et al.  Specificity of unsaturated fatty acid-regulated expression of the Saccharomyces cerevisiae OLE1 gene. , 1992, The Journal of biological chemistry.

[84]  D. M. Greenberg,et al.  Methyl transfering enzyme system of microsomes in the biosynthesis of lecithin (phosphatidylcholine) , 1961 .

[85]  W. Dowhan,et al.  Cloning of a gene (PSD1) encoding phosphatidylserine decarboxylase from Saccharomyces cerevisiae by complementation of an Escherichia coli mutant. , 1993, The Journal of biological chemistry.

[86]  S. Henry,et al.  Functional Characterization of an Inositol-sensitive Upstream Activation Sequence in Yeast , 1995, The Journal of Biological Chemistry.

[87]  H. Rizavi,et al.  Cardiolipin is not essential for the growth of Saccharomyces cerevisiae on fermentable or non‐fermentable carbon sources , 1997, Molecular microbiology.

[88]  J. Nikawa,et al.  Nucleotide sequence and characterization of the yeast PSS gene encoding phosphatidylserine synthase. , 1987, European journal of biochemistry.

[89]  S. Henry,et al.  Expression of the Saccharomyces cerevisiae inositol-1-phosphate synthase (INO1) gene is regulated by factors that affect phospholipid synthesis , 1986, Molecular and cellular biology.

[90]  S. Henry,et al.  Yeast mutants auxotrophic for choline or ethanolamine , 1980, Journal of bacteriology.

[91]  G. Carman,et al.  Phosphorylation and Regulation of Choline Kinase fromSaccharomyces cerevisiae by Protein Kinase A* , 1999, The Journal of Biological Chemistry.

[92]  G. Carman,et al.  Identification of Ser424 as the protein kinase A phosphorylation site in CTP synthetase from Saccharomyces cerevisiae. , 1999, Biochemistry.

[93]  H. Nakamura,et al.  Isolation and characterization of ECT1 gene encoding CTP: phosphoethanolamine cytidylyltransferase of Saccharomyces cerevisiae. , 1996, Journal of biochemistry.

[94]  C. Calkhoven,et al.  Multiple steps in the regulation of transcription-factor level and activity. , 1996, The Biochemical journal.

[95]  E. O’Shea,et al.  Roles of phosphorylation sites in regulating activity of the transcription factor Pho4. , 1999, Science.

[96]  C. McMaster,et al.  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* , 2002, The Journal of Biological Chemistry.

[97]  D. Voelker New perspectives on the regulation of intermembrane glycerophospholipid traffic Published, JLR Papers in Press, January 16, 2003. DOI 10.1194/jlr.R200020-JLR200 , 2003, Journal of Lipid Research.

[98]  C. McMaster,et al.  Phosphatidylcholine biosynthesis via the CDP-choline pathway in Saccharomyces cerevisiae. Multiple mechanisms of regulation. , 1994, The Journal of biological chemistry.

[99]  S. Henry,et al.  Role of the Yeast Phosphatidylinositol/Phosphatidylcholine Transfer Protein (Sec14p) in Phosphatidylcholine Turnover andINO1 Regulation* , 1997, The Journal of Biological Chemistry.

[100]  Zanxian Xia,et al.  Regulation of the Yeast Transcriptional Factor PHO2 Activity by Phosphorylation* , 2000, The Journal of Biological Chemistry.

[101]  G. Carman,et al.  Phosphorylation of CTP Synthetase from Saccharomyces cerevisiae by Protein Kinase C (*) , 1995, The Journal of Biological Chemistry.

[102]  A. Hahn,et al.  Coordinate genetic control of yeast fatty acid synthase genes FAS1 and FAS2 by an upstream activation site common to genes involved in membrane lipid biosynthesis. , 1992, The EMBO journal.

[103]  R. Bell,et al.  The sn-1,2-diacylglycerol ethanolaminephosphotransferase activity of Saccharomyces cerevisiae. Isolation of mutants and cloning of the EPT1 gene. , 1988, The Journal of biological chemistry.

[104]  D. Voelker,et al.  Isolation and Characterization of the Gene (CLS1) Encoding Cardiolipin Synthase in Saccharomyces cerevisiae * , 1998, The Journal of Biological Chemistry.

[105]  E. P. Kennedy,et al.  The enzymatic synthesis of inositol monophosphatide. , 1958, The Journal of biological chemistry.

[106]  D. E. Levin,et al.  A candidate protein kinase C gene, PKC1, is required for the S. cerevisiae cell cycle , 1990, Cell.

[107]  W. Dowhan,et al.  The CDS1 Gene Encoding CDP-diacylglycerol Synthase In Saccharomyces cerevisiae Is Essential for Cell Growth (*) , 1996, The Journal of Biological Chemistry.

[108]  I. Weissman,et al.  Molecular Cloning and Characterization of a Novel Regulator of G-protein Signaling from Mouse Hematopoietic Stem Cells* , 2001, The Journal of Biological Chemistry.

[109]  C Wagner,et al.  The negative regulator Opi1 of phospholipid biosynthesis in yeast contacts the pleiotropic repressor Sin3 and the transcriptional activator Ino2 , 2001, Molecular microbiology.

[110]  G. Carman,et al.  Phosphorylation and Regulation of CTP Synthetase from Saccharomyces cerevisiae by Protein Kinase A* , 1996, The Journal of Biological Chemistry.

[111]  S. Henry,et al.  Regulation of phospholipid biosynthesis in Saccharomyces cerevisiae by inositol. Inositol is an inhibitor of phosphatidylserine synthase activity. , 1988, The Journal of biological chemistry.

[112]  W. Dowhan,et al.  The PEL1 Gene (Renamed PGS1) Encodes the Phosphatidylglycero-phosphate Synthase ofSaccharomyces cerevisiae * , 1998, The Journal of Biological Chemistry.