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Review
. 2012 Feb;190(2):317-49.
doi: 10.1534/genetics.111.130286.

Metabolism and regulation of glycerolipids in the yeast Saccharomyces cerevisiae

Susan A Henry  1 , Sepp D Kohlwein, George M Carman
Affiliations
Review

Metabolism and regulation of glycerolipids in the yeast Saccharomyces cerevisiae

Susan A Henry et al. Genetics. 2012 Feb.

Abstract

Due to its genetic tractability and increasing wealth of accessible data, the yeast Saccharomyces cerevisiae is a model system of choice for the study of the genetics, biochemistry, and cell biology of eukaryotic lipid metabolism. Glycerolipids (e.g., phospholipids and triacylglycerol) and their precursors are synthesized and metabolized by enzymes associated with the cytosol and membranous organelles, including endoplasmic reticulum, mitochondria, and lipid droplets. Genetic and biochemical analyses have revealed that glycerolipids play important roles in cell signaling, membrane trafficking, and anchoring of membrane proteins in addition to membrane structure. The expression of glycerolipid enzymes is controlled by a variety of conditions including growth stage and nutrient availability. Much of this regulation occurs at the transcriptional level and involves the Ino2-Ino4 activation complex and the Opi1 repressor, which interacts with Ino2 to attenuate transcriptional activation of UAS(INO)-containing glycerolipid biosynthetic genes. Cellular levels of phosphatidic acid, precursor to all membrane phospholipids and the storage lipid triacylglycerol, regulates transcription of UAS(INO)-containing genes by tethering Opi1 to the nuclear/endoplasmic reticulum membrane and controlling its translocation into the nucleus, a mechanism largely controlled by inositol availability. The transcriptional activator Zap1 controls the expression of some phospholipid synthesis genes in response to zinc availability. Regulatory mechanisms also include control of catalytic activity of glycerolipid enzymes by water-soluble precursors, products and lipids, and covalent modification of phosphorylation, while in vivo function of some enzymes is governed by their subcellular location. Genome-wide genetic analysis indicates coordinate regulation between glycerolipid metabolism and a broad spectrum of metabolic pathways.

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Figures

Figure 1
Figure 1
Phospholipid structures. The diagram shows the structures of the phospholipid PA and the major phospholipids PI, PS, PE, and PC that are derived from PA. The hydrophilic head groups (H, inositol, serine, ethanolamine, and choline) that are attached to the basic phospholipid structure are shown in red. The four most abundant fatty acids esterified to the glycerol-3-phosphate backbone of the phospholipids are palmitic acid, palmitoleic acid, steric acid, and oleic acid. The type and position of the fatty acyl moieties in the phospholipids are arbitrarily drawn. The relative amounts of the phospholipids as well as their fatty acyl compositions vary depending on strain (e.g., mutation) and growth condition.
Figure 2
Figure 2
Pathways for the synthesis of glycerolipids and their subcellular localization. Phospholipids and TAG share DAG and PA as common precursors. In the de novo synthesis of phospholipids, PA serves as the immediate precursor of CDP-DAG, precursor to PI, PG, and PS. PS is decarboxylated to form PE, which undergoes three sequential methylations resulting in PC. PA also serves as a precursor for PGP, PG, and ultimately CL, which undergoes acyl-chain remodeling to the mature lipid. Alternatively, PA is dephosphorylated, producing DAG, which serves as the precursor of PE and PC in the Kennedy pathway. DAG also serves as the precursor for TAG and can be phosphorylated, regenerating PA. The names of the enzymes that are discussed in detail in this YeastBook chapter are shown adjacent to the arrows of the metabolic conversions in which they are involved and the gene–enzyme relationships are shown in Tables 1–3. Lipids and intermediates are boxed, with the most abundant lipid classes boxed in boldface type. Enzyme names are indicated in boldface type. The abbreviations used are: TAG, triacylglycerols; PI, phosphatidylinositol; PA, phosphatidic acid; CDP-DAG, CDP-diacylglycerol; DAG, diacylglycerol; MAG, monoacylglycerol; Gro, glycerol; DHAP, dihydroxyacetone phosphate, PS, phosphatidylserine; PE, phosphatidylethanolamine; PG, phosphatidylglycerol; PGP phosphatidylglycerol phosphate; CL* precursor cardiolipin; MLCL, monolyso-cardiolipin; CL, mature cardiolipin; PMME, phosphatidylmonomethylethanolamine; PDME, phosphatidyl-dimethylethanolamine; PC, phosphatidylcholine; FFA, free fatty acids; Cho, choline, Etn, ethanolamine, Ins, inositol; Cho-P, choline phosphate; CDP-Cho, CDP-choline; Etn-P, ethanolamine phosphate; CDP-Etn, CDP-ethanolamine; PI 3-P, phosphatidylinositol 3-phosphate; PI 4-P, phosphatidylinositol 4-phosphate; PI 4,5-P2, phosphatidylinositol 4,5-bisphosphate; PI 3,5-P2, phosphatidylinositol 3,5-bisphosphate. Nucl, nucleus; ER, endoplasmic reticulum; Mito, mitochondria; LD, lipid droplets; G/E/V, Golgi, endosomes, vacuole; Pex, peroxisomes; Cyt, cytoplasma; PM, plasma membrane. CL* indicates a precursor of cardiolipin (CL) with saturated acyl-chain that undergoes deacylation/reacylation to mature CL. See text for details.
Figure 3
Figure 3
Model for PA-mediated regulation of phospholipid synthesis genes. (A) Growth conditions (e.g., exponential phase, inositol depletion, or zinc supplementation) under which the levels of PA are relatively high, the Opi1 repressor is tethered to the nuclear/ER membrane, and UASINO-containing genes are maximally expressed (boldface arrow) by the Ino2-Ino4 activator complex. (Inset) Localization of Opi1, fused with GFP at its C-terminal end and integrated into the chromosome, being expressed under its own promoter in live cells growing logarithmically in synthetic complete medium lacking inositol (−Ins) and analyzed by fluorescence microscopy. (B) Growth conditions (e.g., stationary phase, inositol supplementation, or zinc depletion) under which the levels of PA are reduced, Opi1 dissociates from the nuclear/ER membrane, and enters into the nucleus where it binds to Ino2 and attenuates (thin arrow) transcriptional activation by the Ino2–Ino4 complex. (Inset) Localization of Opi1, as described in A, except that the cells are growing logarithmically in medium containing 75 μM inositol. PA level decreases by the stimulation of PI synthesis in response to inositol (Ins) supplementation and by Zap1-mediated induction of PIS1, that results in an increase in PI synthesis in response to zinc depletion. The regulation in response to zinc depletion and stationary phase occurs without inositol supplementation. Pah1 and Dgk1 play important roles in controlling PA content and transcriptional regulation of UASINO-containing genes. The synthesis of TAG (which is stored in lipid droplets, LD) and phospholipids (with the exception of PE, which occurs in the mitochondria and Golgi) occurs in the ER. Fluorescence microscopy images of Opi1 localization courtesy of Yu-Fang Chang, Henry Laboratory, Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY.
Figure 4
Figure 4
Regulation of phospholipid synthesis by soluble lipid precursors and metabolites. The diagram shows the major steps in the synthesis of phospholipids. The enzymes that are biochemically regulated by phospholipid precursors and products are shown. The green arrow designates the stimulation of enzyme activity, whereas the red line designates the inhibition of enzyme activity. Details on the biochemical regulation of these enzymes are discussed in the section Water soluble precursors of phospholipids, metabolism, and regulatory roles and in Carman and Han (2009a). See Figure 2 for abbreviations.
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