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Review
. 2011:80:859-83.
doi: 10.1146/annurev-biochem-060409-092229.

Regulation of phospholipid synthesis in the yeast Saccharomyces cerevisiae

George M Carman  1 , Gil-Soo Han
Affiliations
Review

Regulation of phospholipid synthesis in the yeast Saccharomyces cerevisiae

George M Carman et al. Annu Rev Biochem. 2011.

Abstract

The yeast Saccharomyces cerevisiae, with its full complement of organelles, synthesizes membrane phospholipids by pathways that are generally common to those found in higher eukaryotes. Phospholipid synthesis in yeast is regulated in response to a variety of growth conditions (e.g., inositol supplementation, zinc depletion, and growth stage) by a coordination of genetic (e.g., transcriptional activation and repression) and biochemical (e.g., activity modulation and localization) mechanisms. Phosphatidate (PA), whose cellular levels are controlled by the activities of key phospholipid synthesis enzymes, plays a central role in the transcriptional regulation of phospholipid synthesis genes. In addition to the regulation of gene expression, phosphorylation of key phospholipid synthesis catalytic and regulatory proteins controls the metabolism of phospholipid precursors and products.

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Figures

Figure 1
Figure 1
Basic phospholipid structure. The diagram shows the structure of phosphatidate (PA), the phospholipid precursor, with fatty acyl groups containing 16 carbon atoms (position 1) and 18 carbon atoms with one double bond (position 2).
Figure 2
Figure 2
Phospholipid synthesis pathways in S. cerevisiae. The pathways shown for the synthesis of phospholipids include the relevant steps discussed in this review. The genes that are known to encode enzymes catalyzing individual steps in the lipid synthesis pathways are indicated. The UASINO-containing genes that are subject to regulation by the Ino2p-Ino4p activator complex and the Opi1p repressor are shown (blue). Abbreviations: CDP-DAG, CDP-diacylglycerol; Cho, choline; CL, cardiolipin; Gro, glycerol; DHAP, dihydroxyacetone phosphate; Etn, ethanolamine; Glc, glucose; Ins, inositol; PA, phosphatidate; PC, phosphatidylcholine; PE, phosphatidylethanolamine; PG, phosphatidylglycerol; PGP, phosphatidylglycerophosphate; PDE, phosphatidyldimethylethanolamine; PI, phosphatidylinositol; PME, phosphatidylmonomethylethanolamine; PS, phosphatidylserine; TAG, triacylglycerol; UASINO, an inositol-responsive upstream activating sequence.
Figure 3
Figure 3
Model for the phosphatidate (PA)-mediated regulation of UASINO-containing phospholipid synthesis genes. (a) Under growth conditions whereby the levels of PA are increased, the Opi1p repressor is tethered to the nuclear/endoplasmic reticulum (ER) membrane via interactions with Scs2p and PA, allowing the maximal expression (bold arrow) of UASINO-containing genes (blue) by the Ino2p-Ino4p activator complex. (b) Under growth conditions whereby the levels of PA are reduced, Opi1p is dissociated from the nuclear/ER membrane and enters into the nucleus, where it binds to Ino2p and attenuates (thin arrow) the transcriptional activation by the Ino2p-Ino4p complex. The PA level in the cell is decreased by the stimulation of phosphatidylinositol (PI) synthesis in response to inositol (Ins) supplementation and by the Zap1p-mediated induction of PIS1 that occurs in response to zinc depletion. The regulations that occur in response to zinc depletion and stationary phase occur in the absence of inositol supplementation. PA phosphatase (PAP) and DAG kinase (DGK) play major roles in the regulation of PA content and thereby in the transcriptional regulation of UASINO-containing genes. CDP-DAG, CDP-diacylglycerol; PC, phosphatidylcholine; PE, phosphatidylethanolamine; PS, phosphatidylserine; TAG, triacylglycerol; UASINO, inositol-responsive element; UASZRE, zinc-responsive element; Zap1p, a transcriptional activator protein that interacts with the UASZRE.
Figure 4
Figure 4
Domain structures and phosphorylation sites of Opi1p and phospholipid synthesis enzymes. Opi1p (with 404 amino acids) contains domains for interactions with Sin3p, phosphatidate (PA), Scs2p, and Ino2p. It also contains Ser (S) residues that are sites for phosphorylation by protein kinases A and C and casein kinase II. Phosphatidylserine (PS) synthase (with 277 amino acids) contains a CDP-alcohol phosphotransferase (P-transferase) domain and Ser residues for phosphorylation by protein kinase A. CTP synthetase (with 579 amino acids) contains the CTP synthetase and glutamine amide transfer domains as well as the Ser residues for phosphorylation by protein kinases A and C. Choline kinase (with 582 amino acids) contains the phosphotransferase and choline kinase (CK) domains as well as the Ser residues for phosphorylation by protein kinases A and C. PA phosphatase (with 862 amino acids) contains an amphipathic helix (H), NLIP and haloacid dehalogenase (HAD)-like domains, and 16 Ser/Thr residues for phosphorylation. The seven sites denoted with an asterisk are within the minimal Ser/Thr-Pro motif that is a target of cyclin-dependent kinases.
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