Phospholipid biosynthesis in the yeast Saccharomyces cerevisiae and interrelationship with other metabolic processes
Introduction
In this article, we will review recent progress in elucidating the mechanisms that regulate phospholipid biosynthesis in the yeast Saccharomyces cerevisiae and discuss advances in assigning gene–enzyme relationships in these pathways. Because these subjects have been covered in a number of comprehensive reviews [1], [2], [3], [4], [5], we will focus on aspects of this metabolism that have not been covered in detail in previous reports. For example, we will not be covering the phosphatidylinositol (PI) kinases which have received much recent attention elsewhere [6], [7], [8], [9]. Because a great deal of progress has been made recently in determining the gene–enzyme relationships in those parts of the phospholipid biosynthetic pathway that lead immediately to the phospholipid precursors diacylglycerol (DAG) and CDP-diacylglycerol (CDP-DAG), we will focus special attention on these reactions. We will also focus on recent progress in assigning the gene–enzyme relationships in cardiolipin (CL) synthesis, as well as the CDP-ethanolamine and CDP-choline pathways for phospholipid synthesis. This review will cover new information concerning mechanisms linking the control of phospholipid biosynthesis with other aspects of cellular metabolism, including nucleotide and sphingolipid metabolism and general nutrient control. We will also discuss emerging evidence that several major signal transduction pathways play a role in controlling the expression of genes that respond to the inositol-sensitive transcriptional regulation that coordinates major steps in phospholipid biosynthesis.
Section snippets
Phospholipid biosynthetic pathways
The major phospholipids found in the membranes of S. cerevisiae include phosphatidylcholine (PC), phosphatidylethanolamine (PE), PI, and phosphatidylserine (PS) [1], [2]. Mitochondrial membranes also contain phosphatidylglycerol (PG) and CL [1], [2]. PC is the end product of phospholipid synthesis and the major membrane phospholipid found in S. cerevisiae [1], [2]. In addition to serving as a major structural component of cellular membranes, PC serves as a reservoir for several second
Gene–enzyme relationships in phospholipid synthesis
The availability of the Saccharomyces Genome Database has facilitated the identification and isolation of genes encoding enzymes of lipid metabolism. Although the deduced protein sequence of a gene can be useful in predicting gene function, the data derived is entirely predictive in nature. Sequence homology relationships without genetic and biochemical verification should not be used as the sole evidence in the assignment of a gene–enzyme relationship.
Genetic analyses by themselves provide
Regulation of phospholipid synthesis
Because a number of comprehensive reviews of phospholipid biosynthesis in yeast have been published [1], [2], [3], [11], [103], this review will provide only a summary of key features of the regulatory mechanisms. We will discuss the genetic and biochemical regulation of phospholipid synthesis.
Interrelationships of phospholipid synthesis with other metabolic pathways
Analyses of the regulation of phospholipid synthesis in S. cerevisiae have revealed that phospholipids are synthesized in coordination with other metabolic pathways and cellular processes, including membrane trafficking and signal transduction. In this section of the review, we discuss interrelationships of phospholipid synthesis with the unfolded protein response pathway, the glucose response pathway, lipid signaling pathways, CTP synthesis, sphingolipid synthesis, and the secretory pathway.
Summary
In this review, we have discussed recent progress in the study of the regulation that controls phospholipid metabolism in S. cerevisiae. This regulation occurs on multiple levels and is tightly integrated with a large number of other cellular processes and related metabolic and signal transduction pathways. Progress in deciphering this complex regulation has been very rapid in the last few years, aided by the availability of the sequence of the entire Saccharomyces genome. The assignment of
Acknowledgements
We are grateful to the graduate students and postdoctoral fellows who have worked in our laboratories. Without their hard work and dedication, this work would not be possible. We also acknowledge our collaborators for their valuable contributions to this work. We thank Susan R. Dowd, Miriam L. Greenberg, John M. Lopes, Jana L. Patton-Vogt, David A. Toke, and Manuel Villa for their suggestions on this manuscript. This work was supported by United States Public Health Service, National Institutes
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