Isolation and Expression of an Isoform of Human CDP-Diacylglycerol Synthase cDNA

Weeks, Reitha S.; Dowhan, William; Shen, Haifa; Balantac, Noel; Meengs, Brent; Nudelman, Edward; Leung, David W. M.

doi:10.1089/dna.1997.16.281

Cited by 49 publications

(33 citation statements)

References 24 publications

(31 reference statements)

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“…Early studies described two CDS activities: one associated with the outer surface of the ER (95) and another located in the matrix of mitochondria that was responsible for feeding into cardiolipin synthesis (1360). Mammalian CDS enzymes have been cloned (589, 1325,1688), and two, highly similar but different genes, cds1 and cds2 are found in the human and other mammalian genomes (552,1645). Both CDS proteins localize to the ER, but they do not enter the PIS positive mobile compartment (796).…”

Section: Phosphatidylinositol Synthesismentioning

confidence: 99%

Phosphoinositides: Tiny Lipids With Giant Impact on Cell Regulation

Balla

2013

Physiological Reviews

1,365

1,655

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Phosphoinositides (PIs) make up only a small fraction of cellular phospholipids, yet they control almost all aspects of a cell's life and death. These lipids gained tremendous research interest as plasma membrane signaling molecules when discovered in the 1970s and 1980s. Research in the last 15 years has added a wide range of biological processes regulated by PIs, turning these lipids into one of the most universal signaling entities in eukaryotic cells. PIs control organelle biology by regulating vesicular trafficking, but they also modulate lipid distribution and metabolism via their close relationship with lipid transfer proteins. PIs regulate ion channels, pumps, and transporters and control both endocytic and exocytic processes. The nuclear phosphoinositides have grown from being an epiphenomenon to a research area of its own. As expected from such pleiotropic regulators, derangements of phosphoinositide metabolism are responsible for a number of human diseases ranging from rare genetic disorders to the most common ones such as cancer, obesity, and diabetes. Moreover, it is increasingly evident that a number of infectious agents hijack the PI regulatory systems of host cells for their intracellular movements, replication, and assembly. As a result, PI converting enzymes began to be noticed by pharmaceutical companies as potential therapeutic targets. This review is an attempt to give an overview of this enormous research field focusing on major developments in diverse areas of basic science linked to cellular physiology and disease.

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Section: Phosphatidylinositol Synthesismentioning

confidence: 99%

Phosphoinositides: Tiny Lipids With Giant Impact on Cell Regulation

Balla

2013

Physiological Reviews

1,365

1,655

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“…CDS genes have been identified from a series of eukaryotic organisms: yeast [30], fly [31], P. falciparum [32], mouse [33], and human [34][35][36]. CDS homologues are present in all eukaryotic genomes sequenced to date (Fig.…”

Section: Cdp-diacylglycerol Synthetases (Cdss)mentioning

confidence: 99%

“…Experiments by Weeks et al [34] suggested that even modest overexpression of human CDS1 levels amplifies cellular signaling systems. Drosophila mutants defective in the CDS isoform expressed in the photoreceptor cannot sustain a light-activated current due to rapid depletion of PtdIns-4,5-bisphosphate [31].…”

Section: Cdp-diacylglycerol Synthetases (Cdss)mentioning

confidence: 99%

Comparative genomics and evolution of eukaryotic phospholipid biosynthesis

Lykidis

2007

Progress in Lipid Research

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Phospholipid biosynthetic enzymes produce diverse molecular structures and are often present in multiple forms encoded by different genes. This work utilizes comparative genomics and phylogenetics for exploring the distribution, structure and evolution of phospholipid biosynthetic genes and pathways in 26 eukaryotic genomes. Although the basic structure of the pathways was formed early in eukaryotic evolution, the emerging picture indicates that individual enzyme families followed unique evolutionary courses. For example, choline and ethanolamine kinases and cytidylyltransferases emerged in ancestral eukaryotes, whereas, multiple forms of the corresponding phosphatidyltransferases evolved mainly in a lineage specific manner.Furthermore, several unicellular eukaryotes maintain bacterial-type enzymes and reactions for the synthesis of phosphatidylglycerol and cardiolipin. Also, base-exchange phosphatidylserine synthases are widespread and ancestral enzymes. The multiplicity of phospholipid biosynthetic enzymes has been largely generated by gene expansion in a lineage specific manner. Thus, these observations suggest that phospholipid biosynthesis has been an actively evolving system. 2Finally, comparative genomic analysis indicates the existence of novel phosphatidyltransferases and provides a candidate for the uncharacterized eukaryotic phosphatidylglycerol phosphate phosphatase.

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“…To address this point, we tested the effect of a human CDP-DAG synthase, isolated from a leukocyte cDNA library, on the transcription of the above genes. GAL1 promoter-controlled overexpression of this gene complements the growth phenotype of the yeast cds1 mutant (26). However, CDP-DAG synthase activity is only 20 -30% of the wild type yeast level, resulting in inositol excretion even in the induction medium.…”

Section: Fig 2 Cdp-dag Ps and Pi Synthase Activities As A Functiomentioning

confidence: 98%

Regulation of Phospholipid Biosynthetic Enzymes by the Level of CDP-Diacylglycerol Synthase Activity

Shen¹,

Dowhan²

1997

Journal of Biological Chemistry

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Amine-containing phospholipid synthesis in Saccharomyces cerevisiae starts with the conversion of CDPdiacylglycerol (CDP-DAG) and serine to phosphatidylserine (PS), whereas phosphatidylinositol (PI) is formed from CDP-DAG and inositol (derived from inositol 1-phosphate). In this study the regulation of PS synthase (encoded by CHO1/PSS), PI synthase (encoded by PIS1), and inositol 1-phosphate synthase (encoded by INO1) activities by the in vivo level of CDP-DAG synthase activity (encoded by CDS1) is described. Reduction in the level of CDP-DAG synthase activity from 10-fold over wild type levels to 10% of wild type levels results in a 7-fold increase in PS synthase activity, which follows a similar change in the CHO1/PSS mRNA level. INO1 mRNA also increases but only after CDP-DAG synthase activity falls below the wild type level. PI synthase activity follows the decrease of the CDP-DAG synthase activity, but there is no parallel change in the level of PIS1 mRNA. These changes in CHO1/PSS and INO1 mRNA levels are mediated by a mechanism not dependent on changes in the expression of the INO2-OPI1 regulatory genes. CDS1 expression is repressed in concert with INO2 expression in response to inositol.The major phospholipids in yeast, phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine (PS), 1 and phosphatidylinositol (PI), are synthesized by two branches of the phospholipid biosynthetic pathway that diverge from the common liponucleotide precursor CDP-diacylglycerol (CDP-DAG) (1-3). Synthesis of amine-containing lipids starts with the conversion of CDP-DAG and serine to PS, which is sequentially converted to phosphatidylethanolamine and phosphatidylcholine. PI is synthesized from CDP-DAG and inositol, which can be synthesized de novo from glucose 6-phosphate catalyzed by inositol 1-phosphate synthase, the product of the INO1 gene (4). PS synthase encoded by the CHO1/PSS gene (5, 6) and PI synthase encoded by the PIS1 gene (7), respectively, catalyze the above two CDP-DAG-dependent reactions. The cellular activities of PS synthase and PI synthase, together with the availability of inositol, have been considered to be the major determinants in the partitioning of CDP-DAG between these two branches of the pathway and consequently determine the final membrane phospholipid composition (8). Therefore, it is not surprising that these enzymes are regulated at multiple levels to coordinate phospholipid biosynthesis.Studies of the regulation of phospholipid biosynthesis by inositol demonstrate that the INO1 and CHO1/PSS genes are derepressed in wild type cells grown in medium lacking inositol and choline (or ethanolamine), and repressed when these precursors of phospholipid biosynthesis are present (9, 10); choline and ethanolamine are precursors in the DAG-dependent pathway leading to phosphatidylcholine and phosphatidylethanolamine biosynthesis (1, 3). The regulation of INO1 and CHO1/ PSS gene expression by inositol and choline has been shown to occur at the level of mRNA abundance (11,12) and is mediated by the...

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Isolation and Expression of an Isoform of Human CDP-Diacylglycerol Synthase cDNA

Cited by 49 publications

References 24 publications

Phosphoinositides: Tiny Lipids With Giant Impact on Cell Regulation

Phosphoinositides: Tiny Lipids With Giant Impact on Cell Regulation

Comparative genomics and evolution of eukaryotic phospholipid biosynthesis

Regulation of Phospholipid Biosynthetic Enzymes by the Level of CDP-Diacylglycerol Synthase Activity

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