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Biochimica Et Biophysica Acta.... Jun 2021Phosphatidic acid biosynthesis represents the initial part of de novo formation of all glycerophospholipids (membrane lipids) as well as triacylglycerols (storage... (Review)
Review
Phosphatidic acid biosynthesis represents the initial part of de novo formation of all glycerophospholipids (membrane lipids) as well as triacylglycerols (storage lipids), and is thus the centerpiece of glycerolipid metabolism. The universal route of phosphatidic acid biosynthesis starts from the precursor glycerol-3-phosphate and comprises two consecutive acylation reactions which are catalyzed by a glycerol-3-phosphate acyltransferase and a 1-acyl glycerol-3-phosphate acyltransferase. In addition, yeast and mammals harbor a set of enzymes which can synthesize phosphatidic acid from the precursor dihydroxyacetone phosphate. In the present review our current knowledge about enzymes contributing to phosphatidic acid biosynthesis in the invaluable model organism yeast, Saccharomyces cerevisiae, is summarized. A special focus is laid upon the regulation and the localization of these enzymes. Furthermore, research needs for a deeper insight into the high complexity of phosphatidic acid biosynthesis and consequently the entire lipid metabolic network is presented.
Topics: Phosphatidic Acids; Saccharomyces cerevisiae
PubMed: 33610760
DOI: 10.1016/j.bbalip.2021.158907 -
International Journal of Molecular... Sep 2020The diacylglycerol kinase family, which can attenuate diacylglycerol signaling and activate phosphatidic acid signaling, regulates various signaling transductions in the... (Review)
Review
The diacylglycerol kinase family, which can attenuate diacylglycerol signaling and activate phosphatidic acid signaling, regulates various signaling transductions in the mammalian cells. Studies on the regulation of diacylglycerol and phosphatidic acid levels by various enzymes, the identification and characterization of various diacylglycerol and phosphatidic acid-regulated proteins, and the overlap of different diacylglycerol and phosphatidic acid metabolic and signaling processes have revealed the complex and non-redundant roles of diacylglycerol kinases in regulating multiple biochemical and biological networks. In this review article, we summarized recent progress in the complex and non-redundant roles of diacylglycerol kinases, which is expected to aid in restoring dysregulated biochemical and biological networks in various pathological conditions at the bed side.
Topics: Animals; Diabetes Mellitus; Diacylglycerol Kinase; Diglycerides; Humans; Inflammation; Neoplasms; Nervous System Diseases; Phosphatidic Acids; Protein Isoforms; Signal Transduction
PubMed: 32962151
DOI: 10.3390/ijms21186861 -
Biomolecules Nov 2022Phosphatidic acid (PA) is a signaling lipid that is produced enzymatically from phosphatidylcholine (PC), lysophosphatidic acid, or diacylglycerol. Compared to PC, PA...
Phosphatidic acid (PA) is a signaling lipid that is produced enzymatically from phosphatidylcholine (PC), lysophosphatidic acid, or diacylglycerol. Compared to PC, PA lacks a choline moiety on the headgroup, making the headgroup smaller than that of PC and PA, and PA has a net negative charge. Unlike the cylindrical geometry of PC, PA, with its small headgroup relative to the two fatty acid tails, is proposed to support negatively curved membranes. Thus, PA is thought to play a role in a variety of biological processes that involve bending membranes, such as the formation of intraluminal vesicles in multivesicular bodies and membrane fusion. Using supported tubulated lipid bilayers (STuBs), the extent to which PA localizes to curved membranes was determined. STuBs were created via liposome deposition with varying concentrations of NaCl (500 mM to 1 M) on glass to form supported bilayers with connected tubules. The location of fluorescently labeled lipids relative to tubules was determined by imaging with total internal reflection or confocal fluorescence microscopy. The accumulation of various forms of PA (with acyl chains of 16:0-6:0, 16:0-12:0, 18:1-12:0) were compared to PC and the headgroup labeled phosphatidylethanolamine (PE), a lipid that has been shown to accumulate at regions of curvature. PA and PE accumulated more at tubules and led to the formation of more tubules than PC. Using large unilamellar liposomes in a dye-quenching assay, the location of the headgroup labeled PE was determined to be mostly on the outer, positively curved leaflet, whereas the tail labeled PA was located more on the inner, negatively curved leaflet. This study demonstrates that PA localizes to regions of negative curvature in liposomes and supports the formation of curved, tubulated membranes. This is one way that PA could be involved with curvature formation during a variety of cell processes.
Topics: Lipid Bilayers; Phosphatidic Acids; Lecithins; Unilamellar Liposomes; Membrane Fusion
PubMed: 36421720
DOI: 10.3390/biom12111707 -
Journal of Lipid Research Dec 2015Individual members of the mammalian phospholipase D (PLD) superfamily undertake roles that extend from generating the second messenger signaling lipid, phosphatidic... (Review)
Review
Individual members of the mammalian phospholipase D (PLD) superfamily undertake roles that extend from generating the second messenger signaling lipid, phosphatidic acid, through hydrolysis of the membrane phospholipid, phosphatidylcholine, to functioning as an endonuclease to generate small RNAs and facilitating membrane vesicle trafficking through seemingly nonenzymatic mechanisms. With recent advances in genome-wide association studies, RNA interference screens, next-generation sequencing approaches, and phenotypic analyses of knockout mice, roles for PLD family members are being uncovered in autoimmune, infectious neurodegenerative, and cardiovascular disease, as well as in cancer. Some of these disease settings pose opportunities for small molecule inhibitory therapeutics, which are currently in development.
Topics: Animals; Mice; Neoplasms; Phosphatidic Acids; Phospholipase D; Signal Transduction
PubMed: 25926691
DOI: 10.1194/jlr.R059220 -
The Journal of Biological Chemistry Aug 2014Phosphatidic acid (PA) is a critical metabolite at the heart of membrane phospholipid biosynthesis. However, PA also serves as a critical lipid second messenger that... (Review)
Review
Phosphatidic acid (PA) is a critical metabolite at the heart of membrane phospholipid biosynthesis. However, PA also serves as a critical lipid second messenger that regulates several proteins implicated in the control of cell cycle progression and cell growth. Three major metabolic pathways generate PA: phospholipase D (PLD), diacylglycerol kinase (DGK), and lysophosphatidic acid acyltransferase (LPAAT). The LPAAT pathway is integral to de novo membrane phospholipid biosynthesis, whereas the PLD and DGK pathways are activated in response to growth factors and stress. The PLD pathway is also responsive to nutrients. A key target for the lipid second messenger function of PA is mTOR, the mammalian/mechanistic target of rapamycin, which integrates both nutrient and growth factor signals to control cell growth and proliferation. Although PLD has been widely implicated in the generation of PA needed for mTOR activation, it is becoming clear that PA generated via the LPAAT and DGK pathways is also involved in the regulation of mTOR. In this minireview, we highlight the coordinated maintenance of intracellular PA levels that regulate mTOR signals stimulated by growth factors and nutrients, including amino acids, lipids, glucose, and Gln. Emerging evidence indicates compensatory increases in one source of PA when another source is compromised, highlighting the importance of being able to adapt to stressful conditions that interfere with PA production. The regulation of PA levels has important implications for cancer cells that depend on PA and mTOR activity for survival.
Topics: 1-Acylglycerol-3-Phosphate O-Acyltransferase; Animals; Diacylglycerol Kinase; Glucose; Glutamine; Humans; Phosphatidic Acids; Phospholipase D; Second Messenger Systems; TOR Serine-Threonine Kinases
PubMed: 24990952
DOI: 10.1074/jbc.R114.566091 -
Communications Biology Sep 2022Construction of living artificial cells from genes and molecules can expand our understanding of life system and establish a new aspect of bioengineering. However,...
Construction of living artificial cells from genes and molecules can expand our understanding of life system and establish a new aspect of bioengineering. However, growth and division of cell membrane that are basis of cell proliferation are still difficult to reconstruct because a high-yielding phospholipid synthesis system has not been established. Here, we developed a cell-free phospholipid synthesis system that combines fatty acid synthesis and cell-free gene expression system synthesizing acyltransferases. The synthesized fatty acids were sequentially converted into phosphatidic acids by the cell-free synthesized acyltransferases. Because the system can avoid the accumulation of intermediates inhibiting lipid synthesis, sub-millimolar phospholipids could be synthesized within a single reaction mixture. We also performed phospholipid synthesis inside phospholipid membrane vesicles, which encapsulated all the components, and showed the phospholipids localized onto the mother membrane. Our approach would be a platform for the construction of self-reproducing artificial cells since the membrane can grow sustainably.
Topics: Acyltransferases; Cell Membrane; Escherichia coli; Fatty Acids; Phosphatidic Acids
PubMed: 36167778
DOI: 10.1038/s42003-022-03999-1 -
Biological Reviews of the Cambridge... Aug 2020The phospholipase D (PLD) family has a ubiquitous expression in cells. PLD isoforms (PLDs) and their hydrolysate phosphatidic acid (PA) have been demonstrated to engage... (Review)
Review
The phospholipase D (PLD) family has a ubiquitous expression in cells. PLD isoforms (PLDs) and their hydrolysate phosphatidic acid (PA) have been demonstrated to engage in multiple stages of cancer progression. Aberrant expression of PLDs, especially PLD1 and PLD2, has been detected in various cancers. Inhibition or elimination of PLDs activity has been shown to reduce tumour growth and metastasis. PLDs and PA also serve as downstream effectors of various cell-surface receptors, to trigger and regulate propagation of intracellular signals in the process of tumourigenesis and metastasis. Here, we discuss recent advances in understanding the functions of PLDs and PA in discrete stages of cancer progression, including cancer cell growth, invasion and migration, and angiogenesis, with special emphasis on the tumour-associated signalling pathways mediated by PLDs and PA and the functional importance of PLDs and PA in cancer therapy.
Topics: Angiogenesis Inducing Agents; Animals; Cell Movement; Disease Progression; Epithelial-Mesenchymal Transition; Humans; Mice; Neoplasm Invasiveness; Neoplasm Metastasis; Neoplasms; Phosphatidic Acids; Phospholipase D; Receptors, Growth Factor
PubMed: 32073216
DOI: 10.1111/brv.12592 -
Biochemistry. Biokhimiia Mar 2023Lipids comprise an extremely heterogeneous group of compounds that perform a wide variety of biological functions. Traditional view of lipids as important structural... (Review)
Review
Lipids comprise an extremely heterogeneous group of compounds that perform a wide variety of biological functions. Traditional view of lipids as important structural components of the cell and compounds playing a trophic role is currently being supplemented by information on the possible participation of lipids in signaling, not only intracellular, but also intercellular. The review article discusses current data on the role of lipids and their metabolites formed in glial cells (astrocytes, oligodendrocytes, microglia) in communication of these cells with neurons. In addition to metabolic transformations of lipids in each type of glial cells, special attention is paid to the lipid signal molecules (phosphatidic acid, arachidonic acid and its metabolites, cholesterol, etc.) and the possibility of their participation in realization of synaptic plasticity, as well as in other possible mechanisms associated with neuroplasticity. All these new data can significantly expand our knowledge about the regulatory functions of lipids in neuroglial relationships.
Topics: Arachidonic Acid; Astrocytes; Cell Communication; Cholesterol; Lipids; Microglia; Neuroglia; Neuronal Plasticity; Neurons; Oligodendroglia; Phosphatidic Acids; Signal Transduction; Humans; Animals
PubMed: 37076281
DOI: 10.1134/S0006297923030045 -
Journal of Sports Sciences Feb 2022Phosphatidic acid (PA) is a lipid mediator proposed to increase muscle protein synthesis via direct stimulation of the mammalian target of rapamycin (mTOR) and may act... (Review)
Review
Phosphatidic acid (PA) is a lipid mediator proposed to increase muscle protein synthesis via direct stimulation of the mammalian target of rapamycin (mTOR) and may act as an anabolic supplemental aid. Evidence on the effectiveness of PA as an anabolic supplement is equivocal. We aimed to systematically assess the effect of PA on performance and body composition. Due to the small number of studies, this is a scoping review. A comprehensive search was performed in Pubmed, SPORTDiscus and Web of Science, from the 1 January 2010 to the 31 August 2020. Our search retrieved 2009 articles, which when filtered, resulted in six studies, published between 2012 and 2019, which were analysed further. Five studies were performed in adult male populations and one in an elderly male population. From these, three studies suggested no effect of PA on lean body mass , while the remaining showed a possible positive effect (body composition and performance improvements). In one of these, the supplement included other potentially anabolic substances, precluding an isolated effect of PA. After a thorough analysis of the studies included, the evidence does not support the supplementation with PA to increase performance or improve body composition in young or elderly men.
Topics: Adult; Aged; Body Composition; Dietary Supplements; Humans; Male; Muscle Proteins; Phosphatidic Acids
PubMed: 34706625
DOI: 10.1080/02640414.2021.1994769 -
Advances in Biological Regulation Jan 2019Lipid kinases regulate a wide variety of cellular functions and have emerged as one the most promising targets for drug design. Diacylglycerol kinases (DGKs) are a... (Review)
Review
Lipid kinases regulate a wide variety of cellular functions and have emerged as one the most promising targets for drug design. Diacylglycerol kinases (DGKs) are a family of enzymes that catalyze the ATP-dependent phosphorylation of diacylglycerol (DAG) to phosphatidic acid (PtdOH). Despite the critical role in lipid biosynthesis, both DAG and PtdOH have been shown as bioactive lipids mediating a number of signaling pathways. Although there is increasing recognition of their role in signaling systems, our understanding of the key enzyme which regulate the balance of these two lipid messages remain limited. Solved structures provide a wealth of information for understanding the function and regulation of these enzymes. Solving the structures of mammalian DGKs by traditional NMR and X-ray crystallography approaches have been challenging and so far, there are still no three-dimensional structures of these DGKs. Despite this, some insights may be gained by examining the similarities and differences between prokaryotic DGKs and other mammalian lipid kinases. This review focuses on summarizing and comparing the structure of prokaryotic and mammalian DGKs as well as two other lipid kinases: sphingosine kinase and phosphatidylinositol-3-kinase. How these known lipid kinases structures relate to mammalian DGKs will also be discussed.
Topics: Animals; Crystallography, X-Ray; Diacylglycerol Kinase; Diglycerides; Humans; Phosphatidic Acids; Phosphorylation; Protein Domains; Signal Transduction
PubMed: 30348515
DOI: 10.1016/j.jbior.2018.09.014