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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 -
Science Signaling Apr 2022Diacylglycerol (DAG) is a lipid second messenger that is generated in response to extracellular stimuli and channels intracellular signals that affect mammalian cell... (Review)
Review
Diacylglycerol (DAG) is a lipid second messenger that is generated in response to extracellular stimuli and channels intracellular signals that affect mammalian cell proliferation, survival, and motility. DAG exerts a myriad of biological functions through protein kinase C (PKC) and other effectors, such as protein kinase D (PKD) isozymes and small GTPase-regulating proteins (such as RasGRPs). Imbalances in the fine-tuned homeostasis between DAG generation by phospholipase C (PLC) enzymes and termination by DAG kinases (DGKs), as well as dysregulation in the activity or abundance of DAG effectors, have been widely associated with tumor initiation, progression, and metastasis. DAG is also a key orchestrator of T cell function and thus plays a major role in tumor immunosurveillance. In addition, DAG pathways shape the tumor ecosystem by arbitrating the complex, dynamic interaction between cancer cells and the immune landscape, hence representing powerful modifiers of immune checkpoint and adoptive T cell-directed immunotherapy. Exploiting the wide spectrum of DAG signals from an integrated perspective could underscore meaningful advances in targeted cancer therapy.
Topics: Animals; Diacylglycerol Kinase; Diglycerides; Ecosystem; Mammals; Neoplasms; Signal Transduction
PubMed: 35412850
DOI: 10.1126/scisignal.abo0264 -
Trends in Biochemical Sciences Jan 2007Diacylglycerol (DAG) has unique functions as a basic component of membranes, an intermediate in lipid metabolism and a key element in lipid-mediated signaling. In... (Review)
Review
Diacylglycerol (DAG) has unique functions as a basic component of membranes, an intermediate in lipid metabolism and a key element in lipid-mediated signaling. In eukaryotes, for example, impaired DAG generation and/or consumption have severe effects on organ development and cell growth associated with diseases such as cancer, diabetes, immune system disorders and Alzheimer's disease. Although DAG has been studied intensively as a signaling lipid, early models of its function are no longer adequate to explain its numerous roles. The interplay between enzymes that control DAG levels, the identification of families of DAG-regulated proteins, and the overlap among DAG metabolic and signaling processes are providing new interpretations of DAG function. Recent discoveries are also delineating the complex and strategic role of DAG in regulating biochemical networks.
Topics: Animals; Diglycerides; Lipid Metabolism; Membrane Lipids; Protein Structure, Tertiary; Second Messenger Systems; Signal Transduction
PubMed: 17157506
DOI: 10.1016/j.tibs.2006.11.004 -
Ultrasonics Sonochemistry May 2023The study aimed to evaluate the effect of ultrasonic pretreatment on the transesterification of lard with glycerol monolaurate (GML) using Lipozyme TL IM to synthesize... (Review)
Review
The study aimed to evaluate the effect of ultrasonic pretreatment on the transesterification of lard with glycerol monolaurate (GML) using Lipozyme TL IM to synthesize diacylglycerol (DAG), and the physicochemical properties of lard, GML, ultrasonic-treated diacylglycerol (named U-DAG), purified ultrasonic-treated diacylglycerol obtained by molecular distillation (named P-U-DAG), and without ultrasonic-treated diacylglycerol (named N-U-DAG) were analyzed. The optimized ultrasonic pretreatment conditions were: lard to GML mole ratio 3:1, enzyme dosage 6 %, ultrasonic temperature 80 °C, time 9 min, power 315 W. After ultrasonic pretreatment, the mixtures reacted for 4 h in a water bath at 60 °C, the content of DAG reached 40.59 %. No significant variations were observed between U-DAG and N-U-DAG in fatty acids compositions and iodine value, while P-U-DAG had lower unsaturated fatty acids than U-DAG. Differential scanning calorimetry analysis showed that the melting and crystallization properties of DAGs prepared by ultrasonic pretreatment significantly differed from lard. FTIR spectra noted transesterification reaction from lard and GML with and without ultrasonic pretreatment would not change the structure of lard. However, thermogravimetric analysis proved that N-U-DAG, U-DAG, and P-U-DAG had lower oxidation stability than lard. The higher the content of DAG, the faster the oxidation speed.
Topics: Diglycerides; Dietary Fats; Catalysis; Glycerol
PubMed: 36898248
DOI: 10.1016/j.ultsonch.2023.106354 -
Obesity Reviews : An Official Journal... Dec 2012Obesity is associated with skeletal muscle insulin resistance, which is a crucial step in the development of type 2 diabetes. Among the mechanisms by which obesity may... (Review)
Review
Obesity is associated with skeletal muscle insulin resistance, which is a crucial step in the development of type 2 diabetes. Among the mechanisms by which obesity may lead to insulin resistance, lipotoxicity is one of the hypotheses being explored; others include inflammation or the oxidative stress hypotheses. This review focuses on the role of diacylglycerols (DAG), a family of lipid metabolites implicated in the pathogenesis of lipotoxicity and insulin resistance. While recent studies report contradictory results in humans with regard to the importance of DAG-induced insulin resistance in skeletal muscle, other current literature highlight a potential role for DAG as signalling molecules. This review will discuss possible hypotheses explaining these contradictory results and the need to explore further the role of DAG in human metabolism.
Topics: Animals; Diglycerides; Humans; Insulin; Insulin Resistance; Lipid Metabolism; Muscle, Skeletal; Signal Transduction
PubMed: 23107258
DOI: 10.1111/j.1467-789X.2012.01036.x -
Plant Signaling & Behavior Apr 2012Diacylglycerol (DAG) is an important signaling phospholipid in animals, specifically binding to the C1 domain of proteins such as protein kinase C. In most plant... (Review)
Review
Diacylglycerol (DAG) is an important signaling phospholipid in animals, specifically binding to the C1 domain of proteins such as protein kinase C. In most plant species, however, DAG is present at low abundance, and no interacting proteins have yet been identified. As a result, it has been proposed that the signaling function of DAG has been discarded by plants during their evolution. In this mini-review, we summarize the accumulating experimental evidence which supports that notion that changes in DAG content in response to particular cues are a feature of plant cells. This behavior suggests that DAG does indeed act as a signaling molecule during plant development and in response to certain environmental stimuli.
Topics: Diglycerides; Models, Biological; Phospholipids; Plants; Signal Transduction
PubMed: 22499171
DOI: 10.4161/psb.19644 -
Biochimica Et Biophysica Acta Dec 1998Distinct, structurally different forms of sn-1,2-diacylglycerol are found in cells, these are polyunsaturated, mono- or di-unsaturated and saturated. The pathways that... (Review)
Review
Distinct, structurally different forms of sn-1,2-diacylglycerol are found in cells, these are polyunsaturated, mono- or di-unsaturated and saturated. The pathways that generate or metabolise sn-1, 2-diacylglycerol are reviewed. The evidence that it is the polyunsaturated forms of sn-1,2-diacylglycerol, but the more saturated forms of phosphatidate which function as intracellular signals is considered.
Topics: Animals; Diglycerides; Phosphatidic Acids; Phospholipase D; Signal Transduction; Structure-Activity Relationship
PubMed: 9838074
DOI: 10.1016/s0005-2760(98)00123-4 -
Chemistry and Physics of Lipids Nov 2015The epsilon isoform of mammalian diacylglycerol kinase (DGKϵ) is an enzyme that associates strongly with membranes and acts on a lipid substrate, diacylglycerol. The... (Review)
Review
The epsilon isoform of mammalian diacylglycerol kinase (DGKϵ) is an enzyme that associates strongly with membranes and acts on a lipid substrate, diacylglycerol. The protein has one segment that is predicted to be a transmembrane helix, but appears to interconvert between a transmembrane helix and a re-entrant helix. Despite the hydrophobicity of this segment and the fact that the lipid substrate is also hydrophobic, removal of this hydrophobic segment by truncating the protein at the amino terminus has no effect on its enzymatic activity. The amino acid sequence of the catalytic segment of DGKϵ is highly homologous to that of a bacterial DGK, DgkB. This has allowed us to predict a conformation of DGKϵ based on the known crystal structure of DgkB. An important property of DGKϵ is that it is specific for diacylglycerol species containing an arachidonoyl group. The region of DGKϵ that interacts with this group is found within the accessory domain of the protein and not in the active site nor in the hydrophobic amino terminus. The nature of the acyl chain specificity of the enzyme indicates that DGKϵ is associated with the synthesis of phosphatidylinositol. Defects or deletion of the enzyme give rise to several disease states.
Topics: Amino Acid Sequence; Biocatalysis; Diacylglycerol Kinase; Diglycerides; Humans; Models, Molecular; Phosphatidylinositols; Protein Conformation
PubMed: 26134136
DOI: 10.1016/j.chemphyslip.2015.06.003 -
Current Opinion in Lipidology Feb 2003Diacylglycerol is an intermediate product of triacylglycerol hydrolysis and comprises up to 10% of glycerides in plant-derived edible fats and oils. Recent developments... (Review)
Review
PURPOSE OF REVIEW
Diacylglycerol is an intermediate product of triacylglycerol hydrolysis and comprises up to 10% of glycerides in plant-derived edible fats and oils. Recent developments in oil chemistry have led to the availability of a novel diacylglycerol oil for clinical studies. Recent research has shown that the oil containing 70% of unusual 1,3- species has metabolic characteristics distinct from those of triacylglycerol of similar fatty acid composition. This review summarizes recent research in humans and experimental animals into the metabolic effects and possible mechanisms of action of this oil.
RECENT FINDINGS
Consumption of the oil affects lipid metabolism including lowering of plasma triacylglcerol, decreases postprandial lipemia and reduces body fat mass, compared with triacylglcerol. As the fatty acids of the two oils are similar, the metabolic differences reside in their structural differences.
SUMMARY
It is still uncertain whether longer term consumption of the diacylglycerol oil will lead to persistent and consistent reductions in plasma triacylglycerol and body fat. However future studies may demonstrate a role in managing aspects of the metabolic syndrome.
Topics: Adipose Tissue; Dietary Fats; Diglycerides; Humans; Lipid Metabolism; Lipids
PubMed: 12544658
DOI: 10.1097/00041433-200302000-00006 -
Asia Pacific Journal of Clinical... 2007Obesity resides upstream of the constituents of metabolic syndromes such as diabetes, hypertension, hyperlipidemia, and arteriosclerosis. Postprandial hyperlipidemia is... (Review)
Review
Obesity resides upstream of the constituents of metabolic syndromes such as diabetes, hypertension, hyperlipidemia, and arteriosclerosis. Postprandial hyperlipidemia is also implicated in atherogenesis. Therefore, factors that influence the body adiposity and the magnitude of postprandial hyperlipidemia have been intensively investigated. Diacylglycerol (DAG) oil, which is defined to contain DAG 80% (w/w) or greater in the present presentation, is an edible oil with similar taste and usability compared with conventional edible oil rich in TAG. Safety of DAG has been widely evaluated and listed as a GRAS (Generally Recognized as Safe) substance by US FDA. The aim of this review was to summarize the metabolism and nutritional functions of DAG based on the data from scientific journals and conference publications. Effect of DAG ingestion on postprandial elevations of serum lipids was investigated in several dosages, food formula, and in subjects in various conditions. Postprandial triglyceride in serum and the chylomicron fraction are significantly smaller after DAG consumption compared with TAG with a similar fatty acid composition in healthy subjects, and was remarkably reduced in subjects with insulin resistance. Long-term DAG ingestion in controlled diet or free-living condition significantly decreased body adiposity and improved type II diabetic complications. A single dose DAG consumption significantly increased fat oxidation as compared to eucaloric TAG ingestion. DAG oil consumption might be beneficial in reducing the risk factors for lifestyle-related diseases such as obesity, visceral obesity, postprandial hyperlipidemia, insulin resistance, and atherosclerosis.
Topics: Arteriosclerosis; Diglycerides; Female; Humans; Hyperlipidemias; Male; Obesity; Postprandial Period
PubMed: 17392138
DOI: No ID Found