Distribution of phospholipid biosynthetic enzymes among cell components of rat liver.
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Animals↗
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Results for “Cytidine Diphosphate Diglycerides”
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[3H]myoinositol incorporation into phospholipids in liver microsomes from humans with and without type II diabetes. The lack of synthesis of glycosylphosphatidylinositol, precursor of the insulin mediator inositol phosphate glycan.
A class of inositol phosphate-containing oligosaccharides (IPG) derived from a membrane glycan-phosphatidylinositol precursor (GPI) has been identified as a possible mediator of insulin action. Saltiel's laboratory has recently communicated an in vitro assay for the synthesis of GPI in rat liver microsomes. Herein we have established this method in rat and human liver microsomes, it being our end point to evaluate if the pool of GPI was normal in diabetes and if failure of insulin to generate IPG from GPI could be involved in the mechanism of insulin resistance in Type II diabetes. However, subsequent to the detailed study of [3H]myoinositol incorporation into phospholipids in liver microsomes from our study subjects, we demonstrated by gas chromatography/mass spectrometry analysis that the material reported to be GPI is a mixture of lysophospholipids that does not contain hexosamine, ethanolamine, or amino acids.
Animals↗
Regulation of fatty acid composition of cytidine diphosphate diacylglycerol by acyl transfer reactions.
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Acylation↗
[Efficacy of the "8 drugs in a day" protocol in brain tumors in children].
In the present study, the "8 drugs in 1 day" regimen was tested in 54 children: 27 relapses (brain and/or spinal and/or meningeal sites), 10 refractory progressive diseases, 13 macroscopic residual tumors after partial excision and/or radiotherapy; in 4 cases, this regimen was prescribed as first line treatment. The response rate (complete and partial remission) was 46%. Results were very encouraging in medalloblastomas with a response rate of 76.5% whereas in brain stem gliomas it was only 23% and 33% in other astrocytomas. Immediate toxicity, mainly hematological, was very moderate. These results justify to propose this regimen as adjuvant chemotherapy, mostly in medulloblastomas and to plan other similar trials, using the most active drugs which seem presently to be alkylating and platinum-derived agents.
Adolescent↗
Membrane lipid biogenesis in Escherichia coli: identification of genetic loci for phosphatidylglycerophosphate synthetase and construction of mutants lacking phosphatidylglycerol.
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Chromosome Mapping↗
On the mechanism whereby ACTH and cyclic AMP increase adrenal polyphosphoinositides. Rapid stimulation of the synthesis of phosphatidic acid and derivatives of CDP - diacylglycerol.
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Adrenal Glands↗
A rapid biosynthetic method for the preparation of radioactive phosphatidyl-CMP(CDP-diacylglycerol) of high specific activity.
A procedrue is described for the preparation of [32P]phosphatidyl-CMP(CDP-diacylglycerol) from rat pineal glands incubated with [32P]orthophosphate and DL-propranolol. The product is 95% radiopure and a high specific acitivity. The yield of liponucleotide is 0.4--0.9 micron Ci/mCi of [32P]orthophosphate in the medium. The same method can also be used for the biosynthesis and purification of [3H]phosphatidyl-CMP when [3H]cytidine is the precursor.
Animals↗
Phospholipid derivatives of nucleoside analogs as prodrugs with enhanced catabolic stability.
The nucleoside 5'-diphosphate-L-1,2-dipalmitin derivatives of 1-beta-D-arabinofuranosylcytosine (ara-C), 9-beta-D-arabinofuranosyladenine (ara-A), and tubercidin have been synthesized, and their cytotoxicity has been evaluated against a mouse myeloma cell line (MPC-11) in vitro and against L1210 lymphoid leukemia both in vitro and in vivo. Sonication methods were utilized to solubilize these lipophilic derivatives in aqueous solution in order to facilitate such biological evaluation; the ara-A derivative resisted solubilization by several techniques. The nucleoside:phospholipid conjugates of ara-C and tubercidin both were cytotoxic towards the two cell lines, and detailed experiments were cytotoxic towards the two cell lines, and detailed experiments were carried out to show that the new derivatives (a) were not degraded in the medium prior to cellular uptake and (b) acted as prodrugs or molecular depots of the parent nucleoside analog. In addition, 1-beta-D-arabinofuranosylcytosine 5'-diphosphate'5'-L-1,2-dipalmitin was not a substrate for cytidine deaminase (cytidine aminohydrolase, EC 3.5.4.5), the primary enzyme responsible for the rapid catabolism of ara-C. In in vivo studies against L1210 lymphoid leukemia in mice, the 1-beta-D-arabinofuranosylcytosine 5'-diphosphate-5'-L-1,2-dipalmitin showed an increased efficacy (increased life span, 260%) relative to the parent ara-C (increased life span, 89%) regardless of treatment schedule used, whereas the tubercidin 5'-diphosphate-5'-L-1,2-dipalmitin appeared extremely toxic even at low dosages. That 1-beta-D-arabinofuranosylcytosine 5'-diphosphate-5'-L-1,2-dipalmitin was acting as a sustained release drug in vivo was demonstrated by utilizing a single dose administered on Days -1, 0, +1, and +2 relative to inoculation of the L1210 lymphoid leukemia cells on Day 0. Again, a much increased efficacy relative to the best treatment using ara-C was apparent. The potential advantages and the biochemical rationale for the development of these novel prodrugs are discussed.
Animals↗
Regulation of phosphatidylinositol 4-kinase from the yeast Saccharomyces cerevisiae by CDP-diacylglycerol.
Regulation of the 45- and 55-kDa forms of Saccharomyces cerevisiae membrane-associated phosphatidylinositol (PI) 4-kinase (ATP:phosphatidylinositol 4-phosphotransferase) by phospholipids was examined using Triton X-100/phospholipid-mixed micelles. CDP-diacylglycerol and phosphatidylglycerol inhibited 45-kDa PI 4-kinase activity in a dose-dependent manner. Kinetic analyses of the 45-kDa PI 4-kinase showed that phosphatidylglycerol was a competitive inhibitor with respect to PI (Ki = 2 mol %), and CDP-diacylglycerol was a mixed type of inhibitor with respect to PI (Ki = 4 mol %) and MgATP (Ki = 5 mol %). 55-kDa PI 4-kinase activity was not significantly affected by phospholipids. The physiological relevance of CDP-diacylglycerol inhibition of 45-kDa PI 4-kinase activity was examined using plasma membranes from inositol auxotrophic (ino1) cells. Immunoblot analysis showed that 45-kDa PI 4-kinase expression in plasma membranes was not affected by inositol starvation of ino1 cells. However, both 45-kDa PI 4-kinase activity and its product PI 4-phosphate were reduced in plasma membranes from inositol-starved ino1 cells. The CDP-diacylglycerol concentration (9.6 mol %) in plasma membranes of inositol-starved ino1 cells was 12-fold higher than its concentration (0.8 mol %) in plasma membranes of inositol-supplemented cells. Plasma membranes of inositol-starved ino1 cells also had increased levels of phosphatidate, phosphatidylserine, phosphatidylethanolamine, and cardiolipin. However, these phospholipids did not affect pure 45-kDa PI 4-kinase activity. The concentration of CDP-diacylglycerol in plasma membranes of inositol-starved ino1 cells was in the range of the inhibitor constants determined for CDP-diacylglycerol by kinetic analyses using pure 45-kDa PI 4-kinase. These results raised the suggestion that 45-kDa PI 4-kinase activity may be regulated in vivo by CDP-diacylglycerol.
1-Phosphatidylinositol 4-Kinase↗
Guanine nucleotides activate multiple signaling pathways in permeabilized gastric chief cells. Evidence for GTP gamma S-induced calcium-independent pepsinogen secretion.
Nonhydrolyzable guanine nucleotide analogues were used to evaluate the role of guanine nucleotide binding (G) proteins in regulating pepsinogen secretion from streptolysin O-permeabilized chief cells from guinea pig stomach. In the presence of 100 nM calcium, 100 microM guanosine 5'-(beta,gamma-imido)triphosphate or guanosine 5'-3-O-(thio)triphosphate (GTP gamma S) caused a 2- to 4-fold increase in pepsinogen secretion. GTP gamma S stimulated secretion in the absence of calcium (up to 10 mM EGTA). With or without added calcium, GTP analogues caused a 2- to 3-fold increase in cAMP, whereas guanosine 5'-O-2-(thio)diphosphate and calcium alone had no effect on cAMP levels. GTP analogue-induced activation of phospholipase C was evidenced by a calcium-independent increase in cytidine diphospho-1,2-diacylglycerol levels (50% above basal). Phorbol ester- and GTP gamma S-stimulated phosphorylation of a 72-kDa acidic protein was abolished by an inhibitor of protein kinase C (CGP 41251). However, GTP gamma S-induced pepsinogen secretion was only partially inhibited by adding CGP 41251 or a protein kinase C inhibitor peptide. These results indicate that guanine nucleotides activate major signaling pathways in gastric chief cells. Nevertheless, GTP gamma S can induce pepsinogen secretion independently of changes in calcium, cAMP, or activation of protein kinase C.
Alkaloids↗
Use of a fluorescent analog of CDP-DAG in human skin fibroblasts: characterization of metabolism, distribution, and application to studies of phosphatidylinositol turnover.
We studied the uptake metabolism, and distribution of a fluorescent analog of CDP-diacylglycerol [cytidine diphosphate-1, 2-oleoyl, (N-(4-nitrobenzo-2-oxa-1,3-diazole) aminocaproyl) diacylglycerol; CDP-NBD-DAG]. When cells were incubated with CDP-NBD-DAG for 60 min at 11 degrees C and washed, the fluorescent lipid was localized to the plasma membrane. However, upon warming to 37 degrees C, the fluorescent lipid redistributed into various intracellular membranes and was metabolized primarily to fluorescent analogs of DAG and phosphatidylcholine (PC), although small amounts of fluorescent phosphatidic acid and phosphatidylinositol (PI) were also formed. The incorporation of 32Pi into some of the fluorescent lipids was also determined in order to assess their turnover. Stimulation of cells with platelet-derived growth factor enhanced the synthesis of fluorescent PI relative to unstimulated cells by approximately 68%, while the synthesis of fluorescent PC was unaffected. In addition, the incorporation of 32Pi into fluorescent PI was enhanced. Stimulation of cells with interleukin-1 beta enhanced the synthesis of both fluorescent PI (approximately 88%) and PC (approximately 250%) compared to non-stimulated cells, but with less incorporation of 32Pi into fluorescent PI. Finally, incubation of CDP-NBD-DAG-treated cells with inhibitors of phosphatidic acid phosphohydrolase and DAG kinase resulted in a dramatic increase in the amount of fluorescent PI formed (approximately 64% of all the CDP-NBD-DAG metabolites). We conclude that CDP-NBD-DAG can be used for the de novo synthesis of fluorescent PI, and in combination with 32P labeling, provides a convenient method for studying PI turnover.
4-Chloro-7-nitrobenzofurazan↗
Biosynthesis of phospholipids in Bacillus megaterium.
Information on the biosynthesis of phospholipids in bacteria has been derived principally from the study of Escherichia coli and other gram-negative organisms. We have now carried out a detailed study of the pathways of phospholipid biosynthesis in the gram-positive organism Bacillus megarterium KM in relation to investigations on the biogenesis of lipid asymmetry in membranes. Radioactive precursors such as 32Pi and [3H]palmitate initially label phosphatidylethanolamine much more than phosphatidylglycerol. This raised the possibility that phosphatidylglycerol may be the precursor of phosphatidylethanolamine in a pathway different from that in E. coli. Phosphatidylglycerol is known to be highly reactive metabolically, since it functions as a donor of phosphatidyl residues in the synthesis of cardiolipin and as a donor of glycerophosphate residues in the synthesis of teichoic acids and of membrane-derived oligosaccharides. The large pool of phosphatidylglycerol would dilute the radioactive isotope, slowing the initial rate of incorporation of label into phosphatidylethanolamine. However, assays of cell-free extracts revealed no evidence for such a novel pathway. Instead, phosphatidylserine synthase (cytidine 5'-diphosphate-diglyceride:L-serine phosphatidyl transferase) and phosphatidylserine decarboxylase were detected, although at low levels. These results suggest that the pathway in B. megaterium is the same as that in E. coli in which phosphatidylserine, derived from cytidine 5'-diphosphate-diglyceride, is the precursor of phosphatidylethanolamine. The lag in the appearance of label in phosphatidylethanolamine appears to be the effect of a considerable pool of phosphatidylserine (ca. 5 to 10% of the total phospholipid) in certain strains of B. megaterium. The lag in labeling can be correlated with the size of the pool of phosphatidylserine. Pulse-chase experiments in vivo support the conclusion that in B. megaterium phosphatidylserine is not derived from phosphatidylglycerol. Rates of turnover of the membrane phospholipids of B. megaterium have also been studied.
Bacillus megaterium↗
Phospholipid-synthesizing Enzymes Associated with Golgi Dictyosomes from Pea Tissue.
Golgi dictyosomal membranes isolated from pea (Pisum sativum) stem tissue, using a combination of rate zonal and isopycnic sucrose density centrifugation, were shown to bear cytidine diphosphate-choline:diglyceride phosphorylcholinetransferase, CDP-ethanolamine:diglyceride phosphorylethanolaminetransferase, and CTP:phosphorylcholine cytidyltransferase activities. Although the majority of the activity of the phospholipid-synthesizing enzymes was associated with the endoplasmic reticulum, the activity found in the Golgi system was about 25% of the total activity. These results suggest that Golgi dictyosomes probably synthesize at least part of the membrane phospholipids that they may need for their secretory function and for dictyosomal proliferation during cell growth, rather than importing this material entirely from the endoplasmic reticulum.
Journal Article↗
L-Glyceraldehude 3-phosphate, a bactericidal agent.
At a concentration of 2.5 mM, dl-glyceraldehyde 3-phosphate has a bactericidal effect upon Escherichia coli. The glycerol 3-phosphate transport system is required for the entry of the biologically active l-enantiomer. l-Glyceraldehyde must be phosphorylated by the cell to exert its full effect upon growth. The addition of dl-glyceraldehyde 3-phosphate to a culture of E. coli caused no preferential inhibition of the accumulation of deoxyribonucleic acid, ribonucleic acid, or phosphoglycerides, although protein accumulation was less affected. Studies with mutant strains ruled out catabolic glycerol 3-phosphate dehydrogenase, anabolic nicotinamide adenine dinucleotide (phosphate):sn-glycerol 3-phosphate oxidoreductase, and fructose 1,6-diphosphate aldolase as the primary sites of action. l-Glyceraldehyde 3-phosphate is a competitive inhibitor of sn-glycerol 3-phosphate in the reactions catalyzed by acyl coenzyme A:sn-glycerol 3-phosphate acyltransferase (K(i) of 1.8 mM) and cytidine 5'-diphosphate-diglyceride:sn-glycerol 3-phosphate phosphatidyltransferase (K(i) of 2.7 mM). A K(m) mutant for the former enzyme was susceptible to the inhibitor. l-Glyceraldehyde 3-phosphate does not affect acyl coenzyme A:lysophosphatidate acyltransferase activity. In vivo, phosphatidylethanolamine and phosphatidylglycerol accumulation are inhibited to the same extent by the addition of dl-glyceraldehyde 3-phosphate to a culture of E. coli.
Acyltransferases↗
Phospholipid metabolism during changes in the proportions of membrane-bound respiratory pigments in Haemophilus parainfluenzae.
After a transition from high to low oxygen tension, there was a twofold to 50-fold increase in the content of membrane-bound respiratory pigments of Haemophilus parainfluenzae, and there were concurrent changes in the metabolism of the membrane phospholipids: (i) a twofold decrease in the rate of turnover of the phosphate in all the phospholipids; (ii) a shift from simple one-phase, linear incorporation of phosphate into phospholipids to a complex biphasic incorporation of phosphate into phospholipids; and (iii) an increase in the total phospholipids with a slight increase in the proportion of phosphatidylglycerol (PG) and a slight decrease in the proportion of phosphatidylethanolamine (PE). Changes in the rates of incorporation of phosphate into the phospholipids occurred without a change in the rate of bacterial growth. When the compensatory adjustment of the proportions of the respiratory pigments reached a steady state, the total phospholipid, the rate of incorporation of phosphate into phospholipids, and the proportion of PG fell. At steady-state proportions of cytochromes, the proportion of PE and the rate of turnover of the phosphate in the phospholipids increased. All through an incorporation experiment of 1.5 divisions, the specific activity of the phosphate of PG was twice that of phosphatidic acid (PA). The phosphate of PG turned over 1.2 to 1.5 times more rapidly than the phosphate of PA in cells with high and low cytochrome levels. If the PA was an accurate measure of the precursor for the cytidine-5'-diphosphate-diglyceride, which in turn was the precursor of all the lipids, then the results of these experiments suggested that exchange reactions, in addition to synthesis from PA, were involved in phospholipid metabolism. These reactions were more sensitive to changes in oxygen concentration than was the growth rate.
Amino Alcohols↗
The influence of CDP-choline on brain lipid metabolism during ischemia.
The intraperitoneal administration of CDP-choline to gerbils (Meriones unguiculatus) partially prevented the changes of lipid metabolism found in brain after ischemia due to carotid occlusion. The increase of diglyceride pool and of its content of radioactivity, due to arachidonate labelling, was almost completely corrected by the treatment. The increase of the free fatty acids, due to ischemia, was unaltered. The decrease of the phosphatidylcholine labelling due to ischemia was partially corrected by the administered CDP-choline.
Animals↗
Effect of cytidine diphosphate choline (CDP-choline) on ischemia-induced alterations of brain lipid in the gerbil.
Brain ischemia was produced in gerbils (Meriones unguiculatus) by the bilateral ligation of the carotid arteries. Definite changes in the energy status of brain demonstrated that carotid occlusion was effective. Five minutes before ligation, an intraventricular injection of either saline or cytidine disphosphate choline (CDP-choline, 0.6 micromol/brain, 3 microliter) was given to groups of animals. Control animals, with and without CDP-choline, together with the ischemic groups, were decapitated directly into liquid nitrogen; 10 min after arterial ligation. Brain free fatty acids, neutral lipids and phospholipids, which were labeled in vivo by the intraventricular injection of [1-14C]arachidonic acid (0.4-0.6 micro Ci, 6-9 nmol) 2 hr prior to ligation, were extracted, purified, and separated by thin-layer chromatographic procedures. The CDP-choline treatment noticeably corrected the increase of total and individual fatty acids due to ischemia and the increase of their radioactivity content. The changes in neutral lipids, particularly in the diacyl glycerol fraction, were also corrected by the injection of the nucleotide. CDP-choline partially reversed the decreased of brain phosphatidylcholine and of its labeling, which was due to ischemia. All the data indicate that the prior injection of CDP-choline stimulates the choline phosphotransferase reaction of brain towards synthesis of phosphatidylcholine and prevents the release of free fatty acids, particularly of arachidonic acid, associated with ischemia.
Animals↗
Biosynthesis and localization of phosphatidyl-scyllo-inositol in barley aleurone cells.
A novel isomer of phosphatidylinositol (PI), phosphatidyl-scyllo-inositol, was characterized in the aleurone cells of barley seeds. In this investigation, the subcellular localization of scyllo-PI and the relative rates of biosynthesis and accumulation of [32P]phosphoric acid ([32Pi])-labeled scyllo- and myo-phosphoinositides in the plasma membrane and intracellular membrane pools were investigated. About 25% of the [32Pi]-labeled phospholipids were present in plasma membrane and 75% in intracellular membranes. Incorporation of [32Pi] into scyllo-PI was greater than into myo-PI in both the plasma membranes and intracellular membranes at all time points investigated, thus suggesting a higher rate of biosynthesis; however, the data do not preclude reduced breakdown of labeled scyllo-PI as a contributing factor. In vitro studies were conducted to investigate the presence of cytidinediphosphate diacylglycerol (CDP-DG):scyllo-inositol 3-phosphatidyltransferase (scyllo-PI synthase) and to optimize enzymatic activity. The inclusion of nonionic detergents (Brij 58 and Triton X-100) effected significant enhancement in the biosynthesis of scyllo-PI, whereas anionic, cationic, and zwitterionic detergents had little or no effect. This is the first evidence for CDP-DG:scyllo-inositol 3-phosphatidyltransferase activity.
CDP-Diacylglycerol-Inositol 3-Phosphatidyltransfer↗