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At least 307 records · Page 17Linked to original sources
PubMed1978

Use of fluorescence polarization to monitor intracellular membrane changes during temperature acclimation. Correlation with lipid compositional and ultrastructural changes.

Fluorescence polarization of 1,6-diphenylhexatriene (DPH) was used to study the effects of temperature acclimation on Tetrahymena membranes. The physical properties of membrane lipids were found to be highly dependent on cellular growth temperature. DPH polarization in lipids from three different membrane fractions correlated well with earlier freeze-fracture and electron spin resonance observations showing that membrane fluidity progressively decreases in the order microsomes greater than pellicles greater than cilia throughout a wide range of growth temperatures. Changes in membrane lipid fluidity following a shift from high to low growth temperatures proceed rapidly in the microsomes, whereas there is a pronounced lag in the changes of peripheral cell membrane lipids. These data support previous observations that adaptive changes in membrane fluidity proceed via lipid modifications in the endoplasmic reticulum, followed by dissemination of lipid components to other cell membranes. The rapid changes in polarization observed in the microsomal lipids following a temperature shift correspond closely with the time-dependent alterations in both lipid fatty acid composition and freeze-fracture patterns of membrane particle distribution, suggesting that, in the endoplasmic reticulum, lipid phase separation is the primary cause of membrane particle rearrangements.

Animals↗
PubMed2005

The relative orientation of the lipid and carbohydrate moieties of lipochitooligosaccharides related to nodulation factors depends on lipid chain saturation.

Lipochitooligosaccharides (LCOs) signal the symbiosis of rhizobia with legumes and the formation of nitrogen-fixing root nodules. LCOs 1 and 2 share identical tetrasaccharide scaffolds but different lipid moieties (1, LCO-IV(C16:1[9Z], SNa) and , LCO-IV(C16:2[2E,9Z], SNa)). The conformational behaviors of both LCOs were studied by molecular modeling and NMR. Modeling predicts that a small lipid modification would result in a different relative orientation of the lipid and tetrasaccharide moieties. Diffusion ordered spectroscopy reports that both LCOs form small aggregates above 1 mM. Nuclear Overhauser spectroscopy (NOESY) data, collected under monomeric conditions, reveals lipid-carbohydrate contacts only for 1, in agreement with the modeling data. The distinct molecular structures of 1 and 2 have the potential to contribute to their selective binding by legume proteins.

Carbohydrate Conformation↗
PubMed1997

Current and future drug therapies for claudication.

The primary objectives of claudication treatment are to reduce cardiovascular mortality and improve walking ability. Patients with claudication have 60% mortality over 10 years, with most deaths due to myocardial infarction and stroke. Aggressive risk-factor modification is required in all these patients, particularly smoking cessation, lipid modification, and treatment of hypertension, diabetes and elevated homocysteine levels. Aspirin, ticlopidine and clopidogrel are all effective in reducing the risk of myocardial infarction, stroke and vascular death, and thus antiplatelet therapy should be considered in all claudicants. Patients with disabling claudication should be considered for therapies that relieve claudication pain and improve exercise performance, the most effective being exercise training and smoking cessation. Pentoxifylline, the only approved claudication drug in the United States, has modest efficacy in improving treadmill exercise performance. Other drugs shown to be of some benefit in patients with claudication include propionyl-L-carnitine, cilostazol and possibly prostaglandin derivatives. Several antiplatelet agents and angiogenic growth factors are also being evaluated for the treatment of claudication.

Enzyme Inhibitors↗
PubMed1989

Purification of glycerol dialkyl nonitol tetraether from Sulfolobus acidocaldarius.

A modified procedure for extraction and purification of hydrolyzed archaebacterial lipids is described. Lipids were extracted from Sulfolobus acidocaldarius using a Soxhlet extraction procedure followed by trichloroacetic acid solvent-extraction of the residue. The yield of total extractable material by this protocol was 14% which, after a two-phase wash, yielded 10% lipid. Modifications to the published steps for purifying the subsequently hydrolyzed lipids were developed to purify glycerol dialkyl nonitol tetraether (GDNT). The nearly colorless final macrocyclic product was characterized by TLC, IR, NMR, and mass spectrometry.

Archaea↗
PubMed1989

[The cytotoxicity of oxidized lipoproteins].

The peroxidation of low-density lipoproteins (LDL) and their subsequent cytotoxicity is believed to be involved in the atherogenesis. The aim of this work was to determine the possible involvement of lipid peroxides in the cytotoxicity of lipoproteins. We report a new experimental model system constituted by lipoproteins treated by short-UV radiations which result in a major lipid peroxidation without functional alteration of apoproteins. UV radiations induced the following lipid modifications: the content of polyunsaturated fatty acids decreased considerably in all lipid classes; the level of natural antioxidants, i.e. vitamin E and carotene, dropped dramatically; conjugated dienes and thiobarbituric acid reactive substances (TBARS) were notably increased; apoproteins from LDL exhibited little structural modification but no functional alteration. The cytotoxicity was studied in lymphoblastoid cell lines established from lymphocytes derived from normal subjects or from patients with familial hypercholesterolemia. High density lipoproteins (HDL) were shown to inhibit the cytotoxicity induced by low doses of peroxidized LDL; the protective effect of HDL was complete up to the ratio ApoB/ApoA close to 1. In addition, vitamin E and catechin, two well known antioxidants, blocked the cytotoxicity of peroxidized LDL. These results corroborate the possibility of the synergic effect of HDL and antioxidant molecules for the protection of cells against oxidized LDL that are incorporated through the LDL-receptor pathway.

Antioxidants↗
PubMedDate not supplied

Effects of structural modifications of ether lipids on antiproliferative activity against human glioma cell lines.

The effect of structural modifications of ether lipids on antiproliferative activity was studied in four human glioma cell lines. Drug potency, determined by microtetrazolium assay, varied 7- to 30-fold. CP 46,665 was most potent; Amido-18-OEt was least potent. Antiproliferative activity was highly dependent on drug exposure time. Except for CP 46,665, which reached maximal activity after 2 hr, 40 microM ether lipids were effective only after 24 hr. Structural modifications of ether lipids can increase their potency and reduce the time required for antiproliferative activity. Ether lipid analogs may be useful for treating human gliomas.

Antineoplastic Agents↗
PubMedDate not supplied

Analysis of lipid composition of sarcoplasmic reticulum membranes from normal and malignant hyperthermic pig skeletal muscle.

In search of a general membrane defect hypothesis for malignant hyperthermia syndrome, we analysed the lipid profiles of heavy sarcoplasmic reticulum membranes isolated from normal and malignant hyperthermia longissimus dorsi pig muscle. Malignant hyperthermia susceptibility was assessed by halothane challenge of pigs. Sarcoplasmic reticulum membranes from malignant hyperthermia susceptible pigs differed significantly from control ones in the cholesterol content and phosphatidylethanolamine/phosphatidylcholine ratio; both were higher in former membranes. These latter lipid modifications were in agreement with the significant increase of their bulk lipid viscosity, as evidenced by an increase of diphenyl hexatriene fluorescence anisotropy. The increased level of phosphatidylethanolamine associated with the decreased content of phosphatidylcholine in malignant hyperthermic membranes was shown to be a potential consequence of depressed activities of both phospholipid N-methyltransferase I and II activities. Finally, the distribution of fatty acids in these particular phospholipids showed no change in phosphatidylcholine molecules, whereas the percentage of arachidonate and stearate in the phosphatidylethanolamine species were respectively higher and lower in malignant hyperthermic membranes. These differences in major phospholipids content and the enrichment of a metabolically important fatty acyl chains in malignant hyperthermia sarcoplasmic reticulum membranes strongly suggest that the lipid metabolism may contribute to the molecular mechanism of malignant hyperthermia syndrome.

Animals↗
PubMed1990

Transient shift of diacylglycerol and inositol lipids induced by interferon in Daudi cells. Evidence for a different pattern between nuclei and intact cells.

The effect of human recombinant DNA interferon-alpha type A on inositol lipid and diacylglycerol metabolism was investigated in Daudi lymphoma whole cells and isolated nuclei. In isolated nuclei after 90 min of interferon treatment an enhanced rate of PIP2 phosphorylation and an increase of DAG mass were observed. In whole cells, after 1 min of interferon treatment, there was a rapid and transient shift of DAG mass apparently not related to inositol lipid modifications, thus indicating the presence in nuclear and cytoplasmic compartments of inositol lipid fractions with different metabolic features in response to interferon-alpha.

Adenosine Triphosphate↗
PubMed2003

Role of lipids in chemical modification of proteins and development of complications in diabetes.

Hyperglycaemia is the major risk factor for the development of complications in both Type I and Type II diabetes; however, there is growing evidence from several clinical trials that dyslipidaemia, including hypertriglyceridaemia, is a significant and independent risk factor for diabetic complications. In this paper, we propose that chemical modification of proteins by lipids may be a underlying pathogenic mechanism linking dyslipidaemia to diabetic complications. Thus the major AGEs (advanced glycation end-products) in tissues, such as carboxymethyl-lysine, carboxyethyl-lysine and hydroimidazolones, may, in fact, be ALEs (advanced lipoxidation end-products), derived from lipids. Increased lipid peroxidation and accelerated ALE formation, possibly catalysed by hyperglycaemia and oxidative stress, may be the mechanistic link between dyslipidaemia and diabetic complications. If correct, this proposal would suggest that inhibition or reversal of glycation, which is a central theme of this symposium, may not be sufficient for protection against diabetic complications.

Diabetes Complications↗
PubMed2002

Palmitoylation of the human prostacyclin receptor. Functional implications of palmitoylation and isoprenylation.

We have previously established that isoprenylation of the prostacyclin receptor (IP) is required for its efficient G protein coupling and effector signaling (Hayes, J. S., Lawler, O. A., Walsh, M. T., and Kinsella, B. T. (1999) J. Biol. Chem. 274, 23707-23718). In the present study, we sought to investigate whether the IP may actually be subject to palmitoylation in addition to isoprenylation and to establish the functional significance thereof. The human (h) IP was efficiently palmitoylated at Cys(308) and Cys(311), proximal to transmembrane domain 7 within its carboxyl-terminal (C)-tail domain, whereas Cys(309) was not palmitoylated. The isoprenylation-defective hIP(SSLC) underwent palmitoylation but did not efficiently couple to G(s) or G(q), confirming that isoprenylation is required for G protein coupling. Deletion of C-tail sequences distal to Val(307) generated hIP(Delta307) that was neither palmitoylated nor isoprenylated and did not efficiently couple to G(s) or to G(q), whereas hIP(Delta312) was palmitoylated and ably coupled to both effector systems. Conversion of Cys(308), Cys(309), Cys(311), Cys(308,309), or Cys(309,311) to corresponding Ser residues, while leaving the isoprenylation CAAX motif intact, did not affect hIP coupling to G(s) signaling, whereas mutation of Cys(308,311) and Cys(308,309,311) abolished signaling, indicating that palmitoylation of either Cys(308) or Cys(311) is sufficient to maintain functional G(s) coupling. Although mutation of Cys(309) and Cys(311) did not affect hIP-mediated G(q) coupling, mutation of Cys(308) abolished signaling, indicating a specific requirement for palmitoylation of Cys(308) for G(q) coupling. Consistent with this, neither hIP(C308S,C309S), hIP(C308S,C311S), nor hIP(C308S,C309S,C311S) coupled to G(q). Taken together, these data confirm that the hIP is isoprenylated and palmitoylated, and collectively these modifications modulate its G protein coupling and effector signaling. We propose that through lipid modification followed by membrane insertion, the C-tail domain of the IP may contain a double loop structure anchored by the dynamically regulated palmitoyl groups proximal to transmembrane domain 7 and by a distal farnesyl isoprenoid permanently attached to its carboxyl terminus.

Amino Acid Motifs↗
PubMed2005

Regulation of phototransduction responsiveness and retinal degeneration by a phospholipase D-generated signaling lipid.

Drosophila melanogaster phototransduction proceeds via a phospholipase C (PLC)-triggered cascade of phosphatidylinositol (PI) lipid modifications, many steps of which remain undefined. We describe the involvement of the lipid phosphatidic acid and the enzyme that generates it, phospholipase D (Pld), in this process. Pld(null) flies exhibit decreased light sensitivity as well as a heightened susceptibility to retinal degeneration. Pld overexpression rescues flies lacking PLC from light-induced, metarhodopsin-mediated degeneration and restores visual signaling in flies lacking the PI transfer protein, which is a key player in the replenishment of the PI 4,5-bisphosphate (PIP2) substrate used by PLC to transduce light stimuli into neurological signals. Altogether, these findings suggest that Pld facilitates phototransduction by maintaining adequate levels of PIP2 and by protecting the visual system from metarhodopsin-induced, low light degeneration.

Animals↗
PubMed1981

Membrane fatty acid modification of the neuroblastoma x glioma hybrid, NG108-15.

As a first step in studying the effects of membrane lipid modification on complex cellular functions we have modified the membrane fatty acid composition of the neuroblastoma X glioma hybrid clone, NG108-15. These cultured cells were chosen because they exhibit many complex neuronal functions in vitro. Unsaturated fatty acids (oleate, linoleate, linolenate and arachidonate) were accumulated, metabolized and esterified by the cells. These unsaturated fatty acids stimulated cell growth, whereas saturated fatty acids were toxic to the cells. Changes as large as 40-fold in the ratio of monounsaturated/polyunsaturated fatty acids in the membrane phospholipids were produced by addition of fatty acids directly to serum-containing culture medium. As a result of the exposure of NG108-15 cells to unsaturated fatty acids the amount of phosphatidylethanolamine in the cells was increased by as much as 60%. Polyunsaturated fatty acids also caused a small decrease in the membrane cholesterol/phospholipid molar ratio. These experiments demonstrate that large changes in membrane fatty acid composition can be created in clonal cells capable of differentiated neuronal activities. Additional changes in membrane lipid composition also appear to be induced by these manipulations. The question of the importance of specific membrane lipid composition to neuronal cellular function now can be addressed.

Animals↗
PubMed1986

Effect of amino acid substitutions at the signal peptide cleavage site of the Escherichia coli major outer membrane lipoprotein.

The requirement for the glycine residue at the COOH terminus of the signal peptide of the precursor of the major Escherichia coli outer membrane lipoprotein was examined. Using oligonucleotide-directed site-specific mutagenesis, this residue was replaced by residues of increasing side chain size. Substitution by serine had no effect on the modification or processing of the prolipoprotein. Substitution by valine or leucine resulted in the accumulation of the unmodified precursor, whereas threonine substitution resulted in slow lipid modification and no detectable processing of the lipid modified precursor. The results indicate that serine is the upper limit on size for the residue at the cleavage site. Larger residues at this position prevent the action of both the glyceride transferase and signal peptidase II enzymes, indicating that the cleavage site residue plays a role in events prior to proteolytic cleavage. The upper limit on size of the cleavage site residue is similar to that found for exported proteins cleaved by signal peptidase I, as well as eucaryotic exported proteins. The possibility that the cleavage site residue may have a role other than active site recognition by the signal peptidase is discussed.

Amino Acid Sequence↗
PubMed1998

Characterization of the major bovine brain Go alpha isoforms. Mapping the structural differences between the alpha subunit isoforms identifies a variable region of the protein involved in receptor interactions.

Go is the major G protein in bovine brain, with at least three isoforms, GoA, GoB, and GoC. Whereas alphaoA and alphaoB arise from a single Goalpha gene as alternatively spliced mRNAs, alphaoA and alphaoC are thought to differ by covalent modification. To test the hypothesis that alphaoA and alphaoC have different N-terminal lipid modifications, proteolytic fragments of alphao isoforms were immunoprecipitated with an N terminus-specific antibody and analyzed by matrix-assisted laser desorption ionization mass spectrometry. The major masses observed in immunoprecipitates were the same for all three alphao isoforms and corresponded to the predicted mass of a myristoylated N-terminal fragment. Structural differences between alphaoA and alphaoC were also compared before and after limited tryptic proteolysis using SDS-polyacrylamide gel electrophoresis containing 6 M urea. Based upon the alphao subunit fragments produced under activating and nonactivating conditions, differences between alphaoA and alphaoC were localized to a C-terminal fragment of the protein. This region, involved in receptor and effector interactions, implies divergent signaling roles for these two alphao proteins. Finally, the structural difference between alphaoA and alphaoC is associated with a difference of at most 2 daltons based upon measurements by electrospay ionization mass spectrometry.

Amino Acid Sequence↗
PubMed2004

GPI-anchored proteins and lipid rafts.

Several proteins are anchored to membranes via a post-translational lipid modification, the glycosylphosphatidylinositol (GPI) anchor. In mammals and other vertebrates, GPI-anchored proteins have been found in almost all tissues and cells examined. Several studies have provided significant insight into the functions of this ubiquitous modification. An intriguing relevant feature of GPI-anchored proteins is their association with lipid rafts, specialized regions of elevated cholesterol and sphingolipid content, that are present within most cell membranes. In addition to the structure and biosynthesis of the GPI-anchor, recent researches have focused on its molecular interaction with lipid rafts and the biological meaning of such interaction. The aim of this review is to examine the emerging evidences of association between lipid rafts and GPI-anchored proteins, and their relationship with the modulation of important cellular functions such as protein/lipid sorting, signaling mechanisms and with human disease.

Alzheimer Disease↗
PubMed2007

Palmitoylation: policing protein stability and traffic.

Palmitate modifies both peripheral and integral membrane proteins and its addition can be permanent or transient, which makes it unique among the lipid modifications of proteins. The presence of palmitate on a protein affects how the protein interacts with lipids and proteins in a membrane compartment, and the reversibility of palmitoylation allows different modes of trafficking between membrane compartments. Here, we review recent studies that have provided insights into the mechanisms that mediate the functional consequences of this versatile modification.

Acylation↗
PubMed2001

Regulation of G proteins by covalent modification.

Heterotrimeric G protein alpha,beta, and gamma subunits are subject to several kinds of co- and post-translational covalent modifications. Among those relevant to G protein-coupled receptor signaling in normal cell function are lipid modifications and phosphorylation. N-myristoylation is a co-translational modification occurring for members of the G(i) family of Galpha subunits, while palmitoylation is a post-translational modification that occurs for these and most other Galpha subunits. One or both modifications are required for plasma membrane targeting and contribute to regulating strength of interaction with the Gbetagamma heterodimer, effectors, and regulators of G protein signaling (RGS proteins). Galpha subunits, including those with transforming activity, are often inactive when unable to be modified with lipids. The reversible nature of palmitoylation is intriguing in this regard, as it lends itself to a regulation integrated with the activation state of the G protein. Several Galpha subunits are substrates for phosphorylation by protein kinase C and at least one is a substrate for phosphorylation by the p21-activated protein kinase. Phosphorylation in both instances inhibits the interactions of these subunits with the Gbetagamma heterodimer and RGS proteins. Several Galpha subunits are also substrates for tyrosine phosphorylation. A Ggamma subunit is phosphorylated by protein kinase C, with the consequence that it interacts more tightly with a Galpha subunit but less well with an effector.

Acylation↗