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PubMed2000

Lecithin cholesterol acyltransferase.

Cholesterol transport in circulation and its removal from tissues depends on the activity of lecithin cholesterol acyltransferase (LCAT). LCAT is a soluble enzyme that converts cholesterol and phosphatidylcholines (lecithins) to cholesteryl esters and lyso-phosphatidylcholines on the surface of high-density lipoproteins. This review presents key background information and recent research advances on the structure of human LCAT, its reactions and substrates, and the expression of the LCAT gene. While the three-dimensional structure of LCAT is not yet known, a partial model now exists that facilitates the study of structure-function relationships of the native enzyme, and of natural and engineered mutants. The LCAT reaction on lipoproteins consists of several steps, starting with enzyme binding to the lipoprotein/lipid surface, followed by activation of LCAT by apolipoproteins, binding of lipid substrates and the catalytic steps giving rise to the lipid products. Quantitative data are presented on the kinetic and equilibrium constants of some of the LCAT reaction steps. Finally, overexpression of the human LCAT gene in mice and rabbits has been used to examine the physiologic role of LCAT in vivo and its protective effect against diet induced atherosclerosis.

Amino Acid Sequence↗
PubMed1989

Progress report on the Canadian Multicentre Trial of tetrahydroaminoacridine with lecithin in Alzheimer's disease.

Since the discovery of a significant depletion of acetylcholine in discrete areas of the brain of patients affected by Alzheimer's disease, attempts at symptomatic therapy have concentrated on acetylcholine supplementation, an approach that is based upon the efficacy of dopaminergic supplementation therapy for Parkinson's disease. Choline, then lecithin, used orally, failed to improve symptoms but the hypothesis that long-term choline supplementation might stabilize the course of Alzheimer's disease remains to be tested. Nerve growth factor may also offer that possibility. Bethanechol administered intracerebroventricularly did not help when a fixed dose was used but individual titration of more selective muscarinic agonists may prove more effective. In this article we report that tetrahydroaminoacridine (THA), given together with highly concentrated lecithin, appears to bring improvement in cognition and in functional autonomy using the Mini Mental State and the Rapid Disability Rating Scale-2 respectively, without change in behavior as reflected by the Behave-AD. Double-blind cross-over studies are in progress to establish its efficacy. Improvement in study design and means of assessment of cognition, functional autonomy and behavior have been made possible by these drug trials.

Aged↗
PubMed1993

Affinity labeling of lecithin retinol acyltransferase.

Lecithin retinol acyltransferase (LRAT) transfers acyl groups regiospecifically from the sn-1 position of lecithins to all-trans-retinol (vitamin A) and similar retinoids. LRAT is essential for the biosynthesis of 11-cis-retinal, the visual pigment chromophore. LRAT is also required for the general dietary mobilization of vitamin A. The enzyme is membrane-bound and has been solubilized and partially, but not completely, purified. It is demonstrated here that all-trans-retinyl alpha-bromoacetate (RBA) is a potent irreversible affinity labeling agent of LRAT. The measured KI = 12.1 microM and the pseudo-first-order rate constant for inhibition is kinh = 8.2 x 10(-4) s-1. The specificity of the inhibition process is further evidenced by the observation that alpha-bromoacetate derivatives of hydrophobic alcohols which are not substrates for LRAT, such as cholesterol and beta-ionol, are not inhibitors of the enzyme. Labeling of the partially purified enzyme with 3H-RBA showed a single radiolabeled band of molecular weight approximately 25,000 by sodium dodecyl sulfate-polyacrylamide gel electrophoresis.

Acyltransferases↗
PubMed1993

Phospholipase C-induced aggregation and fusion of cholesterol-lecithin small unilamellar vesicles.

We have investigated the effects of the Ca(2+)-requiring enzyme phospholipase C on the stability of sonicated vesicles made with different molar ratios of cholesterol to lecithin. Vesicle aggregation is detected by following turbidity with time. Upon the addition of phospholipase C and after a short lag period, the turbidity of a vesicle dispersion increases continuously with time. The rate of increase of turbidity increases with both the enzyme-to-vesicle ratio and the cholesterol content of the vesicles. Vesicle fusion and leakage of contents are monitored by a contents-mixing fusion assay using 8-aminonaphthalene-1,3,6-trisulfonic acid (ANTS) and p-xylylenebis(pyridinium bromide) (DPX) as the fluorescence probes [Ellens, H., Bentz, J. & Szoka, F.C. (1985) Biochemistry 24, 3099-3106]. The results clearly show that phospholipase C induces vesicle fusion. The rate of vesicle fusion correlates with the enzyme-to-vesicle ratio but not with the cholesterol content of the membrane. Negligible aggregation and fusion of vesicles occurs when the experiment is repeated with buffer free of Ca2+. The membrane-destabilizing diacylglycerol, a product of lecithin hydrolysis by phospholipase C, is speculated to play a major role in driving the observed vesicle aggregation and fusion. The kinetics of vesicle aggregation and vesicle fusion can be predicted by linking Michaelis-Menten enzyme kinetics to a mass-action model.

Cholesterol↗
PubMed1985

Effects of amino group modification in discoidal apolipoprotein A-I-egg phosphatidylcholine-cholesterol complexes on their reactions with lecithin:cholesterol acyltransferase.

Discoidal complexes of human apolipoprotein A-I-egg phosphatidylcholine-cholesterol were prepared by the sodium cholate dialysis procedure and were reacted to varying extents with the amino group reagents citraconic anhydride, diketene, and formaldehyde in the presence of sodium borohydride. Modification of positive lysine residues with negative or neutral groups (citraconic anhydride and diketene, respectively) resulted, for extensively reacted complexes (90%), in structural alterations and in a marked decrease in reactivity with purified human lecithin:cholesterol acyltransferase. The structural and kinetic effects were partially reversible by removal of the modifying groups or by increased ionic strength. Similar extents of modification (84%) with retention of positive charge and introduction of two methyl groups (reductive methylation) had no effect on the structure or the reactivity of the complexes. These results, together with kinetic data at variable complex concentrations or at variable temperatures, indicate that specific lysine residues of apolipoprotein A-I are not involved in the lecithin:cholesterol acyltransferase activation process; instead, charge interactions and structural changes are responsible for the observed decrease in activating capacity. In terms of kinetic parameters, intrinsic K*m values and probably enzyme-substrate particle dissociation constants are affected, but the activation energies remain the same upon chemical modification.

Apolipoprotein A-I↗
PubMed1986

Spontaneous transmembrane insertion of membrane proteins into lipid vesicles facilitated by short-chain lecithins.

Functional reconstitution of the membrane protein bacteriorhodopsin into lipid vesicles is achieved by mixing aqueous suspensions of long-chain lecithins and purple membrane with the short-chain lecithin diheptanoylphosphatidylcholine (20 mol % of total lipid). The membrane protein is transmembranously inserted in the lipid bilayer of the vesicle and highly active as a light-energized proton pump. This rapid, easy, and gentle procedure might allow functional reconstitution of other membrane systems and isolated membrane proteins as well.

Bacteriorhodopsins↗
PubMed1981

Calorimetric studies on saturated mixed-chain lecithin-water systems. Nonequivalence of acyl chains in the thermotropic phase transition.

Aqueous dispersions of synthetic lecithins with different fatty acids in positions 1 and 2 of the glycerol molecule were studied by calorimetry. The data show that variation of the acyl chains in different positions of the glycerol backbone either have no influence upon or contribute 0.5 kcal/mol per CH2 segment to the phase transition enthalpy. Different molecular ordering of the mixed acyl chain lecithins in the bilayer is discussed in light of the results.

Calorimetry↗
PubMed1977

Effect of lysolecithin on the structure and permeability of lecithin bilayer vesicles.

In order to elucidate the role of lysolecithin in membranes, we have examined the effect of lysolecithin on the structure and permeability of lecithin bilayer membranes. Small L-alpha-dimyristoyllecithin (DML) vesicles with myristoyllysolecithin (MLL) incorporated as well as small L-alpha-dipalmitoyllecithin (DPL) vesicles with palmitoyllysolecithin (PLL) were studied by nuclear magnetic resonance (NMR) methods at temperatures both above and below the alpha-gel in equilibrium liquid crystalline phase transition temperature (Tc) and as a function of the concentration of the incorporated lysolecithin. Europium (III) ion was used as a probe to measure the permeability of the vesicular bilayer membrane. At temperatures below Tc, these vesicles were found to be extremely permeable to europium (III) ions. The ion translocation was found to be too fast to be measured by the NMR method under these conditions. However, above the phase transition temperature the ionic permeability decreases to a rate which could be conveniently monitored, and the permeability was shown to increase with temperature and lysolecithin concentration. Analysis of the lysolecithin concentration dependence suggests the formation of ion channels within the lipid bilayer involving four lysolecithin molecules. The data below Tc suggest a phase separation below the phase transition temperature of the host lipid, leading to the formation of patches of lysolecithin molecules within the lecithin matrix. These lysolecithin clusters are presumably long-lived under these conditions and are sufficiently structurally perturbed or disordered to serve as channels for rapid ion permeation.

Kinetics↗
PubMed2002

Lecithin retinol acyltransferase forms functional homodimers.

Membrane-bound lecithin retinol acyltransferase (LRAT), an essential enzyme in vitamin A processing, catalyzes the formation of retinyl esters from vitamin A and lecithin. Cloned and expressed LRAT has a molecular mass of 25.3 kDa. The enzyme is not homologous to known enzymes and is, therefore, of substantial interest mechanistically. Along these lines, the functional protomeric state of LRAT is of importance. Gel electrophoretic studies on LRAT in the presence of SDS and disulfide reducing agents show the expected 25 kDa monomer. However, gel electrophoresis in the absence of a reducing agent and/or strong denaturing conditions reveals substantial dimer formation. LRAT monomers can be efficiently and irreversibly cross-linked by thiol reactive bismaleimides in retinal pigment epithelial (RPE) membranes generating LRAT homodimers. Cross-linked LRAT homodimers are fully active catalytically. The experiments suggest that LRAT monomers interact in membranes and form functional homodimers through protein-protein interactions and disulfide bond formation.

Acyltransferases↗
PubMed2003

Lecithin retinol acyltransferase is a founder member of a novel family of enzymes.

Lecithin retinol acyltransferase (LRAT) catalyzes the reversible esterification of vitamin A using lecithin as the acyl donor. LRAT is the founder member of a new class of enzymes, which include class II tumor suppressors, proteins essential for development, and putative proteases. All of these proteins possess Cys and His residues homologous to C161 and H60 of LRAT. These two residues are shown here to be essential for LRAT activity and are part of a catalytic dyad reminiscent of that found in thiol proteases. However, the local primary sequence contexts of C161 and H60 of LRAT and family are not at all homologous to those found in the approximately 20 thiol protease families. Moreover, LRAT shows pKs of 8.3 and 10.8, compared to approximately 4.0 and 8.5 observed in the thiol proteases. LRAT also contains Gln177 and Asp67 residues, which are largely conserved in the homologues. However, neither of these residues is essential for catalysis. Thiol proteases often contain catalytically essential Asp or Gln residues. It is concluded that LRAT is the founder member of a new class of Cys-His enzymes with diverse functions.

Amino Acid Sequence↗
PubMed2004

Roles of cysteine 161 and tyrosine 154 in the lecithin-retinol acyltransferase mechanism.

Lecithin-retinol acyltransferase (LRAT) catalyzes the transfer of an acyl moiety from the sn-1 position of lecithin to vitamin A, generating all-trans-retinyl esters. LRAT is a unique enzyme and is the founder member of an expanding group of proteins of largely unknown function. In an effort to understand the mechanism of LRAT action, it was of interest to assign the amino acid residues responsible for the two pK(a) values of 8.22 and 9.95 observed in the pH vs rate profile. Titrating C161 of LRAT with a specific affinity labeling agent at varying pH values shows that this residue has a pK(a) = 8.03. Coupled with previous studies, this titration reveals the catalytically essential C161 as the residue responsible for the ascending limb of the pH vs rate profile. Site-specific mutagenic experiments on the lysine and tyrosine residues of LRAT reveal that only the highly conserved tyrosine 154 is essential for catalytic activity. This residue is likely to be responsible for the pK(a) = 9.95 found in the pH vs rate profile. Thus, LRAT has three essential residues (C161, Y154, and H60), all of which are conserved in the LRAT family of enzymes.

Acyltransferases↗
PubMed2006

Palmitoyl transferase activity of lecithin retinol acyl transferase.

Lecithin retinol acyl transferase (LRAT) has the essential role of catalyzing the transfer of an acyl group from the sn-1 position of lecithin to vitamin A to generate all-trans-retinyl esters (tREs). In vitro studies had shown previously that LRAT also can exchange palmitoyl groups between RPE65, a tRE binding protein essential for vision, and tREs. This exchange is likely to be of regulatory significance in the operation of the visual cycle. In the current study, the substrate specificity of LRAT is explored with palmitoylated amino acids and dipeptides as RPE65 surrogates. Both O- and S-substituted palmitoylated analogues are excellent substrates for tLRAT, a readily expressed and readily purified form of LRAT. Using vitamin A as the palmitoyl acceptor, tREs are readily formed. The cognate of these reactions occurs in crude retinal pigment epithelial (RPE) membranes as well. RPE membranes containing LRAT transfer palmitoyl groups from radiolabeled [1-(14)C]-l-alpha-dipalmitoyl diphosphatidylcholine (DPPC) to RPE65. Palmitoyl transfer is abolished by preincubation with a specific LRAT antagonist both in membranes and with purified tLRAT. These experiments are consistent with an expanded role for LRAT function as a protein palmitoyl transferase.

Acyltransferases↗
PubMed2000

Lecithin retinol acyltransferase contains cysteine residues essential for catalysis.

Lecithin retinol acyltransferase (LRAT) is an essential enzyme in vitamin A metabolism and mobilization. The membrane-bound enzyme catalyzes the transfer of an acyl group from the sn-1 position of lecithin to vitamin A to generate retinyl esters. The sequence of LRAT is novel and hence does not suggest a mechanistic class to which the enzyme belongs. However, the activity of the enzyme is exceedingly sensitive to affinity labeling and group-specific reagents directed toward thiol groups. LRAT from human retinal pigment epithelium has cysteine residues at positions 161, 168, 182, and 208. Site-specific mutagenic studies show that C182 and C208 can be converted to alanines with little affect on activity. The activities of the C161A and C168A mutants are virtually nil. Moreover, while C168S is substantially active, C161S possesses only a few percent of the activity of wild-type (WT) LRAT. Also, pH-rate profiles show that C168S has virtually the same profile as WT LRAT, while C161S shows an aberrant profile quite unlike that of WT LRAT. Therefore, LRAT is a thiol acyltransferase and C161 may be the essential nucleophilic residue critical for catalysis.

Acyltransferases↗
PubMed2006

Core/Shell nanoparticles with lecithin lipid cores for protein delivery.

Core/shell nanoparticles with lipid core, were prepared and characterized as a sustained delivery system for protein. The lipid core is composed of protein-loaded lecithin and the polymeric shell is composed of Pluronics (poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) triblock copolymer, F-127). Based on the preparation method in the previous report by us, the freeze-drying of protein-loaded lecithin was performed in the F-127 aqueous solution containing trehalose used as a cryoprotectant to form stabilized core/shell nanoparticles. Cryo-TEM (transmittance electron microscopy) and a particle size analyzer were used to observe the formation of stabilized core/shell nanoparticles. For the application of core/shell nanoparticles as a protein drug carrier, lysozyme and vascular endothelial growth factor (VEGF) were loaded into the core/shell nanoparticles by electrostatic interaction, and the drug release pattern was observed by manipulating the polymeric shell.

Animals↗
PubMed2004

Production and characterization of O/W emulsions containing droplets stabilized by lecithin-chitosan-pectin mutilayered membranes.

The possibility of producing stable oil-in-water (O/W) emulsions containing oil droplets surrounded by multiple layer interfacial membranes from food grade ingredients has been demonstrated. These emulsions were produced using a three stage process that relies on the adsorption of charged biopolymers to oppositely charged surfaces. Emulsions (0.5 wt % corn oil, 0.1 wt % lecithin, 0.0078 wt % chitosan, 0.02 wt % pectin, and 100 mM acetic acid, pH 3.0) containing oil droplets stabilized by lecithin-chitosan-pectin membranes were formed using this interfacial layer-by-layer deposition process. The droplets in these emulsions had good stability to aggregation over a wide range of pH values and salt concentrations (pH 4-8 at 0 mM NaCl and pH 3-8 at 100 mM NaCl). This technology could be extremely useful to the food industry for the creation of O/W emulsions with improved properties or novel applications, e.g., improved stability to environmental stresses, protection of labile substances, controlled release, and triggered release.

Adsorption↗
PubMed1992

Cholesterol (thermodynamic) activity determinations in bile salt-lecithin-cholesterol systems and cholesterol-rich liquid crystalline mesophase formation.

Previous in vitro studies have shown that tauroursodeoxycholate (TUDC)-lecithin (L) micellar solutions solubilize cholesterol (Ch) poorly compared to its 7 alpha-epimer, taurochenodeoxycholate (TCDC). However, in clinical studies ursodeoxycholic acid (UDC) has been found to be as effective as chenodeoxycholic acid (CDC) in Ch gallstone dissolution, and it has been suggested that, during UDC therapy, liquid crystalline mesophase formation may be involved in enhancing micellar Ch dissolution and dispersion. The purpose of the present study was to investigate whether measurements of the Ch thermodynamic activity (A(T) would provide new insights into the problem of Ch solubilization and mesophase formation in bile salt-lecithin-Ch systems. Using the silicone polymer uptake method developed in this laboratory, A(T) was measured as a function of Ch concentration in the TUDC-L-Ch and TCDC-L-Ch model bile systems. In the TCDC systems Henry's law was obeyed almost up to unit activity (i.e., A(T) was proportional to Ch concentration almost up to A(T) = 1.0). However, in many of the TUDC-containing systems negative deviations from Henry's law were observed well below unit activity and these systems became visibly turbid before saturation with respect to cholesterol monohydrate (ChM) was reached. The effects of varying the TCDC/TUDC ratio upon the A(T) behavior were also studied. With increasing TCDC/TUDC ratio, the onset of mesophase formation was shifted to higher A(T) values. A(T) measurements were also conducted in BS-L-Ch mixtures simulating biles of patients undergoing UDC therapy. The results obtained suggest that mesophase formation may not always occur in biles of patients undergoing UDC therapy.(ABSTRACT TRUNCATED AT 250 WORDS)

Bile↗
PubMed2001

Endothelial cell protection against ischemia/reperfusion injury by lecithinized superoxide dismutase.

BACKGROUND: Organs used for transplantation may experience long periods of cold ischemic preservation and consequently oxygen free radical-mediated damage following reperfusion. Lecithinized superoxide dismutase (lec-SOD) is a novel free radical scavenger that has been shown to bind with high affinity to cell membranes. The aim of this study was to determine whether lec-SOD bound to endothelial cells under organ preservation conditions to mediate direct antioxidant activity at the endothelial cell surface and thus offer protection against the harmful effects of ischemia/reperfusion injury. METHODS: An in vitro study was performed on large vessel endothelial cells (HUVEC) and a human microvascular endothelial cell line HMEC-1, to investigate the potential therapeutic benefits of incorporating lec-SOD into organ preservation solution. A cold hypoxia/reoxygenation system was developed to examine lec-SOD binding affinity to endothelial cells, protection against hypoxia/reoxygenation-induced cell death, and neutrophil adhesion. RESULTS: Lec-SOD bound to endothelial cells with higher affinity than unmodified recombinant human superoxide dismutase (rhSOD) and significantly protected both HUVEC and HMEC-1 from cell death following 27 hours of cold hypoxia (P < 0.01). Furthermore, neutrophil adhesion to the endothelium stimulated by hypoxia and reoxygenation was significantly inhibited by treatment with lec-SOD but not by lecithin or rhSOD (P < 0.01). Analysis by flow cytometry demonstrated that E-selectin and ICAM-1 were up-regulated by hypoxia/reoxygenation that was inhibited in part by lec-SOD. CONCLUSIONS: The results from this study suggest that incorporation of lec-SOD into organ preservation solutions provides effective protection to endothelial cells against cold ischemia and reperfusion injury following transplantation.

Antioxidants↗