Acylation of lipids

Clementz, T., Zhou, Z., Raetz, C.R. Function of the Escherichia coli msbB gene, a multicopy suppressor of htrB knockouts, in the acylation of lipid A. Acylation by MsbB follows laurate incorporation by HtrB. J Biol Chem 272 (1997) 10353-10360. 

Clementz, T., Bednarski, J. J., and Raetz, C. R. H. (1996). Function of the htrB high temperature requirement gene of Escherichia coli in the acylation of lipid A. HtrB catalyzed incorporation of laurate. J. Biol. Chem. 271, 12095-12102. 

Although extraction of lipids from membranes can be induced in atomic force apparatus (Leckband et al., 1994) and biomembrane force probe (Evans et al., 1991) experiments, spontaneous dissociation of a lipid from a membrane occurs very rarely because it involves an energy barrier of about 20 kcal/mol (Cevc and Marsh, 1987). However, lipids are known to be extracted from membranes by various enzymes. One such enzyme is phospholipase A2 (PLA2), which complexes with membrane surfaces, destabilizes a phospholipid, extracts it from the membrane, and catalyzes the hydrolysis reaction of the srir2-acyl chain of the lipid, producing lysophospholipids and fatty acids (Slotboom et al., 1982 Dennis, 1983 Jain et al., 1995). SMD simulations were employed to investigate the extraction of a lipid molecule from a DLPE monolayer by human synovial PLA2 (see Eig. 6b), and to compare this process to the extraction of a lipid from a lipid monolayer into the aqueous phase (Stepaniants et al., 1997). 

Four different types of lipid-anchoring motifs have been found to date. These are amide-linked myristoyl anchors, thioester-linked fatty acyl anchors, thioether-linked prenyl anchors, and amide-linked glycosyl phosphatidylinosi-tol anchors. Each of these anchoring motifs is used by a variety of membrane proteins, but each nonetheless exhibits a characteristic pattern of structural requirements. 

Because skin exhibits many of the properties of a lipid membrane, dermal penetration can often be enhanced by increasing a molecule s lipophilicity. Preparation of an ester of an alcohol is often used for this purpose since this stratagem simultaneously time covers a hydrophilic group and provides a hydrophobic moiety the ready cleavage of this function by the ubiquitous esterase enzymes assures availability of the parent drug molecule. Thus acylation of the primary alcohol in flucinolone (65) with propionyl chloride affords procinonide (66) the same transform... 

S-prenylation is the most recent of the four major types of lipid modifications to be described. As with -acylation, S-prenylation is posttranslational. The lipid substrates for these modifications are farnesyl diphosphate and geranylgeranyl diphosphate. The mechanism... 

Effect of Cholesterol. Cholesterol inclusion into the lipid bilayers composed of DPPC or DSPC, eliminates apparent Tc and reduces permeability at and above the usual Tc. On the other hand, cholesterol inclusion increases packing of fluid bilayer composed of lipids with unsaturated fatty acyl chains. Since cholesterol rich liposomes are stable in plasma, cholesterol is commonly used as a liposomal component. 

Glutaric aciduria type II, which is a defect of P-oxida-tion, may affect muscle exclusively or in conjunction with other tissues. Glutaric aciduria type II, also termed multiple acyl-CoA dehydrogenase deficiency (Fig. 42-2), usually causes respiratory distress, hypoglycemia, hyperammonemia, systemic carnitine deficiency, nonketotic metabolic acidosis in the neonatal period and death within the first week. A few patients with onset in childhood or adult life showed lipid-storage myopathy, with weakness or premature fatigue [4]. Short-chain acyl-CoA deficiency (Fig. 42-2) was described in one woman with proximal limb weakness and exercise intolerance. Muscle biopsy showed marked accumulation of lipid droplets. Although... 

This scenario for molecular packing leading to biased chiral symmetrybreaking is quite speculative. However, it makes an important point for molecular modeling of lipid membranes The unusual feature of diacetylenic lipids does not have to be associated with the stereocenter of the molecules but rather may be a broken symmetry in the packing of the kinks in the acyl chains. This speculation needs to be investigated by detailed molecular modeling calculations. 

Bufotenine has been found to be behaviorally inactive, or only weakly active, in most animal studies, although at 15 mg/kg, it did produce the head-twitch resonse in mice (43). It was also behaviorally active in experiments in which the blood-brain barrier was bypassed (78). Acylation of the polar hydroxy group of bufotenine increases its lipid solubility (65,74) and apparently enhances its ability to cross the blood-brain barrier (64). For example, O-acetylbufotenine (5-acetoxy-N,N-dimethyltryptamine 54) disrupted conditioned avoidance behavior in rodents (65) and produced tremorigenic activity similar to that elicited by DMT (37) or 5-OMeDMT (59) when administered to mice (64). In this latter study, a comparison of brain levels of bufotenine after administration of O-acetylbufotenine with those of DMT and 5-OMeDMT revealed bufotenine to be the most active of the three agents, based on brain concentration. The pivaloyl ester of bufotenine also appears to possess behavioral activity, since stimulus generalization was observed when this agent was administered to animals trained to discriminate 5-OMeDMT from saline (74). 

Lipid assemblies of the lamellar type, such as lipid bilayers, can feature a true phase transition in which the topology does not change. Upon cooling, the bilayer goes from the fluid phase to the gel phase. In the fluid phase, the acyl chains are disordered, in the sense that there is enough free volume around the chains to allow for chain conformation variations. In the gel phase, the acyl chains are more densely packed and believed to be ordered in an all-trans (straight) configuration. For very pure systems, at temperatures below this sharp gel-to-liquid phase transition, there are several other states and distinct transitions detectable (pre-transition, ripple phase, etc.). These phases will not be reviewed here. In biomembranes, many type of lipids (and other molecules) occur, and it is known that for this reason the gel-to-liquid phase transition is... 

From the modelling results for bilayers composed of unsaturated lipids one can begin to speculate about the various roles unsaturated lipids play in biomembranes. One very well-known effect is that unsaturated bonds suppress the gel-to-liquid phase transition temperature. Unsaturated lipids also modulate the lateral mobility of molecules in the membrane matrix. The results discussed above suggest that in biomembranes the average interpenetration depth of lipid tails into opposite monolayers can be tuned by using unsaturated lipids. Rabinovich and co-workers have shown that the end-to-end distance of multiple unsaturated acyl chains was significantly less sensitive to the temperature than that of saturated acyls. They suggested from this that unsaturated... 

Fig. 2.—Chemical structure of lipid A of the Escherichia coli Re mutant strain F515. The hydroxyl group at position 6 constitutes the attachment site of Kdo. The numbers in circles indicate the number of carbon atoms present in the fatty acyl chains. The 14 0(3-OH) residues possess the (Reconfiguration. The glycosylic phosphate group may be substituted by a phosphate group (see Table I) (46,65,69).

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