Conformational analysis of arachidonic and related fatty acids using molecular dynamics simulations

Rich, Mark A.

doi:10.1016/0167-4889(93)90113-4

Cited by 81 publications

(76 citation statements)

References 32 publications

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“…Conformer A depicted in Fig. 4 has a hairpin conformation similar to that described by others for anandamide (23) and arachidonic acid (24). The preferred conformers of all anandamide analogs were generated from A by appropriate structural modifications followed by minimization.…”

Section: Methodsmentioning

confidence: 99%

“…Replacement of the hydroxyethyl with a hydroxyphenyl group leads to relatively potent uptake inhibitors, with the 4-hydroxyphenyl analog (AM404, 22) being distinctly the most successful. Conversely, the 4-methylphenyl analog 25 as well as other analogs with electron donating (24) or electron withdrawing (26 and 27) para substituents display no significant activity. Varying these substituents from the para to the meta or ortho position does not restore activity (data not shown).…”

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confidence: 99%

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Structural determinants for recognition and translocation by the anandamide transporter

Piomelli

Beltramo

Glasnapp

et al. 1999

Proc. Natl. Acad. Sci. U.S.A.

251

205

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The biological actions of anandamide (arachidonylethanolamide), an endogenous cannabinoid lipid, are terminated by a two-step inactivation process consisting of carrier-mediated uptake and intracellular hydrolysis. Anandamide uptake in neurons and astrocytes is mediated by a high-affinity, Na ؉ -independent transporter that is selectively inhibited by N-(4-hydroxyphenyl)-arachidonamide (AM404). In the present study, we examined the structural determinants governing recognition and translocation of substrates by the anandamide transporter constitutively expressed in a human astrocytoma cell line. Competition experiments with a select group of analogs suggest that substrate recognition by the transporter is favored by a polar nonionizable head group of defined stereochemical configuration containing a hydroxyl moiety at its distal end. The secondary carboxamide group interacts favorably with the transporter, but may be replaced with either a tertiary amide or an ester, suggesting that it may serve as hydrogen acceptor. Thus, 2-arachidonylglycerol, a putative endogenous cannabinoid ester, also may serve as a substrate for the transporter. Substrate recognition requires the presence of at least one cis double bond situated at the middle of the fatty acid carbon chain, indicating a preference for ligands whose hydrophobic tail can adopt a bent U-shaped conformation. On the other hand, uptake experiments with radioactively labeled substrates show that no fewer than four cis nonconjugated double bonds are required for optimal translocation across the cell membrane, suggesting that substrates are transported in a folded hairpin conformation. These results outline the general structural requisites for anandamide transport and may assist in the development of selective inhibitors with potential clinical applications.

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Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

Structural determinants for recognition and translocation by the anandamide transporter

Piomelli

Beltramo

Glasnapp

et al. 1999

Proc. Natl. Acad. Sci. U.S.A.

251

205

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“…5 show that DHA is enriched in the vicinity of gA channels, whereas OA is not. Such local enrichment results because the free energy cost of the enrichment is balanced by a decreased bilayer deformation energy, and could occur because DHA with its six double bonds is more flexible than saturated or mono-unsaturated FAs (54,55), which should enable DHA to pack more efficiently than OA into the perturbed bilayer region adjacent to a gA channel (membrane protein). This suggestion is consistent with the results of Feller et al (56) who, based on molecular dynamics simulations on rhodopsin imbedded in 1-stearoyl-2-docosahexaenoyl-PC bilayers, found the docosahexaenoyl chain on average to be closer to rhodopsin than the stearoyl chain.…”

Section: )mentioning

confidence: 99%

Docosahexaenoic acid alters bilayer elastic properties

Bruno

Koeppe²,

Andersen³

2007

Proc. Natl. Acad. Sci. U.S.A.

136

187

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At low micromolar concentrations, polyunsaturated fatty acids (PUFAs) alter the function of many membrane proteins. PUFAs exert their effects on unrelated proteins at similar concentrations, suggesting a common mode of action. Because lipid bilayers serve as the common ''solvent'' for membrane proteins, the common mechanism could be that PUFAs adsorb to the bilayer/solution interface to promote a negative-going change in lipid intrinsic curvature and, like other reversibly adsorbing amphiphiles, increase bilayer elasticity. PUFA adsorption thus would alter the bilayer deformation energy associated with protein conformational changes involving the protein/bilayer boundary, which would alter protein function. To explore the feasibility of such a mechanism, we used gramicidin (gA) analogues of different lengths together with bilayers of different thicknesses to assess whether docosahexaenoic acid (DHA) could exert its effects through a bilayer-mediated mechanism. Indeed, DHA increases gA channel appearance rates and lifetimes and decreases the free energy of channel formation. The appearance rate and lifetime changes increase with increasing channel-bilayer hydrophobic mismatch and are not related to differing DHA bilayer absorption coefficients. DHA thus alters bilayer elastic properties, not just lipid intrinsic curvature; the elasticity changes are important for DHA's bilayer-modifying actions. Oleic acid (OA), which has little effect on membrane protein function, exerts no such effects despite OA's adsorption coefficient being an order of magnitude greater than DHA's. These results suggest that DHA (and other PUFAs) may modulate membrane protein function by bilayer-mediated mechanisms that do not involve specific protein binding but rather changes in bilayer material properties.bilayer material properties ͉ bilayer stiffness ͉ gramicidin channels ͉ hydrophobic mismatch ͉ polyunsaturated fatty acid

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“…38 The conformational space of the two dihedral angles involved shows a large occupied region. 39 MD studies were performed with AEA, 5S-, 5R-, 11S-, 12S-, and 15S-HAEA, to investigate whether the 1-hydroxy-2E,4Z-pentadiene system was responsible for inducing conformations different from AEA, which affect its ability to adopt folded conformations, and thus its bioactivity.…”

Section: Conformational Analysis Of (H)aeasmentioning

confidence: 99%

Oxygenated Metabolites of Anandamide and 2-Arachidonoylglycerol: Conformational Analysis and Interaction with Cannabinoid Receptors, Membrane Transporter, and Fatty Acid Amide Hydrolase

et al. 2002

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This study was aimed at finding structural requirements for the interaction of the acyl chain of endocannabinoids with cannabinoid receptors, membrane transporter protein, and fatty acid amide hydrolase (FAAH). To this end, the flexibility of the acyl chain was restricted by introduction of an 1-hydroxy-2Z,4E-pentadiene system in anandamide (N-arachidonoylethanolamine, AEA) and 2-arachidonoylglycerol (2-AG) at various positions using different lipoxygenases. This brought about selectivity and attenuated the binding potency of AEA and 2-AG. Although the displacement constants were modest, 15(S)-hydroxy-eicosa-5Z,8Z,11Z,-13E-tetraenoyl-N-(2-hydroxyethyl)amine was found to bind selectively to the CB 1 receptor, whereas its 1-arachidonoyl-sn-glycerol analogue and 13(S)-hydroxy-octadeca-9Z,11E-dienoyl-N-(2-hydroxyethyl)amine could selectively bind to the CB 2 receptor. 11(S)-Hydroxy-eicosa-5Z,8Z,12E,14Z-tetraenoyl-N-(2-hydroxyethyl)amine did not bind to either receptor, whereas 12(S)-hydroxy-eicosa-5Z,8Z,10E,14Z-tetraenoyl-N-(2-hydroxyethyl)amine did bind to both CB receptors with an affinity similar to that of AEA. All oxygenated anandamide derivatives were good inhibitors of FAAH (low micromolar K i ) but were ineffective on the AEA transporter. 2-AG rapidly isomerizes into 1(3)-arachidonoyl-sn-glycerol. Both 1-and 3-arachidonoyl-snglycerol did not bind to either CB receptor and did not interfere with AEA transport. Thus, after it is isomerized, 2-AG is inactivated, thereby decreasing effective concentrations of 2-AG. Analysis of 1 H NMR spectra revealed that chloroform did not induce notably different conformations in the acyl chain of 15(S)-hydroxy-eicosa-5Z,8Z,11Z,13E-tetraenoic acid as compared with water. Molecular dynamics (MD) simulations of AEA and its analogues in the presence of explicit water molecules revealed that a tightly folded conformation of the acyl chain is not the only requirement for CB 1 binding. Structural details of the C 2 -C 15 loop, such as an sp 2 carbon at position 11, are necessary for receptor binding. The MD simulations may suggest that the average orientations of the pentyl tail of AEA and 12(S)-hydroxy-eicosa-5Z,8Z,-10E,14Z-tetraenoyl-N-(2-hydroxyethyl)amine are different from that of the low-affinity, inactive ligands.

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Conformational analysis of arachidonic and related fatty acids using molecular dynamics simulations

Cited by 81 publications

References 32 publications

Structural determinants for recognition and translocation by the anandamide transporter

Structural determinants for recognition and translocation by the anandamide transporter

Docosahexaenoic acid alters bilayer elastic properties

Oxygenated Metabolites of Anandamide and 2-Arachidonoylglycerol: Conformational Analysis and Interaction with Cannabinoid Receptors, Membrane Transporter, and Fatty Acid Amide Hydrolase

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