Structural Adaptations in a Membrane Enzyme That Terminates Endocannabinoid Signaling

@article{Bracey2002StructuralAI,
  title={Structural Adaptations in a Membrane Enzyme That Terminates Endocannabinoid Signaling},
  author={Michael H. Bracey and Michael A. Hanson and Kim Masuda and Raymond C. Stevens and Benjamin F. Cravatt},
  journal={Science},
  year={2002},
  volume={298},
  pages={1793 - 1796}
}
Cellular communication in the nervous system is mediated by chemical messengers that include amino acids, monoamines, peptide hormones, and lipids. An interesting question is how neurons regulate signals that are transmitted by membrane-embedded lipids. Here, we report the 2.8 angstrom crystal structure of the integral membrane protein fatty acid amide hydrolase (FAAH), an enzyme that degrades members of the endocannabinoid class of signaling lipids and terminates their activity. The structure… 
Membrane lipids are key modulators of the endocannabinoid-hydrolase FAAH.
TLDR
It is reported that the FAAH dimer is stabilized by the lipid bilayer and shows a higher membrane-binding affinity and enzymatic activity within membranes containing both cholesterol and the natural FAAH substrate AEA (anandamide).
Structure and function of fatty acid amide hydrolase.
TLDR
Investigations into the structure and function of FAAH have engendered provocative molecular models to explain how this enzyme integrates into cell membranes and terminates fatty acid amide signaling in vivo, as well as their biological and therapeutic implications.
Fatty Acid Amide Hydrolase: From Characterization to Therapeutics
TLDR
Investigations into the structure and function of FAAH, its biological and therapeutic implications, as well as a description of different families of FAAh inhibitors are the topic of this review.
Structural analysis of a plant fatty acid amide hydrolase provides insights into the evolutionary diversity of bioactive acylethanolamides
TLDR
The structural divergence in bioactive acylethanolamides in plants is reflected in part in the structural and functional properties of plant FAAHs, suggesting a unique “squeeze and lock” substrate-binding mechanism.
The anandamide membrane transporter and the therapeutic implications of its inhibition
TLDR
Evidence in favor or against the existence of a true anandamide membrane transporter (AMT) is reviewed and the structural properties of compounds that inhibit AMT without affecting other proteins of the endocannabinoid system, such as cannabinoid receptors or FAAH are discussed.
Fatty Acid Amide Hydrolase and the Metabolism of N-Acylethanolamine Lipid Mediators in Plants
TLDR
The inactivation of NAEs is accomplished by an enzyme identified as a functional homolog of the fatty acid amide hydrolase (FAAH) that regulates endocannabinoid metabolism in vertebrates, and its role in NAE metabolism in plants is reviewed.
Structure and Dynamics of the Acyl Chains in the Membrane Trafficking and Enzymatic Processing of Lipids.
TLDR
By using molecular simulations to investigate lipid plasticity and substrate flexibility, researchers can enrich their interpretation of experimental results about the structure-function relationships of lipids and ultimately support protein engineering studies and structure-based drug discovery to target lipid-processing enzymes.
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References

SHOWING 1-10 OF 59 REFERENCES
Molecular characterization of an enzyme that degrades neuromodulatory fatty-acid amides
TLDR
It is shown that oleamide hydrolase may serve as the general inactivating enzyme for a growing family of bioactive signalling molecules, the fatty-acid amides6–8, and the structure and sleep-inducing properties of cis-9-octadecenamide, a lipid isolated from the cerebrospinal fluid of sleep-deprived cats are reported.
Characterization and manipulation of the acyl chain selectivity of fatty acid amide hydrolase.
TLDR
The significant changes in substrate selectivity achieved by single amino acid changes suggest that FAAH possesses a rather malleable substrate binding domain and may serve, along with other AS enzymes, as a template for the engineering of amidases with novel and/or tailored specificities.
The X-ray crystal structure of the membrane protein prostaglandin H2 synthase-1
TLDR
The three-dimensional structure of prostaglandin H2 synthase-1, an integral membrane protein, has been determined at 3.5 Å resolution by X-ray crystallography and suggests that the enzyme integrates into only one leaflet of the lipid bilayer and is thus a monotopic membrane protein.
Structure and function of a squalene cyclase.
TLDR
The crystal structure of squalene-hopene cyclase from Alicyclobacillus acidocaldarius was determined and reveals a membrane protein with membrane-binding characteristics similar to those of prostaglandin-H2 synthase, the only other reported protein of this type.
Chemical and mutagenic investigations of fatty acid amide hydrolase: evidence for a family of serine hydrolases with distinct catalytic properties.
TLDR
The unusual properties of FAAH identified here suggest that this enzyme, and possibly the amidase signature family as a whole, may hydrolyze amides by a novel catalytic mechanism.
Exceptionally potent inhibitors of fatty acid amide hydrolase: the enzyme responsible for degradation of endogenous oleamide and anandamide.
  • D. Boger, H. Satō, B. Cravatt
  • Biology, Chemistry
    Proceedings of the National Academy of Sciences of the United States of America
  • 2000
TLDR
The development of exceptionally potent inhibitors of fatty acid amide hydrolase (FAAH), the enzyme responsible for the degradation of oleamide, and anandamide (an endogenous ligand for cannabinoid receptors) is detailed.
Pharmacological activity of fatty acid amides is regulated, but not mediated, by fatty acid amide hydrolase in vivo.
TLDR
The results indicate that FAAH is a key regulator, but not mediator of FAA activity in vivo, and suggest that FAAs represent a family of signaling lipids that, despite sharing similar chemical structures and a common pathway for catabolism, produce their behavioral effects through distinct receptor systems in vivo.
A new perspective on cannabinoid signalling: complimentary localization of fatty acid amide hydrolase and the CB1 receptor in rat brain.
TLDR
The close correspondence in the distribution of FAAH and CB1 in rat brain and the complimentary pattern of CB1 and FAAH expression at the cellular level provides important new evidence that FAAH may participate in cannabinoid signalling mechanisms of the brain.
Isolation and structure of a brain constituent that binds to the cannabinoid receptor.
Arachidonylethanolamide, an arachidonic acid derivative in porcine brain, was identified in a screen for endogenous ligands for the cannabinoid receptor. The structure of this compound, which has
An anorexic lipid mediator regulated by feeding
TLDR
It is shown that, in rats, food deprivation markedly reduces OEA biosynthesis in the small intestine, and results indicate that OEA is a lipid mediator involved in the peripheral regulation of feeding.
...
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