ArticleThe Journal of biological chemistry2015
13-Methylarachidonic acid is a positive allosteric modulator of endocannabinoid oxygenation by cyclooxygenase.
Article in The Journal of biological chemistry, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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Who cites it
19 citing papers in PubMed, 30 citations in OpenAlex.
- Exceptionally Potent Chiral Anandamide Analogs.Journal of medicinal chemistry · 2025Article
- Novel Tetraolefinic Chain Phenyl Substituted Endocannabinoid Probes.Journal of medicinal chemistry · 2025Article
- Defining the Conformational Ensembles Associated with Ligand Binding to Cyclooxygenase-2.Biochemistry · 2023Article
- Substrate-selective small-molecule modulators of enzymes: Mechanisms and opportunities.Current opinion in chemical biology · 2023Review
- Harmaline Analogs as Substrate-Selective Cyclooxygenase-2 Inhibitors.ACS medicinal chemistry letters · 2020Article
- Structural and Chemical Biology of the Interaction of Cyclooxygenase with Substrates and Non-Steroidal Anti-Inflammatory Drugs.Chemical reviews · 2020Review
- Arg-513 and Leu-531 Are Key Residues Governing Time-Dependent Inhibition of Cyclooxygenase-2 by Aspirin and Celebrex.Biochemistry · 2019Article
- A seven-step plan for becoming a moderately rich and famous biochemist.The Journal of biological chemistry · 2019Article
- Interactions of fatty acids, nonsteroidal anti-inflammatory drugs, and coxibs with the catalytic and allosteric subunits of cyclooxygenases-1 and -2.The Journal of biological chemistry · 2019Review
- Signal integration and information transfer in an allosterically regulated network.NPJ systems biology and applications · 2019Article
- Dual cyclooxygenase-fatty acid amide hydrolase inhibitor exploits novel binding interactions in the cyclooxygenase active site.The Journal of biological chemistry · 2018Article
- Prokaryotic expression, purification and characterization of human cyclooxygenase-2.International journal of molecular medicine · 2017Article
- Fatty Acid Binding to the Allosteric Subunit of Cyclooxygenase-2 Relieves a Tonic Inhibition of the Catalytic Subunit.The Journal of biological chemistry · 2016Article
- Substrate-selective Inhibition of Cyclooxygeanse-2 by Fenamic Acid Derivatives Is Dependent on Peroxide Tone.The Journal of biological chemistry · 2016Article
- Interactions of 2-O-arachidonylglycerol ether and ibuprofen with the allosteric and catalytic subunits of human COX-2.Journal of lipid research · 2016Article
- Crystal Structure of Aspirin-Acetylated Human Cyclooxygenase-2: Insight into the Formation of Products with Reversed Stereochemistry.Biochemistry · 2016Article
- Different Fatty Acids Compete with Arachidonic Acid for Binding to the Allosteric or Catalytic Subunits of Cyclooxygenases to Regulate Prostanoid Synthesis.The Journal of biological chemistry · 2016Article
- Conservative Secondary Shell Substitution In Cyclooxygenase-2 Reduces Inhibition by Indomethacin Amides and Esters via Altered Enzyme Dynamics.Biochemistry · 2016Article
- Competition and allostery govern substrate selectivity of cyclooxygenase-2.Proceedings of the National Academy of Sciences of the United States of America · 2015Article
Corrections and comments
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Authors and funding
11 authors at 3 institutions in 1 country.
Funding
Abstract
Cyclooxygenase-2 (COX-2) oxygenates arachidonic acid (AA) and the endocannabinoids 2-arachidonoylglycerol (2-AG) and arachidonylethanolamide to prostaglandins, prostaglandin glyceryl esters, and prostaglandin ethanolamides, respectively. A structural homodimer, COX-2 acts as a conformational heterodimer with a catalytic and an allosteric monomer. Prior studies have demonstrated substrate-selective negative allosteric regulation of 2-AG oxygenation. Here we describe AM-8138 (13(S)-methylarachidonic acid), a substrate-selective allosteric potentiator that augments 2-AG oxygenation by up to 3.5-fold with no effect on AA oxygenation. In the crystal structure of an AM-8138·COX-2 complex, AM-8138 adopts a conformation similar to the unproductive conformation of AA in the substrate binding site. Kinetic analysis suggests that binding of AM-8138 to the allosteric monomer of COX-2 increases 2-AG oxygenation by increasing kcat and preventing inhibitory binding of 2-AG. AM-8138 restored the activity of COX-2 mutants that exhibited very poor 2-AG oxygenating activity and increased the activity of COX-1 toward 2-AG. Competition of AM-8138 for the allosteric site prevented the inhibition of COX-2-dependent 2-AG oxygenation by substrate-selective inhibitors and blocked the inhibition of AA or 2-AG oxygenation by nonselective time-dependent inhibitors. AM-8138 selectively enhanced 2-AG oxygenation in intact RAW264.7 macrophage-like cells. Thus, AM-8138 is an important new tool compound for the exploration of allosteric modulation of COX enzymes and their role in endocannabinoid metabolism.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.