ArticleProceedings of the National Academy of Sciences of the United States of America2015
Competition and allostery govern substrate selectivity of cyclooxygenase-2.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 14 papers.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
14 citing papers in PubMed, 31 citations in OpenAlex.
- Tissue-specific roles of monoacylglycerol (MAG) in metabolic diseases.Immunometabolism (Cobham, Surrey) · 2026Review
- Structural and functional relevance of the DUF4352 domain in antiviral immunity and physiology of mycobacteria.Nucleic acids research · 2025Article
- Deciphering Complex Interactions in Bioactive Lipid Signaling.Molecules (Basel, Switzerland) · 2023Article
- Harmaline Analogs as Substrate-Selective Cyclooxygenase-2 Inhibitors.ACS medicinal chemistry letters · 2020Article
- Modeling the Control of TGF-β/Smad Nuclear Accumulation by the Hippo Pathway Effectors, Taz/Yap.iScience · 2020Article
- Structural and Chemical Biology of the Interaction of Cyclooxygenase with Substrates and Non-Steroidal Anti-Inflammatory Drugs.Chemical reviews · 2020Review
- A New Look at the Structures of Old Sepsis Actors by Exploratory Data Analysis Tools.Antibiotics (Basel, Switzerland) · 2019Article
- Arg-513 and Leu-531 Are Key Residues Governing Time-Dependent Inhibition of Cyclooxygenase-2 by Aspirin and Celebrex.Biochemistry · 2019Article
- 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
- PyDREAM: high-dimensional parameter inference for biological models in python.Bioinformatics (Oxford, England) · 2018Article
- Antitumor Activity of Cytotoxic Cyclooxygenase-2 Inhibitors.ACS chemical biology · 2016Article
- Crystal Structure of Aspirin-Acetylated Human Cyclooxygenase-2: Insight into the Formation of Products with Reversed Stereochemistry.Biochemistry · 2016Article
- Conservative Secondary Shell Substitution In Cyclooxygenase-2 Reduces Inhibition by Indomethacin Amides and Esters via Altered Enzyme Dynamics.Biochemistry · 2016Article
Corrections and comments
- Erratum issued
Authors and funding
9 authors at 1 institution in 1 country.
Funding
Abstract
Cyclooxygenase-2 (COX-2) oxygenates arachidonic acid (AA) and its ester analog, 2-arachidonoylglycerol (2-AG), to prostaglandins (PGs) and prostaglandin glyceryl esters (PG-Gs), respectively. Although the efficiency of oxygenation of these substrates by COX-2 in vitro is similar, cellular biosynthesis of PGs far exceeds that of PG-Gs. Evidence that the COX enzymes are functional heterodimers suggests that competitive interaction of AA and 2-AG at the allosteric site of COX-2 might result in differential regulation of the oxygenation of the two substrates when both are present. Modulation of AA levels in RAW264.7 macrophages uncovered an inverse correlation between cellular AA levels and PG-G biosynthesis. In vitro kinetic analysis using purified protein demonstrated that the inhibition of 2-AG oxygenation by high concentrations of AA far exceeded the inhibition of AA oxygenation by high concentrations of 2-AG. An unbiased systems-based mechanistic model of the kinetic data revealed that binding of AA or 2-AG at the allosteric site of COX-2 results in a decreased catalytic efficiency of the enzyme toward 2-AG, whereas 2-AG binding at the allosteric site increases COX-2's efficiency toward AA. The results suggest that substrates interact with COX-2 via multiple potential complexes involving binding to both the catalytic and allosteric sites. Competition between AA and 2-AG for these sites, combined with differential allosteric modulation, gives rise to a complex interplay between the substrates, leading to preferential oxygenation of AA.
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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.