Expression and selective inhibition of the constitutive and inducible forms of human cyclo-oxygenase
| Autor: | Peter C. Isakson, Karen Seibert, James K. Gierse, D P Creely, Carol M. Koboldt, Scott D. Hauser, S H Rangwala |
|---|---|
| Rok vydání: | 1995 |
| Předmět: |
DNA
Complementary Time Factors Mefenamic acid Indomethacin Thiophenes Spodoptera Biology Biochemistry Isozyme Gene Expression Regulation Enzymologic chemistry.chemical_compound Enzyme activator Oxygen Consumption Non-competitive inhibition medicine Animals Humans Cyclooxygenase Inhibitors Cloning Molecular Molecular Biology Nitrobenzenes chemistry.chemical_classification Sulfonamides Arachidonic Acid Dose-Response Relationship Drug Cell Biology Molecular biology Recombinant Proteins Enzyme Activation Enzyme chemistry Prostaglandin-Endoperoxide Synthases Specific activity Arachidonic acid Cyclo-oxygenase Baculoviridae Research Article medicine.drug |
| Zdroj: | Biochemical Journal. 305:479-484 |
| ISSN: | 1470-8728 0264-6021 |
| DOI: | 10.1042/bj3050479 |
| Popis: | The enzyme cyclo-oxygenase catalyses the oxygenation of arachidonic acid, leading to the formation of prostaglandins. Recently two forms of cyclo-oxygenase have been described: a constitutive (COX-1) enzyme present in most cells and tissues, and an inducible (COX-2) isoenzyme observed in many cells in response to pro-inflammatory cytokines. Constitutive and inducible forms of human cyclo-oxygenase (hCOX-1 and hCOX-2) were cloned and expressed in insect cells, utilizing a baculovirus expression system. hCOX-1 had a specific activity of 18.8 mumol of O2/mg with a Km of 13.8 microM for arachidonate and Vmax. of 1500 nmol of O2/nmol of enzyme, whereas hCOX-2 had a specific activity of 12.2 mumol of O2/mg with a Km of 8.7 microM for arachidonate and a Vmax. of 1090 nmol of O2/nmol of enzyme. Indomethacin inhibited both hCOX-1 and hCOX-2, whereas NS-398 and Dup-697 selectively inhibited hCOX-2. Both NS-398 and Dup-697 exhibited time-dependent inactivation of hCOX-2, as did indomethacin on both enzymes. The competitive inhibitor of hCOX-1, mefenamic acid, also displayed competitive inhibition of hCOX-2. These results demonstrate the ability to generate selective non-steroidal anti-inflammatory drugs (NSAIDs), which could provide useful improvement therapeutically in the treatment of chronic inflammatory disease. |
| Databáze: | OpenAIRE |
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