Structural insights into the stereochemistry of the cyclooxygenase reaction

Kiefer, James R.; Pawlitz, Jennifer L.; Moreland, Kirby T.; Stegeman, Roderick A.; Hood, William F.; Gierse, James K.; Stevens, Anna M.; Goodwin, Douglas C.; Rowlinson, Scott W.; Marnett, Lawrence J.; Stallings, William C.; Kurumbail, Ravi G.

doi:10.1038/35011103

Cited by 224 publications

(225 citation statements)

References 28 publications

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“…32 Although the product species is ambiguous (it could be PGG 2 or PGH 2 ), the carboxylate of the molecule is positioned near Arg-120 and Tyr-355 and the ω-end is bound in the top channel, similar to arachidonic acid. 41 This conformation of product, in which the PGG 2 /PGH 2 species hydrogen-bonds with the constriction site residues and bends in an L-shaped fashion at Tyr-385, suggests that arachidonic acid was positioned properly for catalysis. The mixed structure cocrystal also yielded a conformer of arachidonic acid that is bound in an inverted configuration with its carboxylate hydrogen-bonded to Tyr-385 and Ser-530.…”

Section: Cyclooxygenase Enzymes: Structure and Mechanismsmentioning

confidence: 99%

“…57,59 The presence of Tyr-385 across the active site from Ser-530 appears to be a critical determinant of acetylation. 41,60 Mutation of Tyr-385 to Phe reduces aspirin acetylation of the serine hydroxyl by 93%. 58 Tyr-385 hydrogen-bonds to the acetyl group of aspirin, which increases its reactivity by stabilizing the negative charge of the tetrahedral intermediate of acetylation.…”

Section: Cyclooxygenase Enzymes: Structure and Mechanismsmentioning

confidence: 99%

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Structural and Functional Basis of Cyclooxygenase Inhibition

2007

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Section: Cyclooxygenase Enzymes: Structure and Mechanismsmentioning

confidence: 99%

Section: Cyclooxygenase Enzymes: Structure and Mechanismsmentioning

confidence: 99%

Structural and Functional Basis of Cyclooxygenase Inhibition

2007

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“…It is also known as prostaglandin endoperoxide H synthase, COX is responsible for both the cyclooxygenase reaction, in which arachidonic acid is converted to prostaglandin G2 (PGG2), and the peroxidase reaction, in which this intermediate undergoes a bi-electron reduction to PGH2 (Kiefer et al, 2000). Two forms of COX have been identified, which are encoded by distinct genes, but which exhibit structural and enzymatic similarities.…”

Section: Introductionmentioning

confidence: 99%

Methyl-β-cyclodextrin inhibits cell growth and cell cycle arrest via a prostaglandin E(2) independent pathway

Choi

Chin²,

Rhee³

et al. 2004

Exp Mol Med

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A bstractMethyl-β-cyclodextrin, a cyclic oligosaccharide know n for its interaction w ith the plasm a m em brane induces several events in cells including cell growth and anti-tum or activity. In this study, w e have investigated the possible role of cyclooxygenase 2 (COX-2) in cell growth arrest induced by m ethyl-β-cyclodextrin in Raw264.7 macrophage cells. M ethyl-β-cyclodextrin inhibited cell grow th and arrested the cell cycle, and this cell cycle arrest reduced the population of cells in the S phase, and concom itantly reduced cyclin A and D expressions. M ethyl-β-cyclodextrin in a dose-and tim e-dependent manner, also induced COX-2 expression, prostaglandin E 2 (PG E 2 ) synthesis, and CO X-2 prom oter activity. Pretreatm ent of cells w ith NS398, a CO X-2 specific inhibitor com pletely blocked PG E 2 synthesis induced by m ethyl-β-cyclodextrin, how ever inhibition on cell proliferation and cell cycle arrest w as not effected, suggesting nonas so cia tio n o f C O X -2 in th e ce ll cy cle arres t. These results suggest that m ethyl-β-cyclodextrin induced cell growth inhibition and cell cycle arrest in Raw 264.7 cells m ay be m ediated by cyclin A and D1 expression.

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“…COX-2 has an epidermal growth factor (EGF)-like domain at its NH 2 terminus that functions in Ca 2+ -related signaling pathways such as the protein kinase C (PKC) pathway, whereas the COOH terminus has a peroxidase domain that acts in cellular oxidation and reduction. Thus, COX-2 is a bifunctional enzyme that has both cyclooxygenase and peroxidase activities (10,11). Cyclooxygenase activity of COX-2 transforms arachidonic acid into intermediate prostaglandin G 2 , which is subsequently converted to prostaglandin H 2 through peroxidase activity, and finally, prostaglandins [prostaglandin E 2 (PGE 2 ), prostaglandin D 2 , prostaglandin F 2 α, thromboxane A, etc.]…”

Section: Introductionmentioning

confidence: 99%

Cyclooxygenase-2 (COX-2) Negatively Regulates Expression of Epidermal Growth Factor Receptor and Causes Resistance to Gefitinib in COX-2–Overexpressing Cancer Cells

Kim

Park

Pyo

2009

Molecular Cancer Research

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Overexpression of cyclooxygenase-2 (COX-2) and epidermal growth factor receptor (EGFR) has been detected in many types of cancer. Although COX-2 and EGFR are closely related to each other, the exact mechanism of COX-2 in tumors has not been well understood. In this study, we investigated the relationship between COX-2 and EGFR in cancer cells. Using two cell lines stably overexpressing COX-2 (HCT-116-COX-2 and H460-COX-2) and a stable line of COX-2 knockdown MOR-P cells, we analyzed patterns of COX-2 and EGFR expression. To observe the effects of COX-2 on EGFR expression and activity, we did comparative analyses after treatment with various drugs (EGF, celecoxib, prostaglandin E 2 , gefitinib, Ro-31-8425, PD98059, and SP600125) in HCT-116-Mock versus HCT-116-COX-2 cells and H460-Mock versus H460-COX-2 cells. Overexpression of COX-2 specifically down-regulated EGFR expression at the level of transcription. COX-2-overexpressing cells have a decreased sensitivity to gefitinib. COX-2 induced activation of extracellular signal-regulated kinase (ERK) and c-Jun NH 2 -terminal kinase (JNK) but suppressed Akt activation. JNK inhibition by SP600125, a specific JNK inhibitor, resulted in restoration of EGFR levels in COX-2-overexpressing cells, whereas ERK inhibition by PD98059 did not. Overexpressed COX-2 negatively regulates EGFR expression via JNK activation, leading to gefitinib resistance. COX-2 may also regulate ERK activity independently of EGFR. Therefore, resistance of COX-2-overexpressing cells to gefitinib may be due to decreased expression of EGFR by JNK activation and EGFR-independent elevation of ERK activity by COX-2. The ability of COX-2 to inhibit EGFR expression and gefitinib effects may have significance in clinical cancer therapy.

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Structural insights into the stereochemistry of the cyclooxygenase reaction

Cited by 224 publications

References 28 publications

Structural and Functional Basis of Cyclooxygenase Inhibition

Structural and Functional Basis of Cyclooxygenase Inhibition

Methyl-β-cyclodextrin inhibits cell growth and cell cycle arrest via a prostaglandin E(2) independent pathway

Cyclooxygenase-2 (COX-2) Negatively Regulates Expression of Epidermal Growth Factor Receptor and Causes Resistance to Gefitinib in COX-2–Overexpressing Cancer Cells

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