The Experts below are selected from a list of 174 Experts worldwide ranked by ideXlab platform
Ahlim Tsai - One of the best experts on this subject based on the ideXlab platform.
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a quantum chemical study of the synthesis of Prostaglandin g2 by the cyclooxygenase active site in Prostaglandin Endoperoxide h synthase 1
Journal of Physical Chemistry B, 2003Co-Authors: Mattias L Blomberg, Wilfred Adrianus Van Der Donk, Per E M Siegbahn, Ahlim TsaiAbstract:A Quantum Chemical Study of the Synthesis of Prostaglandin G2 by the Cyclooxygenase Active Site in Prostaglandin Endoperoxide H Synthase 1
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a quantum chemical study of the synthesis of Prostaglandin g2 by the cyclooxygenase active site in Prostaglandin Endoperoxide h synthase 1
Journal of Physical Chemistry B, 2003Co-Authors: Mattias L Blomberg, Wilfred Adrianus Van Der Donk, Per E M Siegbahn, Margareta R A Blomberg, Ahlim TsaiAbstract:A Quantum Chemical Study of the Synthesis of Prostaglandin G2 by the Cyclooxygenase Active Site in Prostaglandin Endoperoxide H Synthase 1
Mattias L Blomberg - One of the best experts on this subject based on the ideXlab platform.
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a quantum chemical study of the synthesis of Prostaglandin g2 by the cyclooxygenase active site in Prostaglandin Endoperoxide h synthase 1
Journal of Physical Chemistry B, 2003Co-Authors: Mattias L Blomberg, Wilfred Adrianus Van Der Donk, Per E M Siegbahn, Ahlim TsaiAbstract:A Quantum Chemical Study of the Synthesis of Prostaglandin G2 by the Cyclooxygenase Active Site in Prostaglandin Endoperoxide H Synthase 1
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a quantum chemical study of the synthesis of Prostaglandin g2 by the cyclooxygenase active site in Prostaglandin Endoperoxide h synthase 1
Journal of Physical Chemistry B, 2003Co-Authors: Mattias L Blomberg, Wilfred Adrianus Van Der Donk, Per E M Siegbahn, Margareta R A Blomberg, Ahlim TsaiAbstract:A Quantum Chemical Study of the Synthesis of Prostaglandin G2 by the Cyclooxygenase Active Site in Prostaglandin Endoperoxide H Synthase 1
Wilfred Adrianus Van Der Donk - One of the best experts on this subject based on the ideXlab platform.
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a quantum chemical study of the synthesis of Prostaglandin g2 by the cyclooxygenase active site in Prostaglandin Endoperoxide h synthase 1
Journal of Physical Chemistry B, 2003Co-Authors: Mattias L Blomberg, Wilfred Adrianus Van Der Donk, Per E M Siegbahn, Ahlim TsaiAbstract:A Quantum Chemical Study of the Synthesis of Prostaglandin G2 by the Cyclooxygenase Active Site in Prostaglandin Endoperoxide H Synthase 1
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a quantum chemical study of the synthesis of Prostaglandin g2 by the cyclooxygenase active site in Prostaglandin Endoperoxide h synthase 1
Journal of Physical Chemistry B, 2003Co-Authors: Mattias L Blomberg, Wilfred Adrianus Van Der Donk, Per E M Siegbahn, Margareta R A Blomberg, Ahlim TsaiAbstract:A Quantum Chemical Study of the Synthesis of Prostaglandin G2 by the Cyclooxygenase Active Site in Prostaglandin Endoperoxide H Synthase 1
William L. Smith - One of the best experts on this subject based on the ideXlab platform.
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Peroxidase site of Prostaglandin Endoperoxide H synthase-1: Docking and molecular dynamics studies with a Prostaglandin Endoperoxide analog
The Journal of Physical Chemistry B, 2004Co-Authors: Steve A. Seibold, William L. Smith, Robert I. CukierAbstract:Prostaglandin Endoperoxide H synthases-1 and -2 (PGHS-1 and PGHS-2) catalyze the first step in the biosynthetic pathway that produces Prostaglandins and thromboxanes. The fatty acid Endoperoxide/hydroperoxide substrate, PGG2, binds on the distal side of the heme that forms the peroxidase (POX) site of PGHSs and generates the alcohol PGH2 by cleaving the oxygen−oxygen bond of the 15-hydroperoxide group. The structure of the POX site of PGHS, as with other peroxidases, includes the invariant distal histidine residue His207 and a glutamine, Gln203. We report the first molecular dynamics (MD) simulation of a PGG2 analogue (pseudo-PGG2) bound to the peroxidase site of PGHS-1; pseudo-PGG2 lacks the Endoperoxide group and double bonds of PGG2 but is otherwise identical to PGG2. In the MD of the substrate-free state of PGHS-1, a water migrated to the heme active site to become the sixth ligand of the iron, and in time, it hydrogen bonded to other waters, forming chains that extended into the bulk solvent. A locat...
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the enzymology of Prostaglandin Endoperoxide h synthases 1 and 2
Prostaglandins & Other Lipid Mediators, 2002Co-Authors: William L. Smith, Inseok SongAbstract:We summarize the enzymological properties of Prostaglandin Endoperoxide H synthases (PGHs)-1 and -2, the enzymes that catalyze the committed step in Prostaglandin biosynthesis. These isoenzymes are closely related structurally and mechanistically. Each catalyzes a peroxidase and a cyclooxygenase reaction at spatially separate but neighboring, electronically interrelated active sites. The peroxidase is necessary to activate the cyclooxygenase; oxidation of the heme group of the peroxidase by peroxide leads to oxidation of a cyclooxygenase active site tyrosine. The tyrosine radical abstracts hydrogen from arachidonic acid to form an arachidonate radical which reacts sequentially with two oxygen molecules forming the intermediate product PGG2. PGG2 is then reduced by the peroxidase activity to PGH2. Based on the crystal structure of PGHS-1 arachidonate complex, it is now possible to envision how arachidonate is bound and oxygenation occurs. Recently, it has become possible to distinguish kinetically between the cyclooxygenase and peroxidase suicide inactivation reactions.
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A Novel Method for Prostaglandin Endoperoxide H Synthase Activity in Individual Intact Cells
Advances in experimental medicine and biology, 1997Co-Authors: Ikuo Morita, Sei-itsu Murota, Melvin Schindler, David L. Dewitt, William L. SmithAbstract:Prostaglandins are key mediators of inflammation1. Prostaglandin Endoperoxide H is synthesized by two related Prostaglandin Endoperoxide H synthases (PGHS-1 and PGHS-2, COX-1 and COX-2). PGHS-1 is a constitutive enzyme present in many but not all mammalian cells2. PGHS-2 is undetectable in most mammalian tissues, but expression of this isozyme can be induced by cytokines, growth factors, and tumor promoters3. This means that PGHS-2 will be closely related with inflammation. Therefore, a development of nonsteroidal anti-inflammatory drugs (NSAIDs) which inhibit PGHS-2 specifically is undergoing in the world. In the present paper, we will show a novel and convenient method for PGHS activity in intact individual cells.
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Prostaglandin Endoperoxide h synthases 1 and 2
Advances in Immunology, 1996Co-Authors: William L. Smith, David L. DewittAbstract:Publisher Summary The chapter compares and contrasts the structural and kinetic properties of Prostaglandin Endoperoxide H synthase-1 (PGHS-1) and -2. It also discusses the description of the interactions of the two isozymes with nonsteroidal anti-inflammatory drugs (NSAIDs). There are three general areas of study important to understanding more about PGHS isozymes: mechanisms of catalysis, regulation of gene expression, and subcellular functional independence. The chapter also explain how is arachidonic acid specifically channeled to PGHS-2 following mobilization in cells in response to TPA and how is the localization of PGHS-2 in the nuclear envelope important for PGHS-2 functioning. The chapter also describes the structures and regulation of expression of the PGHS-1 and -2 genes. The concepts that PGHS-1 and PGHS-2 represent two separate Prostaglandin biosynthetic pathways and two separate Prostaglandin signaling pathways need to be tested. The chapter also discusses how the two isozymes may act independently in intact cells to mediate the formation of prostanoids destined to act on cell surface and/or nuclear targets to mediate different biological and pathobiological events.
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selective inhibition of Prostaglandin Endoperoxide synthase 1 cyclooxygenase 1 by valerylsalicylic acid
Archives of Biochemistry and Biophysics, 1995Co-Authors: D K Bhattacharyya, M Lecomte, J Dunn, D J Morgans, William L. SmithAbstract:Aspirin causes a time-dependent inhibition of Prostaglandin Endoperoxide H synthases (PGHS)-1 and -2 by acetylating active site serines present in both isozymes. In the case of PGHS-1, aspirin acetylation blocks cyclooxygenase activity, apparently by preventing arachidonate binding to the cyclooxygenase active site. With PGHS-2, acetylation does not block substrate binding but rather alters the enzyme in such a way that the acetylated form of PGHS-2 produces 15R-hydroxy-eicosatetraenoic acid (15R-HETE) instead of the usual Prostaglandin Endoperoxide product. Based on these differences between PGHS-1 and PGHS-2, we reasoned that a salicylate ester containing an acyl group somewhat larger than the acetyl group of aspirin might be a selective inhibitor of PGHS-2. Accordingly, we prepared and tested eight different acyl salicylates as inhibitors of human (h) PGHS-1 and -2 expressed transiently in cos-1 cells. Valeryl(pentanoyl)salicylate (VSA) was the only compound in this series which showed isozyme selectivity, and, surprisingly, VSA inhibited hPGHS-1 much more effectively than hPGHS-2. Inhibition of hPGHS-1 by VSA was time-dependent. VSA also inhibited ovine PGHS-1 but did not inhibit the S530A mutant of ovine PGHS-1. This latter mutant, which lacks the active site serine hydroxyl group, is also refractory to inhibition by acetylsalicylate. Thus, we conclude that VSA acylates the active site serine of PGHS-1, VSA inhibited prostanoid synthesis by serum-starved murine NIH 3T3 cells which express only PGHS-1; in contrast, VSA caused only partial inhibition of prostanoid synthesis by serum-stimulated 3T3 cells which express both PGHS isozymes. Our results establish that VSA can be used as a reasonably selective inhibitor of PGHS-1.
Tadashi Tanabe - One of the best experts on this subject based on the ideXlab platform.
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the cyclic amp response element plays an essential role in the expression of the human Prostaglandin Endoperoxide synthase 2 gene in differentiated u937 monocytic cells
FEBS Letters, 1994Co-Authors: Hiroyuki Inoue, Shuntaro Hara, Chieko Yokoyama, Toyomichi Nanayama, Tadashi TanabeAbstract:The promoter activity of 1432 bp upstream of the human Prostaglandin-Endoperoxide synthase 2 gene (PTGS2) was examined in differentiated U937 monocytic cells expressing Prostaglandin-Endoperoxide synthase 2 mRNA. Transient transfection experiments were performed using these cells and reporter vectors containing the upstream region of the gene with deletions or site-specific mutations and the luciferase gene. The deletion or destruction of the cyclic AMP response element (nucleotides −59 to −53) markedly reduced the promoter activity of this gene. Electrophoretic mobility shift assays showed that a nuclear protein(s) binding to the cyclic AMP response element was induced during monocytic differentiation of U937 cells. These results indicate that expression of the human Prostaglandin-Endoperoxide synthase 2 gene in differentiated U937 monocytic cells is regulated by the cyclic AMP response element.
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characterization of the human gene ptgs2 encoding Prostaglandin Endoperoxide synthase 2
FEBS Journal, 1994Co-Authors: Tetsuya Kosaka, Atsuro Miyata, Hayato Ihara, Shuntaro Hara, Tamiko Sugimoto, Osamu Takeda, Eiichi Takahashi, Tadashi TanabeAbstract:The human gene (PTGS2) encoding an inducible isozyme of Prostaglandin-Endoperoxide synthase (Prostaglandin-Endoperoxide synthase 2) that is distinct from the well-characterized and constitutive isozyme (Prostaglandin-Endoperoxide synthase 1), was isolated using a polymerase-chain reaction-generated cDNA fragment probe for human Prostaglandin-Endoperoxide synthase 2. Nucleotide sequence analysis of the entire human Prostaglandin-Endoperoxide-synthase-2 gene demonstrated that it is more than 8.3 kb in size and consists of ten exons; this gene is very similar to the murine and chicken Prostaglandin-Endoperoxide-synthase-2 genes. The structures of exons in the human Prostaglandin-Endoperoxide-synthase-2 gene were also similar to those of the human Prostaglandin-Endoperoxide-synthase-1 gene (PTGS1). However, the sizes of introns in the human Prostaglandin-Endoperoxide-synthase-2 gene were generally smaller than those of the human Prostaglandin-Endoperoxide-synthase-1 gene. Primer-extension analysis indicated that the transcriptional-start site is 134 bases upstream of the translational-initiation site. The sequence of the 1.69-kb region of nucleotides preceding the transcriptional-start site and the first 0.8-kb intron contained a canonical TATA box and various transcriptional-regulatory elements (CArG box, NF-IL6, PEA-1, myb, GATA-1, xenobiotic-response element, cAMP-response element, NF-kappa B, PEA-3, Sp-1 and 12-O-tetradecanoyl-phorbol-13-acetate-response element). The nucleotide sequence of the 5'-flanking region (275 bp) of the human Prostaglandin-Endoperoxide-synthase-2 gene showed 63% similarity to the sequence of murine Prostaglandin-Endoperoxide-synthase-2/TIS10 gene, but essentially no homology to the chicken Prostaglandin-Endoperoxide-synthase-2 gene, and human and murine Prostaglandin-Endoperoxide-synthase-1 genes. A fluorescence in situ hybridization study showed that the human genes coding for Prostaglandin-Endoperoxide synthase 1 (PTGS1) and Prostaglandin-endoperoxidase synthase 2 (PTGS2) were mapped to distinct chromosomes 9q32-q33.3 and 1q25.2-q25.3, respectively, indicating that these genes are not genetically linked.
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Characterization of the human gene (PTGS2) encoding Prostaglandin‐Endoperoxide synthase 2
European journal of biochemistry, 1994Co-Authors: Tetsuya Kosaka, Atsuro Miyata, Hayato Ihara, Shuntaro Hara, Tamiko Sugimoto, Osamu Takeda, Eiichi Takahashi, Tadashi TanabeAbstract:The human gene (PTGS2) encoding an inducible isozyme of Prostaglandin-Endoperoxide synthase (Prostaglandin-Endoperoxide synthase 2) that is distinct from the well-characterized and constitutive isozyme (Prostaglandin-Endoperoxide synthase 1), was isolated using a polymerase-chain reaction-generated cDNA fragment probe for human Prostaglandin-Endoperoxide synthase 2. Nucleotide sequence analysis of the entire human Prostaglandin-Endoperoxide-synthase-2 gene demonstrated that it is more than 8.3 kb in size and consists of ten exons; this gene is very similar to the murine and chicken Prostaglandin-Endoperoxide-synthase-2 genes. The structures of exons in the human Prostaglandin-Endoperoxide-synthase-2 gene were also similar to those of the human Prostaglandin-Endoperoxide-synthase-1 gene (PTGS1). However, the sizes of introns in the human Prostaglandin-Endoperoxide-synthase-2 gene were generally smaller than those of the human Prostaglandin-Endoperoxide-synthase-1 gene. Primer-extension analysis indicated that the transcriptional-start site is 134 bases upstream of the translational-initiation site. The sequence of the 1.69-kb region of nucleotides preceding the transcriptional-start site and the first 0.8-kb intron contained a canonical TATA box and various transcriptional-regulatory elements (CArG box, NF-IL6, PEA-1, myb, GATA-1, xenobiotic-response element, cAMP-response element, NF-kappa B, PEA-3, Sp-1 and 12-O-tetradecanoyl-phorbol-13-acetate-response element). The nucleotide sequence of the 5'-flanking region (275 bp) of the human Prostaglandin-Endoperoxide-synthase-2 gene showed 63% similarity to the sequence of murine Prostaglandin-Endoperoxide-synthase-2/TIS10 gene, but essentially no homology to the chicken Prostaglandin-Endoperoxide-synthase-2 gene, and human and murine Prostaglandin-Endoperoxide-synthase-1 genes. A fluorescence in situ hybridization study showed that the human genes coding for Prostaglandin-Endoperoxide synthase 1 (PTGS1) and Prostaglandin-endoperoxidase synthase 2 (PTGS2) were mapped to distinct chromosomes 9q32-q33.3 and 1q25.2-q25.3, respectively, indicating that these genes are not genetically linked.
