The Experts below are selected from a list of 147 Experts worldwide ranked by ideXlab platform
Mattias L Blomberg - One of the best experts on this subject based on the ideXlab platform.
-
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, Per E M Siegbahn, Wilfred Adrianus Van Der Donk, 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.
-
Synthesis of 7-thiaarachidonic acid as a mechanistic probe of Prostaglandin H synthase-2
Bioorganic & Medicinal Chemistry Letters, 2007Co-Authors: Chris M. Mcginley, Cyril Jacquot, Wilfred Adrianus Van Der DonkAbstract:The mechanism by which Prostaglandin synthase converts arachidonic acid to Prostaglandin G2, creating five new chiral centers in the process, is still incompletely understood. The first radical intermediate has been characterized by EPR spectroscopy but subsequent proposed intermediates have not succumbed to detection. We report the synthesis of 7-thiaarachidonic acid designed to stabilize one of the proposed radical intermediates, which may allow its detection.
-
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, Per E M Siegbahn, Wilfred Adrianus Van Der Donk, Ahlim TsaiAbstract:A Quantum Chemical Study of the Synthesis of Prostaglandin G2 by the Cyclooxygenase Active Site in Prostaglandin Endoperoxide H Synthase 1
-
Synthesis of isotopically labeled arachidonic acids to probe the reaction mechanism of Prostaglandin H synthase
Journal of the American Chemical Society, 2002Co-Authors: Sheng Peng, Ahlim Tsai, Richard J Kulmacz, Gang Wu, Nicole M. Okeley, Wilfred Adrianus Van Der DonkAbstract:Prostaglandin H synthase (PGHS) catalyzes the conversion of arachidonic acid to Prostaglandin G2 in the cyclooxygenase reaction. The first step of the mechanism has been proposed to involve abstraction of the pro-S hydrogen atom from C13 to generate a pentadienyl radical spanning C11−C15. We report here the synthesis of six site-specifically deuterated arachidonic acids to investigate the structure of the radical intermediate. The preparation of these compounds was achieved using a divergent scheme that involved one advanced intermediate for all targets. The synthetic design introduced the label late in the routes and allowed the utilization of common synthetic intermediates in the preparation of various targets. Both 13(R)- and 13(S)-deuterium-labeled arachidonic acids were synthesized in high enantiomeric purity as deduced from soybean lipoxygenase assays and mass spectrometric analysis of the resulting enzymatic products. Each synthetic compound was reacted under anaerobic conditions with the wide sing...
Ahlim Tsai - One of the best experts on this subject based on the ideXlab platform.
-
Kinetic Isotope Effect of Prostaglandin H Synthase Exhibits Inverted Temperature Dependence
Catalysts, 2014Co-Authors: Gang Wu, Richard J Kulmacz, Ahlim TsaiAbstract:Conversion of arachidonic acid to Prostaglandin G2/H2 catalyzed by Prostaglandin H synthase (PGHS) is proposed to involve initial transfer of the C13 pro-(S) hydrogen atom from arachidonate to the Tyr385 radical in PGHS, followed by insertion of two oxygen molecules and several chemical bond rearrangements. The initial hydrogen-transfer was recently concluded to be a rate-limiting step in cyclooxygenase catalysis based on the observed intrinsic deuterium kinetic isotope effect values (Dkcat). In the present study, we have found that Dkcat values of both PGHS-1 and -2 show an unusual increase with temperatures in the range of 288–310 K, exhibiting an inverted temperature dependence. The value of lnDkcat, however, decreased linearly with 1/T, consistent with a typical Arrhenius relationship.
-
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, Per E M Siegbahn, Wilfred Adrianus Van Der Donk, Ahlim TsaiAbstract:A Quantum Chemical Study of the Synthesis of Prostaglandin G2 by the Cyclooxygenase Active Site in Prostaglandin Endoperoxide H Synthase 1
-
Synthesis of isotopically labeled arachidonic acids to probe the reaction mechanism of Prostaglandin H synthase
Journal of the American Chemical Society, 2002Co-Authors: Sheng Peng, Ahlim Tsai, Richard J Kulmacz, Gang Wu, Nicole M. Okeley, Wilfred Adrianus Van Der DonkAbstract:Prostaglandin H synthase (PGHS) catalyzes the conversion of arachidonic acid to Prostaglandin G2 in the cyclooxygenase reaction. The first step of the mechanism has been proposed to involve abstraction of the pro-S hydrogen atom from C13 to generate a pentadienyl radical spanning C11−C15. We report here the synthesis of six site-specifically deuterated arachidonic acids to investigate the structure of the radical intermediate. The preparation of these compounds was achieved using a divergent scheme that involved one advanced intermediate for all targets. The synthetic design introduced the label late in the routes and allowed the utilization of common synthetic intermediates in the preparation of various targets. Both 13(R)- and 13(S)-deuterium-labeled arachidonic acids were synthesized in high enantiomeric purity as deduced from soybean lipoxygenase assays and mass spectrometric analysis of the resulting enzymatic products. Each synthetic compound was reacted under anaerobic conditions with the wide sing...
Jan Svensson - One of the best experts on this subject based on the ideXlab platform.
-
Physiological Role of an Endoperoxide in Due to Platelet Cyclo-Oxygenase Deficient
2016Co-Authors: Curt Malmsten, Mats Hamberg, Jan SvenssonAbstract:The endoperoxide Prostaglandin G2 (PGG2) induced platelet aggregation as well as the platelet release reaction (release of ADP and serotonin) when added to human platelet-rich plasma. Formation of a metabolite of PGG2 (8-(l-hydroxy-3-oxopropyl)-9,12L-dihydroxy-5,10- heptadecadienoic acid) and a lipoxygenase product (12L- hydroxy-5,8,10,14-eicosatetraenoic acid) accompanied the release reaction caused by aggregating agents such as col- lagen, ADP, epinephrine, and thrombin. Indomethacin inhibited the release reaction and PGG2 formation in- duced by these agents but had no effect on PGG2-induced release reaction. The aggregating effect of PGG2 was abol- ished by furosemide, which is a competitive inhibitor of ADP-induced primary aggregation. These data indicate that the aggregating effect of PGG2 is due to release of ADP and that PGG2 synthesis is required for induction of the release reaction by various aggregating agents. A subject with a hemostatic defect due to abnormal re- lease mechanism (decreased aggregation with epinephrine (second wave) and collagen and normal platelet ADP) had a deficiency of the cyclo-oxygenase that catalyzes forma- tion of PGG2. Normal aggregation and release reaction were obtained with added PGG2. It is concluded that the endoperoxide (PGG2) is essential in normal hemostasis because of its role in initiating the release reaction required for aggregation by collagen and the second wave of aggregation caused by, e.g., ADP.
-
Isolation and Structure of Two Prostaglandin Endoperoxides That Cause
2016Co-Authors: Mats Hamberg, Jan Svensson, Toshio Wakabayashi, Bengt SamuelssonAbstract:Incubation for a short time of arachidonic acid with the microsomal fraction of a homogenate of the vesicular gland of sheep in the presence of 1 mlMl p-mer- curibenzoate followed by extraction and silicic acid chromatography yielded two Prostaglandin endoper- oxides. The structures of these compounds, i.e., 15-hy- droperoxy-9a ,lla-peroxidoprosta-5,13-dienoic acid (pros- taglandin G2) and 15-hydroxy-9a,lla-peroxidoprosta- 5,13-dienoic acid (Prostaglandin H2), were assigned mainly by a number of chemical transformations into previously known Prostaglandins. The new Prostaglandins were 50- 200 times (Prostaglandin G2) and 100-450 times (prosta- glandin H2) more active than Prostaglandin E2 on the super- fused aorta strip. The half-life of the Prostaglandin endo- peroxides in aqueous medium (about 5 min) was signifi- cantly longer than that of "rabbit aorta-contracting sub- stance" released from guinea pig lung, indicating that none of the Prostaglandin endoperoxides is identical with this factor. Addition of 10-300 ng/ml of the endoperoxides to suspensions of washed human platelets resulted in rapid aggregation. Furthermore, platelet aggregation in- duced by thrombin was accompanied by release of ma- terial reducible by stannous chloride into Prostaglandin F2a, thus indicating the involvement of endogenous Prostaglandin endoperoxides in platelet aggregation. Direct evidence for the formation of an endoperoxide during Prostaglandin (PG) biosynthesis was recently obtained (1).
Mats Hamberg - One of the best experts on this subject based on the ideXlab platform.
-
Physiological Role of an Endoperoxide in Due to Platelet Cyclo-Oxygenase Deficient
2016Co-Authors: Curt Malmsten, Mats Hamberg, Jan SvenssonAbstract:The endoperoxide Prostaglandin G2 (PGG2) induced platelet aggregation as well as the platelet release reaction (release of ADP and serotonin) when added to human platelet-rich plasma. Formation of a metabolite of PGG2 (8-(l-hydroxy-3-oxopropyl)-9,12L-dihydroxy-5,10- heptadecadienoic acid) and a lipoxygenase product (12L- hydroxy-5,8,10,14-eicosatetraenoic acid) accompanied the release reaction caused by aggregating agents such as col- lagen, ADP, epinephrine, and thrombin. Indomethacin inhibited the release reaction and PGG2 formation in- duced by these agents but had no effect on PGG2-induced release reaction. The aggregating effect of PGG2 was abol- ished by furosemide, which is a competitive inhibitor of ADP-induced primary aggregation. These data indicate that the aggregating effect of PGG2 is due to release of ADP and that PGG2 synthesis is required for induction of the release reaction by various aggregating agents. A subject with a hemostatic defect due to abnormal re- lease mechanism (decreased aggregation with epinephrine (second wave) and collagen and normal platelet ADP) had a deficiency of the cyclo-oxygenase that catalyzes forma- tion of PGG2. Normal aggregation and release reaction were obtained with added PGG2. It is concluded that the endoperoxide (PGG2) is essential in normal hemostasis because of its role in initiating the release reaction required for aggregation by collagen and the second wave of aggregation caused by, e.g., ADP.
-
Isolation and Structure of Two Prostaglandin Endoperoxides That Cause
2016Co-Authors: Mats Hamberg, Jan Svensson, Toshio Wakabayashi, Bengt SamuelssonAbstract:Incubation for a short time of arachidonic acid with the microsomal fraction of a homogenate of the vesicular gland of sheep in the presence of 1 mlMl p-mer- curibenzoate followed by extraction and silicic acid chromatography yielded two Prostaglandin endoper- oxides. The structures of these compounds, i.e., 15-hy- droperoxy-9a ,lla-peroxidoprosta-5,13-dienoic acid (pros- taglandin G2) and 15-hydroxy-9a,lla-peroxidoprosta- 5,13-dienoic acid (Prostaglandin H2), were assigned mainly by a number of chemical transformations into previously known Prostaglandins. The new Prostaglandins were 50- 200 times (Prostaglandin G2) and 100-450 times (prosta- glandin H2) more active than Prostaglandin E2 on the super- fused aorta strip. The half-life of the Prostaglandin endo- peroxides in aqueous medium (about 5 min) was signifi- cantly longer than that of "rabbit aorta-contracting sub- stance" released from guinea pig lung, indicating that none of the Prostaglandin endoperoxides is identical with this factor. Addition of 10-300 ng/ml of the endoperoxides to suspensions of washed human platelets resulted in rapid aggregation. Furthermore, platelet aggregation in- duced by thrombin was accompanied by release of ma- terial reducible by stannous chloride into Prostaglandin F2a, thus indicating the involvement of endogenous Prostaglandin endoperoxides in platelet aggregation. Direct evidence for the formation of an endoperoxide during Prostaglandin (PG) biosynthesis was recently obtained (1).
