Intimate Relation between Cyclooxygenase and Peroxidase Activities of Prostaglandin H Synthase. Peroxidase Reaction of Ferulic Acid and Its Influence on the Reaction of Arachidonic Acid

Bakovic, Marica; Dunford, H. Brian

doi:10.1021/bi00187a013

Cited by 37 publications

(58 citation statements)

References 26 publications

(29 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…There has been considerable experimental debate about whether the Tyr-385 radical is regenerated at the end of each cyclooxygenase catalytic cycle or requires reoxidation by another peroxidase catalytic cycle (29,30). Detailed kinetic investigations confirm observations extant at the onset of the debate that strongly support the regeneration of the catalytic tyrosyl radical at the end of each cycle of arachidonic acid oxidation (4,31,32).…”

Section: Cyclooxygenase Catalysismentioning

confidence: 58%

Arachidonic Acid Oxygenation by COX-1 and COX-2

Marnett

Rowlinson

Goodwin

et al. 1999

Journal of Biological Chemistry

481

285

View full text Add to dashboard Cite

Prostaglandins were discovered in human semen in 1930, but their low concentrations and instability precluded identification for nearly 30 years (for a brief historical review, see Ref. 1). Once they were identified, it was clear they arose from polyunsaturated fatty acids by a complex series of reactions involving oxygenation, cyclization, and the generation of five chiral centers from an achiral substrate. The mechanism of prostaglandin biosynthesis was outlined in 1967 by Hamberg and Samuelsson (2), and the basic tenets have been confirmed in subsequent studies. The key step in their proposed mechanism was the formation of bicyclic peroxides (endoperoxides) as the initial products of polyunsaturated fatty acid oxygenation (Fig. 1). The term cyclooxygenase (COX) 1, 2 was coined to describe the enzyme that carried out this complex chemical transformation, and its role was confirmed by the isolation of prostaglandin endoperoxides in 1973 (3, 4).In addition to catalyzing a fascinating metabolic transformation, COX is an enormously important pharmacological target. Vane reported in 1971 (5) that non-steroidal anti-inflammatory drugs (NSAIDs) inhibit prostaglandin formation and demonstrated that their relative inhibitory potency in vitro correlates to their antiinflammatory activity in vivo. This not only explained the beneficial activity of NSAIDs but also their side effects such as gastrointestinal toxicity and bleeding because prostaglandins and related molecules (i.e. thromboxane) are involved in a very broad range of physiological and pathophysiological responses. The importance of these molecules as autocrine and paracrine mediators has been confirmed recently by the phenotypes of mice bearing targeted deletions in COX genes or prostaglandin receptor genes.The discovery of a second gene (COX-2) coding for cyclooxygenase and the demonstration that its protein product is distributed differently from the originally discovered enzyme (COX-1) raised the possibility that some of the beneficial effects of NSAIDs may be separable from their side effects by development of isoform-selective inhibitors (6 -9). This hypothesis has been dramatically validated by the demonstration that selective COX-2 inhibitors are anti-inflammatory and analgesic but lack the gastric toxicity associated with all currently available NSAIDs (10, 11). Cyclooxygenase CatalysisSubstantial evidence supports the hypothesis that COX oxygenates arachidonic acid by a free radical mechanism (Fig. 1). Thus, COX appears to have co-opted the process that gives rise to isoprostanes to generate prostaglandins. The major differences between COX-catalyzed and spontaneous oxidation of arachidonic acid are the increased rate and high degree of stereochemical control of the enzymatic reaction (1 of 64 possible isomers predominates). Thus, the overall role of COX is rather simple: stereospecifically remove the 13-pro-S-hydrogen and control the stereochemistry of oxygenation. How does it do this?Oxidizing Agent-A protein tyrosyl radical appears to be the oxidiz...

show abstract

Section: Cyclooxygenase Catalysismentioning

confidence: 58%

Arachidonic Acid Oxygenation by COX-1 and COX-2

Marnett

Rowlinson

Goodwin

et al. 1999

Journal of Biological Chemistry

481

285

View full text Add to dashboard Cite

show abstract

“…An alternative second model invokes a one to one correspondence between the cyclooxygenase and peroxidase activities ( Figure 18B). 328 In this case two cosubstrates are required at the end of the cyclooxygenase reaction to reduce the oxoferryl-heme and Tyr • back to the resting state. The hydroperoxide, PGG 2 , is therefore not a priming reagent, but is essential for each catalytic step.…”

Section: B Proposed Role Of the Tyrosyl Radical In Catalysismentioning

confidence: 99%

Protein Radicals in Enzyme Catalysis

1998

View full text Add to dashboard Cite

ContentsI. Introduction 705 II. General Principles 706 A. One Electron Oxidized Amino Acids Thus Far Identified in Proteins 706 B. Biosynthesis of (Modified) Amino Acid Radicals 706 C. Emerging General Chemical Properties of Enzymes Utilizing Protein Radicals for Catalysis 708 D. Methods To Examine Radical Dependent Reactions 710 III. Background on Ribonucleotide Reductases 710 IV. Class I Ribonucleotide Reductases 712 A. Formation of the Tyrosyl Radical 713 B. Function of the Tyrosyl Radical 714 C. Thiyl Radical Involvement in Catalysis 716 D. Evidence for Enzyme-Mediated Radical Chemistry Using Nucleotide Analogues 717 E. Structure 719 V. Class II Ribonucleotide Reductases 719 A. Exchange Reaction: Detection of the Elusive Thiyl Radical 719 B. Role of the Thiyl Radical in Catalysis 721 VI. Pyruvate Formate Lyase 722 A. Characterization of the Glycyl Radical 723 B. Formation of the Glycyl Radical 723 C. Catalytic Mechanism 724 D. Enzyme-Mediated Radical Chemistry with Pyruvate Analogues 727 VII. Anaerobic Ribonucleotide Reductase 728 A. Background 728 B. Requirement for a Glycyl Radical 728 C. Mechanism of Nucleotide Reduction 729 VIII. Cytochrome c Peroxidase 730 A. Formation of the Ferryl Heme/Tryptophan Cation Radical 730 B. Proposed Function of the Tryptophan Radical in Electron Transfer 731 IX. Prostaglandin H Synthase 733 A. Structure: A Tyrosine Residue Revealed 733 B. Proposed Role of the Tyrosyl Radical in Catalysis 734 X. Photosynthetic Oxygen Evolution 736 A. Background 736 B. Proposed Roles of Tyrosyl Radicals Y Z • and Y D • 737 C. Spectroscopic Studies on Y Z • and Y D • 738 D. Proposed Mechanisms for Water Oxidation and O 2 Evolution 739 XI. Galactose Oxidase 741 A. Different Redox States of Galactose Oxidase 741 B. Structure: A Modified Tyrosine Residue Revealed 742 C. Is the Oxidized Amino Acid Associated with Apo Oxidized GAO the Novel Ortho-Thiol-Substituted Tyrosine? 743 D. Catalytic Mechanism 743 XII. Quinoproteins 744 A. Copper-Dependent Amine Oxidases 744 B. Methylamine Dehydrogenase 749 XIII. Other Systems in Which Protein-Based Radicals Have Been Proposed or Detected 751 A. Bovine Liver Catalase 751 B. DNA Photolyase 751 C. Dopamine β Monooxygenase 752 XIV. Summary and Outlook 754 XV. Abbreviations 754 XVI. Acknowledgments 755 XVII. References 755 JoAnne Stubbe is the Novartis professor of Chemistry and Biology at the Massachusetts Institute of Technology. She received her undergraduate degree from the University of Pennsylvania working with Ed Thornton and did NSF-sponsored undergraduate research with Ed Trachtenberg at Clark University. These mentors played a strong role in her interest in physical organic chemistry. She received her Ph.D.

show abstract

“…The algal PGHS suggests that the His386Arg substitution is not critical for peroxidase activity. The cyclooxygenase and peroxidase activities in mammalian PGHS are coupled [101]; this peroxidase cycle is prerequisite for the formation of the tyrosyl radical needed to catalyzes cyclooxygenase activity and subsequent self-inactivation. Second, a second tyrosine radical species has been characterized that originates at Tyr504 and is functionally important for both isoforms of mammalian PGHS [102,103].…”

Section: The Peroxidase Active Sitementioning

confidence: 99%

Bacterial and algal orthologs of prostaglandin H2 synthase: novel insights into the evolution of an integral membrane protein

Gupta

Selinsky

2015

Biochimica et Biophysica Acta (BBA) - Biomembranes

View full text Add to dashboard Cite

Prostaglandin H₂synthase (PGHS; EC 1.14.99.1), a bi-functional heme enzyme that contains cyclooxygenase and peroxidase activities, plays a central role in the inflammatory response, pain, and blood clotting in higher eukaryotes. In this review, we discuss the progenitors of the mammalian enzyme by using modern bioinformatics and homology modeling to draw comparisons between this well-studied system and its orthologs from algae and bacterial sources. A clade of bacterial and algal orthologs is described that have salient structural features distinct from eukaryotic counterparts, including the lack of a dimerization and EGF-like domains, the absence of gene duplicates, and minimal membrane-binding domains. The functional implications of shared and variant features are discussed.

show abstract

Intimate Relation between Cyclooxygenase and Peroxidase Activities of Prostaglandin H Synthase. Peroxidase Reaction of Ferulic Acid and Its Influence on the Reaction of Arachidonic Acid

Cited by 37 publications

References 26 publications

Arachidonic Acid Oxygenation by COX-1 and COX-2

Arachidonic Acid Oxygenation by COX-1 and COX-2

Protein Radicals in Enzyme Catalysis

Bacterial and algal orthologs of prostaglandin H2 synthase: novel insights into the evolution of an integral membrane protein

Contact Info

Product

Resources

About