Catalysis by Prostaglandin Endoperoxide H Synthases

前列腺素内过氧化物 H 合成酶的催化

• 批准号: 8323415
• 负责人: William L Smith
• 金额: $ 47.06万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-01 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8323415
• 关键词: Adverse drug effect; Adverse effects; Affect; Allosteric Regulation; Amino Acid Sequence; Anabolism; Analgesics; Animals; Anti Inflammatory Analgesics; Arachidonic Acids; Aspirin; Binding; Biochemical; Blood Platelets; Blood Vessels; Cardiac; Cardiovascular system; Catalysis; Cells; Cessation of life; Colon Carcinoma; Commit; Coxibs; Crystallography; Culture Media; Cyclooxygenase Inhibitors; Diclofenac; Diet; Diet Habits; Dietary Fats; Dinoprostone; Eicosapentaenoic Acid; Environment; Enzymes; Epoprostenol; Event; Exhibits; Fatty Acids; Fatty acid glycerol esters; Fibroblasts; Fish Oils; Flurbiprofen; Functional disorder; Genetic; Goals; Human; Ibuprofen; Individual; Inflammation; Inflammatory; Kidney; Lead; Linoleic Acids; Measurement; Measures; Mediating; Molecular; Molecular Conformation; Monounsaturated Fatty Acids; Mus; Naproxen; Non-Steroidal Anti-Inflammatory Agents; Nonesterified Fatty Acids; Oleic Acids; PTGS1 gene; PTGS2 gene; Palmitic Acids; Pharmaceutical Preparations; Pharmacologic Substance; Phospholipids; Physiological; Prostaglandin Endoperoxides; Prostaglandin H2; Prostaglandin Production; Prostaglandins; Prostaglandins I; Protein Isoforms; Public Health; Regulation; Relative (related person); Research; Risk; Saturated Fatty Acids; Stearic Acids; Structure; System; Thromboxane A2; United States National Institutes of Health; Zymosan; adverse outcome; base; celecoxib; clinically relevant; cyclooxygenase 1; dimer; feeding; gastrointestinal; in vivo; inhibitor/antagonist; monomer; overexpression; preference; response; urinary

DESCRIPTION (provided by applicant): Prostaglandin endoperoxide H synthases-1 and -2 (PGHS-1 and -2), also known as cyclooxygenases-1 and -2 (COX-1 and COX-2), catalyze the conversion of arachidonic acid (AA) to prostaglandin H2 (PGH2) in the committed step of prostaglandin (PG) biosynthesis. PGHSs are the primary targets of COX inhibitors, which include nonspecific nonsteroidal anti-inflammatory drugs (nsNSAIDs) and COX-2 specific inhibitors called coxibs. COX inhibitors are the most widely used pharmaceutical agents in the U.S. However, the use of these inhibitors carries significant risks. About 20,000 deaths annually are attributable to adverse effects of these drugs, the molecular basis for which is unknown. Using purified human PGHSs, we have discovered that PGHS activities are modulated through an unusual allosteric mechanism by all common fatty acids (FAs) including those that are not PGHS substrates. FAs can stimulate or inhibit PGHS activity with the specific effect being dependent on the PGHS isoform and the FA. The effects occur at physiologic FA concentrations and are observed in cells as well as with purified enzymes. The biochemical basis for the regulation of PGHSs by FAs involves cross-talk between monomers comprising PGHS homodimers. Although the monomers have identical amino acid sequences, the conformations of the two monomers comprising a PGHS homodimer differ. One monomer binds FAs and behaves as an allosteric monomer while the other acts as the catalytic monomer. Finally and importantly, responses of purified human PGHSs to COX inhibitors are modulated by FAs, again depending on the FA, the inhibitor and the PGHS isoform. With different COX inhibitors, FAs can influence binding of an inhibitor to one or to both monomers. The goals of the proposed research are to determine how PGHSs and their responses to widely used COX inhibitors are affected by FAs at the molecular, cellular and whole animal levels. Our underlying hypothesis is that both in vivo PG production and responses to COX inhibitors are significantly modulated by the milieu of FAs in which the enzymes find themselves-the FA tone--and that this FA environment is importantly influenced by the FA composition of the diet. We presume that every individual establishes a FA tone as a consequence of dietary habits in the context of their genetic background. We speculate that certain FA tones predispose susceptible individuals to adverse consequences of COX inhibitors. We expect that our studies delineating FA/COX inhibitor interactions will be a first step leading to changes in the way COX inhibitors are prescribed to people on different diets and to dietary adjustments to provide for the safer use of COX inhibitors.

描述（由申请人提供）：前列腺素内过氧化物氧化酶H合酶-1和-2（PGHS-1和-2），也称为环氧酶-1和-2（COX-1和-2（COX-1和COX-2）），在Prostaglandin H2（PGH2）中催化了蛛网膜酸（AA）在Prostage consitted Steptag的步骤（aa）的转化。 PGHS是COX抑制剂的主要靶标，其中包括非特异性非甾体类抗炎药（NSNSAID）和称为Coxibs的COX-2特异性抑制剂。 COX抑制剂是美国使用最广泛的药物，但是，这些抑制剂的使用具有很大的风险。每年约有20,000例死亡归因于这些药物的不良影响，这是未知的分子基础。 使用纯化的人类PGHS，我们发现PGHS活性是通过所有常见的脂肪酸（FAS）通过异常的变构机制调节的，包括那些不是PGHS底物的脂肪酸。 FA可以刺激或抑制PGHS活性，其特定作用取决于PGHS同工型和FA。该作用在生理FA浓度下发生，并在细胞以及纯化的酶中观察到。 FAS调节PGHS的生化基础涉及包含PGH同二聚体的单体之间的串扰。尽管单体具有相同的氨基酸序列，但包含PGHS同二聚体的两个单体的构象不同。一个单体结合FAS并表现为变构单体，而另一种则充当催化单体。最后，重要的是，纯化的人类PGHS对COX抑制剂的反应再次由FAS调节，再次取决于FA，抑制剂和PGHS同工型。使用不同的COX抑制剂，FA可以影响抑制剂与一个或两个单体的结合。 拟议的研究的目标是确定PGHS及其对广泛使用的COX抑制剂的反应如何受到分子，细胞和整个动物水平的FA的影响。我们的基本假设是，体内PG的产生和对Cox抑制剂的反应都受到FA的环境的显着调节，在这种情况下，酶发现自己是FA的张力，而FA环境则受饮食FA组成的影响重要。我们认为，每个人在饮食习惯的遗传背景下都建立了FA态。我们推测某些FA色调使易感个体易于抑制剂的不利后果。我们预计，我们的研究描述了FA/COX抑制剂相互作用将是第一步，导致对不同饮食中的人开了Cox抑制剂的方式变化，并调整饮食调整以提供更安全的COX抑制剂。