权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Catalysis by Prostaglandin Endoperoxide H Synthases

前列腺素内过氧化物 H 合成酶的催化作用

基本信息

批准号：
8658102
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
项目类别：
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/8658102
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

项目摘要

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（申请人提供）：前列腺素内过氧化物H合酶-1和-2（PGHS-1和-2），也称为环氧合酶-1和-2（COX-1和COX-2），在前列腺素（PG）生物合成的关键步骤中催化花生四烯酸（AA）转化为前列腺素H2（PGH2）。 PGHS 是 COX 抑制剂的主要靶点，其中包括非特异性非甾体类抗炎药 (nsNSAID) 和称为昔布 (coxib) 的 COX-2 特异性抑制剂。 COX 抑制剂是美国使用最广泛的药剂。然而，使用这些抑制剂会带来巨大的风险。每年约有 20,000 人死亡归因于这些药物的不良反应，其分子基础尚不清楚。使用纯化的人 PGHS，我们发现 PGHS 活性通过一种不寻常的变构机制受到所有常见脂肪酸 (FA) 的调节，包括那些不是 PGHS 底物的脂肪酸。 FA 可以刺激或抑制 PGHS 活性，具体效果取决于 PGHS 亚型和 FA。这种效应在 FA 生理浓度下发生，并且可以在细胞以及纯化的酶中观察到。 FA 调节 PGHS 的生化基础涉及包含 PGHS 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，但是构成PGHS同型二聚体的两个单体的构象不同。一种单体与 FA 结合并充当变构单体，而另一种则充当催化单体。最后也是重要的是，纯化的人 PGHS 对 COX 抑制剂的反应受到 FA 的调节，同样取决于 FA、抑制剂和 PGHS 亚型。对于不同的 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 抑制剂的反应如何在分子、细胞和整个动物水平上受到 FA 的影响。我们的基本假设是，体内 PG 的产生和对 COX 抑制剂的反应均受到酶所处的 FA 环境（FA 基调）的显着调节，并且这种 FA 环境很大程度上受到饮食中 FA 组成的影响。我们假设每个人都会根据其遗传背景的饮食习惯建立 FA 基调。我们推测某些 FA 音调会使易感个体容易遭受 COX 抑制剂的不良后果。我们预计，我们描述 FA/COX 抑制剂相互作用的研究将成为改变 COX 抑制剂对不同饮食人群的处方方式以及饮食调整以更安全地使用 COX 抑制剂的第一步。

项目成果

期刊论文数量（25）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Major urinary metabolites of 6-keto-prostaglandin F2α in mice.

小鼠 6-酮前列腺素 F2α 的主要尿液代谢物。

DOI：
10.1194/jlr.m037192
发表时间：
2013
期刊：
Journal of lipid research
影响因子：
6.5
作者：
Kuklev,DmitryV;Hankin,JosephA;Uhlson,CharisL;Hong,YuH;Murphy,RobertC;Smith,WilliamL
通讯作者：
Smith,WilliamL

Chemical C2-elongation of polyunsaturated fatty acids.

多不饱和脂肪酸的化学C2延伸。

DOI：
10.1016/j.chemphyslip.2006.09.002
发表时间：
2006
期刊：
Chemistry and physics of lipids
影响因子：
3.4
作者：
Kuklev,DmitryV;Smith,WilliamL
通讯作者：
Smith,WilliamL

Human cyclooxygenase-1 activity and its responses to COX inhibitors are allosterically regulated by nonsubstrate fatty acids.

人类 cyclooxygenase-1 活性及其对 COX 抑制剂的反应受到非底物脂肪酸的变构调节。

DOI：
10.1194/jlr.m026856
发表时间：
2012
期刊：
Journal of lipid research
影响因子：
6.5
作者：
Zou,Hechang;Yuan,Chong;Dong,Liang;Sidhu,RanjinderS;Hong,YuH;Kuklev,DmitryV;Smith,WilliamL
通讯作者：
Smith,WilliamL

Comparison of cyclooxygenase-1 crystal structures: cross-talk between monomers comprising cyclooxygenase-1 homodimers.