Microsomal Cytochromes P450 and their Interactions with their Redox Partners
微粒体细胞色素 P450 及其与氧化还原伙伴的相互作用
基本信息
- 批准号:8641389
- 负责人:
- 金额:$ 35.61万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2011
- 资助国家:美国
- 起止时间:2011-04-01 至 2015-03-31
- 项目状态:已结题
- 来源:
- 关键词:Active SitesAddressAlanineAnabolismBile AcidsBindingBinding SitesBiochemicalBlood coagulationCarcinogensCardiovascular systemCatalysisChemicalsCholesterolClinicalCollaborationsComplexCytochrome P450Cytochromes b5DevelopmentDrug InteractionsDrug usageEicosanoidsElectron Nuclear Double ResonanceElectronicsElectronsEnvironmental PollutionEnzymesEstrogensFlavin MononucleotideFreezingGoalsHigh Pressure Liquid ChromatographyHumanHuman ActivitiesHydrocortisoneHydroquinonesIn VitroIndividualInvestigationIsoenzymesKnowledgeLGLALaboratoriesLengthLifeLightLipidsLyaseMass Spectrum AnalysisMeasuresMechanicsMediatingMembraneMetabolismMixed Function OxygenasesModelingMolecularMolecular ConformationMothersMutagenesisMutateNADPH-Ferrihemoprotein ReductaseNatureOrganOrganismOxidation-ReductionOxidoreductasePharmaceutical PreparationsPhysiological ProcessesPlantsPolychlorinated BiphenylsProceduresProdrugsPropertyProteinsPsychotropic DrugsReactionRegulationResearch PersonnelRouteSeriesSite-Directed MutagenesisSteroidsSubstrate SpecificitySurfaceTechniquesTestingTestosteroneTherapeutic AgentsToxic effectVitamin DXenobioticsbasebisphenol Achemotherapeutic agentcytochrome b5 reductasedesigndrug metabolismenvironmental agentflavin mononucleotide semiquinonehuman tissuehydroquinonein vivoinsightmembermembrane activitymutantnovelphthalatespublic health relevancequantumresearch study
项目摘要
DESCRIPTION (provided by applicant): The cytochrome P450 (cyt P450) superfamily consists of more than 11,000 members. They are ubiquitous, being found in all kingdoms of living organisms and plants and are referred to as Mother Nature's blowtorch, due to their ability to oxidize a vast number of stable chemical entities. Humans possess 56 different cyts P450, many of which are essential for early development and life itself. Other human cyts P450 determine the toxicity, duration of action, and elimination of the vast majority of therapeutic agents, carcinogens, and environmental agents to which humans are exposed. Xenobiotic metabolizing cyts P450 are also responsible for the majority of drug-drug interactions and adverse drug reactions. A third group of cyts P450 are responsible for the biosynthesis or metabolism of essential endogenous compounds. This includes virtually all steroids (cholesterol, bile acids, estrogens, testosterone, cortisol, and vitamin D) and many lipids and eicosanoids. Cyts P450 exists in virtually every organ and tissue of humans. The cyts P450 are not self-sufficient but rather require interactions with other proteins in order to function. Cyt P450 reductase and cytochrome b5 (cyt b5), which provide electrons to cyt P450, are two proteins that support the activity of cyt P450. The long-term goal of this project is to understand the structural and mechanistic basis for the regulation of the activity of the membrane-bound microsomal cyts P450 by its redox partners, cyt P450 reductase and cyt b5. The short-term goals of this proposal, using both human and model cyts P450, are to understand the biochemical basis of how the redox partners of cyt P450 regulate its activity, substrate specificity, and catalytic mechanism. Experimental techniques, including site-directed mutagenesis, rapid quenching of cyt P450 activity by chemical means, and freezing, HPLC-mass spectrometry, and quantum mechanical/molecular mechanical calculations will be employed to elucidate how the activity of microsomal cyts P450 is regulated by its redox partners. Understanding how nature designs cyt P450 active sites is a fundamental question with implications for predicting and eventually modifying the routes of metabolism of a large number of environmental contaminants such as phthalates, bisphenol A, polychlorinated biphenyls (PCBs) and many currently used drugs, including chemotherapeutic agents, psychoactive compounds, and cardiovascular therapies. Knowledge of the molecular mechanism by which the activity of human cyts P450 can be regulated will also prove to be a tremendous asset in developing drugs and procedures to alter the large number of critical physiologic processes in which the human cyts P450 participate, as well as in designing less toxic and more specific therapeutic agents and prodrugs, especially chemotherapeutic agents and environmental contaminants.
描述(由申请人提供):细胞色素 P450 (cyt P450) 超家族由 11,000 多个成员组成。它们无处不在,存在于所有生物体和植物界中,由于它们能够氧化大量稳定的化学实体,因此被称为大自然的喷灯。人类拥有 56 种不同的细胞色素 P450,其中许多对于早期发育和生命本身至关重要。其他人类细胞色素 P450 决定人类接触的绝大多数治疗剂、致癌物和环境因素的毒性、作用持续时间和消除。异生素代谢细胞 P450 也是大多数药物相互作用和药物不良反应的原因。第三组细胞色素 P450 负责必需内源化合物的生物合成或代谢。这几乎包括所有类固醇(胆固醇、胆汁酸、雌激素、睾酮、皮质醇和维生素 D)以及许多脂质和类二十烷酸。 Cyts P450 几乎存在于人类的每个器官和组织中。 细胞色素 P450 不是自给自足的,而是需要与其他蛋白质相互作用才能发挥作用。 Cyt P450 还原酶和细胞色素 b5 (cyt b5) 为 cyt P450 提供电子,是支持 cyt P450 活性的两种蛋白质。该项目的长期目标是了解膜结合微粒体细胞色素 P450 的氧化还原伙伴、细胞色素 P450 还原酶和细胞色素 b5 调节其活性的结构和机制基础。 该提案的短期目标是使用人类和模型细胞色素 P450,了解细胞色素 P450 的氧化还原伙伴如何调节其活性、底物特异性和催化机制的生化基础。实验技术,包括定点诱变、通过化学手段快速猝灭细胞色素 P450 活性以及冷冻、高效液相色谱质谱法和量子力学/分子力学计算,将用于阐明微粒体细胞色素 P450 的活性如何受其调节。氧化还原伙伴。了解大自然如何设计 cyt P450 活性位点是一个基本问题,对于预测和最终改变大量环境污染物(如邻苯二甲酸盐、双酚 A、多氯联苯 (PCB) 和许多当前使用的药物,包括化疗药物)的代谢途径具有重要意义。剂、精神活性化合物和心血管疗法。对调节人类细胞色素 P450 活性的分子机制的了解也将被证明是开发药物和程序的巨大财富,以改变人类细胞色素 P450 参与的大量关键生理过程,以及设计毒性更低、特异性更强的治疗剂和前药,特别是化疗剂和环境污染物。
项目成果
期刊论文数量(2)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
A single-site mutation (F429H) converts the enzyme CYP 2B4 into a heme oxygenase: a QM/MM study.
单位点突变 (F429H) 将 CYP 2B4 酶转化为血红素加氧酶:一项 QM/MM 研究。
- DOI:10.1021/ja211905e
- 发表时间:2012
- 期刊:
- 影响因子:15
- 作者:Usharani,Dandamudi;Zazza,Costantino;Lai,Wenzhen;Chourasia,Mukesh;Waskell,Lucy;Shaik,Sason
- 通讯作者:Shaik,Sason
How Do Perfluorinated Alkanoic Acids Elicit Cytochrome P450 to Catalyze Methane Hydroxylation? An MD and QM/MM Study.
- DOI:10.1039/c2ra22294a
- 发表时间:2013-03-07
- 期刊:
- 影响因子:3.9
- 作者:Li C;Shaik S
- 通讯作者:Shaik S
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LUCY A WASKELL其他文献
LUCY A WASKELL的其他文献
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{{ truncateString('LUCY A WASKELL', 18)}}的其他基金
Microsomal Cytochromes P450 and their Interactions with their Redox Partners
微粒体细胞色素 P450 及其与氧化还原伙伴的相互作用
- 批准号:
8447079 - 财政年份:2011
- 资助金额:
$ 35.61万 - 项目类别:
Microsomal Cytochromes P450 and their Interactions with their Redox Partners
微粒体细胞色素 P450 及其与氧化还原伙伴的相互作用
- 批准号:
8244399 - 财政年份:2011
- 资助金额:
$ 35.61万 - 项目类别:
Microsomal Cytochromes P450 and their Interactions with their Redox Partners
微粒体细胞色素 P450 及其与氧化还原伙伴的相互作用
- 批准号:
8108965 - 财政年份:2011
- 资助金额:
$ 35.61万 - 项目类别:
WHY DO SUBSTRATES REQUIRE CYTOCHROME B5 FOR OXIDATION BY CYTOCHROME P450
为什么底物需要细胞色素 B5 才能被细胞色素 P450 氧化
- 批准号:
6119109 - 财政年份:1999
- 资助金额:
$ 35.61万 - 项目类别:
WHY DO SUBSTRATES REQUIRE CYTOCHROME B5 FOR OXIDATION BY CYTOCHROME P450
为什么底物需要细胞色素 B5 才能被细胞色素 P450 氧化
- 批准号:
6280130 - 财政年份:1998
- 资助金额:
$ 35.61万 - 项目类别:
PARTICIPATION OF CYTOCHROME B5 IN ANESTHETIC METABOLISM
细胞色素 B5 参与麻醉代谢
- 批准号:
6046025 - 财政年份:1985
- 资助金额:
$ 35.61万 - 项目类别:
PARTICIPATION OF CYTOCHROME B5 IN ANESTHETIC METABOLISM
细胞色素 B5 参与麻醉代谢
- 批准号:
2177950 - 财政年份:1985
- 资助金额:
$ 35.61万 - 项目类别:
PARTICIPATION OF CYTOCHROME B5 IN ANESTHETIC METABOLISM
细胞色素 B5 参与麻醉代谢
- 批准号:
2177948 - 财政年份:1985
- 资助金额:
$ 35.61万 - 项目类别:
PARTICIPATION OF CYTOCHROME B5 IN ANESTHETIC METABOLISM
细胞色素 B5 参与麻醉代谢
- 批准号:
3288451 - 财政年份:1985
- 资助金额:
$ 35.61万 - 项目类别:
Participation of Cytochrome b5 in Anesthetic Metabolism
细胞色素 b5 参与麻醉代谢
- 批准号:
7214130 - 财政年份:1985
- 资助金额:
$ 35.61万 - 项目类别:
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