Simulation of Proton and Hydride Transfer in Enzymes
酶中质子和氢化物转移的模拟
基本信息
- 批准号:7194904
- 负责人:
- 金额:$ 27.04万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:1998
- 资助国家:美国
- 起止时间:1998-05-01 至 2011-04-30
- 项目状态:已结题
- 来源:
- 关键词:Active SitesAddressAlanineAmino AcidsAnabolismAspartateAsthmaAtherosclerosisCatalysisChemotherapy-Oncologic ProcedureClassComputing MethodologiesCysteineDataDependenceDeuteriumDevelopmentDihydrofolate ReductaseDihydroorotate dehydrogenaseDiseaseElectron TransportElectronicsElectrostaticsEnzymesEukaryotaEukaryotic CellFolic Acid AntagonistsGrowthHealthHumanHydrogenHydrogen BondingImmunityImmunosuppressionInflammationIsomeraseIsomerismIsotopesKetosteroidsKineticsLeadLeukotriene ProductionLipoxinsLipoxygenaseMaintenanceMalariaMalignant NeoplasmsMammalsMeasurementMeasuresMotionMutagenesisMutationNuclearOxidation-ReductionPharmaceutical PreparationsPrecursor RNAProkaryotic CellsPropertyProteinsProtonsPsoriasisPublic HealthPurinesPurposePyrimidinePyrimidine NucleotidesPyrimidinesRabiesRangeRateReactionResearchResearch PersonnelRheumatoid ArthritisRoleSeriesSerineSteroid IsomerasesSteroid delta-isomeraseSteroidsStructureSystemTemperatureTestingTetrahydrofolatesTyrosineUnsaturated Fatty AcidsX-Ray Crystallographybasedeprotonationenzyme deficiencyfolic acid metabolisminhibitor/antagonistmutantoxidationprogramspurinequantumresearch studyresponsesimulationsingle-molecule FRETsteroid hormone
项目摘要
DESCRIPTION (provided by applicant): The broad, long-term objectives of this research are to elucidate the fundamental principles and mechanisms of hydrogen transfer in enzyme catalysis and to address unresolved issues in biologically important systems. These objectives will be accomplished with computational methods that include electronic and nuclear quantum effects, as well as the motion of the entire solvated enzyme. The calculations will probe the roles of electrostatics, hydrogen bonding, hydrogen tunneling, and protein motion in enzyme reactions. The four enzyme reactions that will be studied have been chosen on the basis of their biomedical importance and the availability of relevant experimental data. The first specific aim centers on the enzyme dihydrofolate reductase (DHFR), which is required for normal folate metabolism in prokaryotes and eukaryotes. This enzyme maintains tetrahydrofolate levels required to support the biosynthesis of purines, pyrimidines, and amino acids. DHFR is medically relevant in that inhibition of DHFR with potent antifolates has been used successfully in cancer chemotherapy. The second specific aim centers on the enzyme dihydroorotate dehydrogenase (DHOD). This enzyme catalyzes the only redox reaction in the biosynthesis of pyrimidines, which are required for the supply of precursors for RNA and DMA synthesis. DHOD is medically relevant in that the immunosuppressive effects of inhibiting this enzyme have been used therapeutically to treat diseases such as rheumatoid arthritis. The third specific aim centers on the enzyme lipoxygenase. This enzyme aids in the production of leukotrienes and lipoxins, which regulate responses in inflammation and immunity. In mammals, lipoxygenases are medically relevant in that inhibitors have been used as drug agents to treat diseases such as asthma, atherosclerosis, psoriasis, and cancer. The fourth specific aim centers on the enzyme ketosteroid isomerase (KSI), which catalyzes the isomerization of steroids. In mammals, this enzyme is medically relevant in that it controls the synthesis of steroid hormones. Deficiencies of KSI and related enzymes in humans lead to a wide range of diseases and health problems. All of these studies are relevant to public health because the elucidation of the mechanisms will facilitate the development of more effective drugs for a broad range of diseases, including cancer, asthma, malaria, and rheumatoid arthritis.
描述(由申请人提供):本研究的广泛、长期目标是阐明酶催化中氢转移的基本原理和机制,并解决重要生物学系统中未解决的问题。这些目标将通过包括电子和核量子效应以及整个溶剂化酶的运动在内的计算方法来实现。计算将探讨静电、氢键、氢隧道和蛋白质运动在酶反应中的作用。将要研究的四种酶反应是根据其生物医学重要性和相关实验数据的可用性而选择的。第一个具体目标集中在二氢叶酸还原酶(DHFR)上,它是原核生物和真核生物正常叶酸代谢所必需的。这种酶维持支持嘌呤、嘧啶和氨基酸生物合成所需的四氢叶酸水平。 DHFR 具有医学相关性,因为用强效抗叶酸剂抑制 DHFR 已成功用于癌症化疗。第二个具体目标集中在二氢乳清酸脱氢酶(DHOD)上。该酶催化嘧啶生物合成中唯一的氧化还原反应,而嘧啶是提供 RNA 和 DMA 合成前体所需的。 DHOD 具有医学相关性,因为抑制这种酶的免疫抑制作用已被用于治疗类风湿性关节炎等疾病。第三个具体目标集中在脂氧合酶上。这种酶有助于白三烯和脂氧素的产生,调节炎症和免疫反应。在哺乳动物中,脂氧合酶在医学上具有重要意义,因为抑制剂已被用作治疗哮喘、动脉粥样硬化、牛皮癣和癌症等疾病的药物。第四个具体目标集中在酮类固醇异构酶(KSI)上,它催化类固醇的异构化。在哺乳动物中,这种酶具有医学意义,因为它控制类固醇激素的合成。人类缺乏 KSI 和相关酶会导致多种疾病和健康问题。所有这些研究都与公共卫生相关,因为阐明其机制将有助于开发更有效的药物来治疗多种疾病,包括癌症、哮喘、疟疾和类风湿关节炎。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
SHARON HAMMES-SCHIFFER其他文献
SHARON HAMMES-SCHIFFER的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('SHARON HAMMES-SCHIFFER', 18)}}的其他基金
Coupled Protons and Electrons in Biological Systems
生物系统中的质子和电子耦合
- 批准号:
10543740 - 财政年份:2021
- 资助金额:
$ 27.04万 - 项目类别:
Coupled Protons and Electrons in Biological Systems
生物系统中的质子和电子耦合
- 批准号:
10321617 - 财政年份:2021
- 资助金额:
$ 27.04万 - 项目类别:
Simulation of Proton and Hydride Transfer in Enzymes
酶中质子和氢化物转移的模拟
- 批准号:
7941376 - 财政年份:2009
- 资助金额:
$ 27.04万 - 项目类别:
SIMULATION OF PROTON AND HYDRIDE TRANSFER IN ENZYMES
酶中质子和氢化物转移的模拟
- 批准号:
6340282 - 财政年份:2000
- 资助金额:
$ 27.04万 - 项目类别:
SIMULATION OF PROTON AND HYDRIDE TRANSFER IN ENZYMES
酶中质子和氢化物转移的模拟
- 批准号:
6386717 - 财政年份:2000
- 资助金额:
$ 27.04万 - 项目类别:
Simulation of Proton and Hydride Transfer in Enzymes
酶中质子和氢化物转移的模拟
- 批准号:
8247720 - 财政年份:1998
- 资助金额:
$ 27.04万 - 项目类别:
SIMULATION OF PROTON AND HYDRIDE TRANSFER IN ENZYMES
酶中质子和氢化物转移的模拟
- 批准号:
2910352 - 财政年份:1998
- 资助金额:
$ 27.04万 - 项目类别:
Simulation of Protein and Hydride Transfer in Enzymes
酶中蛋白质和氢化物转移的模拟
- 批准号:
6579729 - 财政年份:1998
- 资助金额:
$ 27.04万 - 项目类别:
Simulation of Proton and Hydride Transfer in Enzymes
酶中质子和氢化物转移的模拟
- 批准号:
7385038 - 财政年份:1998
- 资助金额:
$ 27.04万 - 项目类别:
SIMULATION OF PROTON AND HYDRIDE TRANSFER IN ENZYMES
酶中质子和氢化物转移的模拟
- 批准号:
2608983 - 财政年份:1998
- 资助金额:
$ 27.04万 - 项目类别:
相似海外基金
Rational design of rapidly translatable, highly antigenic and novel recombinant immunogens to address deficiencies of current snakebite treatments
合理设计可快速翻译、高抗原性和新型重组免疫原,以解决当前蛇咬伤治疗的缺陷
- 批准号:
MR/S03398X/2 - 财政年份:2024
- 资助金额:
$ 27.04万 - 项目类别:
Fellowship
CAREER: FEAST (Food Ecosystems And circularity for Sustainable Transformation) framework to address Hidden Hunger
职业:FEAST(食品生态系统和可持续转型循环)框架解决隐性饥饿
- 批准号:
2338423 - 财政年份:2024
- 资助金额:
$ 27.04万 - 项目类别:
Continuing Grant
Re-thinking drug nanocrystals as highly loaded vectors to address key unmet therapeutic challenges
重新思考药物纳米晶体作为高负载载体以解决关键的未满足的治疗挑战
- 批准号:
EP/Y001486/1 - 财政年份:2024
- 资助金额:
$ 27.04万 - 项目类别:
Research Grant
Metrology to address ion suppression in multimodal mass spectrometry imaging with application in oncology
计量学解决多模态质谱成像中的离子抑制问题及其在肿瘤学中的应用
- 批准号:
MR/X03657X/1 - 财政年份:2024
- 资助金额:
$ 27.04万 - 项目类别:
Fellowship
CRII: SHF: A Novel Address Translation Architecture for Virtualized Clouds
CRII:SHF:一种用于虚拟化云的新型地址转换架构
- 批准号:
2348066 - 财政年份:2024
- 资助金额:
$ 27.04万 - 项目类别:
Standard Grant
BIORETS: Convergence Research Experiences for Teachers in Synthetic and Systems Biology to Address Challenges in Food, Health, Energy, and Environment
BIORETS:合成和系统生物学教师的融合研究经验,以应对食品、健康、能源和环境方面的挑战
- 批准号:
2341402 - 财政年份:2024
- 资助金额:
$ 27.04万 - 项目类别:
Standard Grant
The Abundance Project: Enhancing Cultural & Green Inclusion in Social Prescribing in Southwest London to Address Ethnic Inequalities in Mental Health
丰富项目:增强文化
- 批准号:
AH/Z505481/1 - 财政年份:2024
- 资助金额:
$ 27.04万 - 项目类别:
Research Grant
ERAMET - Ecosystem for rapid adoption of modelling and simulation METhods to address regulatory needs in the development of orphan and paediatric medicines
ERAMET - 快速采用建模和模拟方法的生态系统,以满足孤儿药和儿科药物开发中的监管需求
- 批准号:
10107647 - 财政年份:2024
- 资助金额:
$ 27.04万 - 项目类别:
EU-Funded
Ecosystem for rapid adoption of modelling and simulation METhods to address regulatory needs in the development of orphan and paediatric medicines
快速采用建模和模拟方法的生态系统,以满足孤儿药和儿科药物开发中的监管需求
- 批准号:
10106221 - 财政年份:2024
- 资助金额:
$ 27.04万 - 项目类别:
EU-Funded
Recite: Building Research by Communities to Address Inequities through Expression
背诵:社区开展研究,通过表达解决不平等问题
- 批准号:
AH/Z505341/1 - 财政年份:2024
- 资助金额:
$ 27.04万 - 项目类别:
Research Grant