Transition Metal Catalysis and Metabolic Engineering using Artificial Metalloenzy
使用人工金属酶的过渡金属催化和代谢工程
基本信息
- 批准号:8413621
- 负责人:
- 金额:$ 23.11万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2010
- 资助国家:美国
- 起止时间:2010-02-01 至 2013-12-31
- 项目状态:已结题
- 来源:
- 关键词:AcademiaAchievementAerobicAlkenesAmazeAmino AcidsAmino Acyl-tRNA SynthetasesAnabolismBindingBiologicalBiological FactorsBiologyBoronic AcidsCaliforniaCatalysisChemicalsCollectionComplexCouplingDevelopmentDevelopment PlansDiagnosticDisciplineDrug IndustryEngineeringEnsureEnvironmentEnzymesEscherichia coliFacultyFosteringFranceGoalsHealthHumanIndividualIndustryInstitutesInstitutionIonsLaboratoriesLifeMedicalMentorsMentorshipMetabolic PathwayMetalsMolecular ConformationNatureOrganic SynthesisOrganic solvent productOrganismPalladiumPathway interactionsPeptidesPetroleumPharmacologic SubstancePhasePhysiologicalPreparationProceduresProductionProtein EngineeringProteinsPublic HealthReactionReagentResearchScaffolding ProteinScienceScientistSideSiteSpecificitySpeedSystemTechnologyTransfer RNATransition ElementsTryptophanWorkWritingaqueousaryl halidecareer developmentcatalystchemical reactionchemical synthesisdesigndirected evolutionexperienceimprovedin vivomembermetabolic engineeringmetalloenzymenovelpractical applicationprofessorsuccesstrend
项目摘要
Practical application of new synthetic molecules for the betterment of human health depends directly on the
efficiency with which these compounds can be synthesized, but this is frequently limited by poor reaction yields
throughout long reaction sequences in which intermediate compounds must be isolated and purified.
Metabolic engineers have demonstrated that novel biosynthetic pathways can be assembled in order to
produce chemicals in vivo with no isolation of intermediates in an aqueous aerobic environment, but these
sequences are limited to transformations catalyzed by natural enzymes. This proposal describes the design,
preparation, and application of a new class of artificial metalloenzymes that combines the scope of chemical
catalysis with the efficiency of biosynthesis in an unprecedented manner to produce molecules of exceptional
biological importance. The proposed system offers a number of significant advantages over previous artificial
metalloenzyme constructs, which enable its use for in vivo catalysis and metabolic engineering. This ambitious
project will be conducted as part of the candidate's long term goals of increasing the efficiency of organic
synthesis, particularly for the production of biologically active molecules.
In the mentored phase (K99) of the proposed research, amino acids with catalytically active palladacycle
side chains will be synthesized, characterized, and incorporated into a suitable scaffold protein. The catalytic
activity of the resulting metalloenzymes will be evaluated using a variety of C-C bond forming reactions. The
proposed amino acids catalysts could prove highly useful for a variety of applications in their own right, and
their incorporation into proteins would mark a significant achievement in the fields of UAA incorporation and
biocatalysis with potential applications well beyond the scope of this application. This research will be
conducted in the laboratory of Professor Frances Arnold, a leader in the field of protein engineering, at the
California Institute of Technology, a world-renowned research institution. Professor Arnold has a strong record
as a mentor of successful members of industry and academia, and she and the candidate have outlined a
career development plan focusing on mentorship, writing, and research to ensure the candidate continues this
trend. The facilities, faculty, and staff at Caltech are ideal for completion of the proposed research and will
contribute greatly to the candidate's overall development as an independent scientist.
Independent (R00) research will focus on directed evolution of artificial metalloenzymes for in vivo
palladium catalysis of pharmaceutically important cross-coupling reactions with potential applications in organic
synthesis and bio-orthogonal diagnostics. Optimized metalloenzymes will also be expressed with additional
enzymes in E. coli in order to biosynthesize biologically active molecules, including indolocarbazole natural
product derivatives. Success in this venture would greatly expand the scope of molecules available via
metabolic engineering and simplify the production of new compounds for the betterment of human health. This
work will build directly on the candidate's experiences in the Arnold lab, and should foster the development of
an exciting and collaborative research environment in the candidate's independent laboratory focusing on the
development and application of enzymes for sustainable organic synthesis.
新合成分子改善人类健康的实际应用直接取决于
这些化合物的合成效率很高,但这通常受到反应产率低的限制
在整个长反应序列中,必须分离和纯化中间化合物。
代谢工程师已经证明,可以组装新的生物合成途径,以便
在水性有氧环境中无需分离中间体即可在体内产生化学物质,但是这些
序列仅限于天然酶催化的转化。该提案描述了设计,
结合了化学领域的一类新型人工金属酶的制备和应用
以前所未有的方式催化生物合成效率,产生特殊的分子
生物学重要性。与之前的人工系统相比,所提出的系统具有许多显着的优点
金属酶结构,使其可用于体内催化和代谢工程。这个雄心勃勃的
该项目将作为候选人提高有机效率的长期目标的一部分进行
合成,特别是用于生物活性分子的生产。
在拟议研究的指导阶段(K99),具有催化活性的环钯氨基酸
侧链将被合成、表征并整合到合适的支架蛋白中。催化
所得金属酶的活性将使用各种 C-C 键形成反应进行评估。这
所提出的氨基酸催化剂本身可以证明对于各种应用非常有用,并且
它们与蛋白质的结合将标志着 UAA 结合和领域的重大成就
生物催化的潜在应用远远超出了本应用的范围。这项研究将
该研究是在蛋白质工程领域的领军人物 Frances Arnold 教授的实验室进行的。
加州理工学院,世界著名研究机构。阿诺德教授有着良好的记录
作为工业界和学术界成功人士的导师,她和候选人概述了
职业发展计划侧重于指导、写作和研究,以确保候选人继续这一点
趋势。加州理工学院的设施、教职员工非常适合完成拟议的研究,并且将
对候选人作为独立科学家的全面发展做出了巨大贡献。
独立(R00)研究将重点关注体内人工金属酶的定向进化
钯催化药学上重要的交叉偶联反应及其在有机领域的潜在应用
合成和生物正交诊断。优化的金属酶也将通过额外的表达
大肠杆菌中的酶,用于生物合成生物活性分子,包括天然吲哚并咔唑
产品衍生品。这项事业的成功将极大地扩大可通过以下方式获得的分子范围
代谢工程并简化新化合物的生产以改善人类健康。这
工作将直接建立在候选人在阿诺德实验室的经验基础上,并应促进发展
候选人独立实验室中令人兴奋的协作研究环境,重点关注
可持续有机合成酶的开发和应用。
项目成果
期刊论文数量(3)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Synthesis and Catalytic Activity of Amino Acids and Metallopeptides with Catalytically Active Metallocyclic Side Chains.
具有催化活性金属环侧链的氨基酸和金属肽的合成和催化活性。
- DOI:
- 发表时间:2012
- 期刊:
- 影响因子:2.8
- 作者:Zhong, Zhihui;Yang, Hao;Zhang, Chen;Lewis, Jared C
- 通讯作者:Lewis, Jared C
Improving the stability and catalyst lifetime of the halogenase RebH by directed evolution.
通过定向进化提高卤化酶 RebH 的稳定性和催化剂寿命。
- DOI:
- 发表时间:2014-06-16
- 期刊:
- 影响因子:0
- 作者:Poor, Catherine B;Andorfer, Mary C;Lewis, Jared C
- 通讯作者:Lewis, Jared C
Metallopeptide catalysts and artificial metalloenzymes containing unnatural amino acids.
含有非天然氨基酸的金属肽催化剂和人造金属酶。
- DOI:10.1016/j.cbpa.2014.12.016
- 发表时间:2015-04
- 期刊:
- 影响因子:7.8
- 作者:Lewis, Jared C.
- 通讯作者:Lewis, Jared C.
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{{ truncateString('JARED C LEWIS', 18)}}的其他基金
Directed Evolution of Halogenases for Small Molecule Functionalization
用于小分子功能化的卤化酶的定向进化
- 批准号:
10425376 - 财政年份:2015
- 资助金额:
$ 23.11万 - 项目类别:
Directed Evolution of Halogenases for Small Molecule Functionalization
用于小分子功能化的卤化酶的定向进化
- 批准号:
8944011 - 财政年份:2015
- 资助金额:
$ 23.11万 - 项目类别:
Directed Evolution of Halogenases for Small Molecule Functionalization
用于小分子功能化的卤化酶的定向进化
- 批准号:
9312283 - 财政年份:2015
- 资助金额:
$ 23.11万 - 项目类别:
Directed Evolution of Halogenases for Small Molecule Functionalization
用于小分子功能化的卤化酶的定向进化
- 批准号:
10183266 - 财政年份:2015
- 资助金额:
$ 23.11万 - 项目类别:
Transition Metal Catalysis and Metabolic Engineering using Artificial Metalloenzy
使用人工金属酶的过渡金属催化和代谢工程
- 批准号:
8214701 - 财政年份:2010
- 资助金额:
$ 23.11万 - 项目类别:
Transition Metal Catalysis and Metabolic Engineering using Artificial Metalloenzy
使用人工金属酶的过渡金属催化和代谢工程
- 批准号:
8206335 - 财政年份:2010
- 资助金额:
$ 23.11万 - 项目类别:
Transition Metal Catalysis and Metabolic Engineering using Artificial Metalloenzy
使用人工金属酶的过渡金属催化和代谢工程
- 批准号:
7787792 - 财政年份:2010
- 资助金额:
$ 23.11万 - 项目类别:
Directed Evolution of a Cytochrome p450 for Synthesis of Artemisinic Alcohol
细胞色素 p450 的定向进化用于合成青蒿醇
- 批准号:
7220822 - 财政年份:2007
- 资助金额:
$ 23.11万 - 项目类别:
Directed Evolution of a Cytochrome p450 for Synthesis of Artemisinic Alcohol
细胞色素 p450 的定向进化用于合成青蒿醇
- 批准号:
7658151 - 财政年份:2007
- 资助金额:
$ 23.11万 - 项目类别:
Directed Evolution of a Cytochrome p450 for Synthesis of Artemisinic Alcohol
细胞色素 p450 的定向进化用于合成青蒿醇
- 批准号:
7479375 - 财政年份:2007
- 资助金额:
$ 23.11万 - 项目类别:
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