Metallopeptide Based Mimics of Mononuclear Nonheme Iron Enzymes: Understanding Enzymatic Reactivity Using Designed Metallopeptides
基于金属肽的单核非血红素铁酶模拟物:使用设计的金属肽了解酶反应性
基本信息
- 批准号:10201144
- 负责人:
- 金额:$ 39.44万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-04-01 至 2025-03-31
- 项目状态:未结题
- 来源:
- 关键词:Active SitesAnabolismAntibioticsBiochemical ProcessBiochemistryBioinorganic ChemistryBiologicalCardiovascular DiseasesChemicalsChemistryComputing MethodologiesCysteineCysteine dioxygenaseDNA RepairDataDiabetes MellitusDioxygenDiseaseElementsEnvironmentEnzymesEventFunctional disorderGoalsHealthHumanHydrocarbonsHydrogenHydroxylationInfrastructureInstitutionInvestigationIonsIronLaboratoriesLibrariesLigandsLiteratureMalignant NeoplasmsMetabolic PathwayMinorMononuclearMossbauer SpectroscopyNerve DegenerationPathway interactionsPenicillinsPeptidesPlayPositioning AttributeProductionReactionResearchResearch PersonnelRoentgen RaysRoleSeriesSiteSpecificityStructureSulfhydryl CompoundsSulfurSystemTherapeuticThermodynamicsTrainingWorkabsorptionadductbasecomputer studiescysteine sulfinic aciddesignelectronic structureexperiencegeometric structurehuman diseaseinsightinterestisopenicillin Nmetalloenzymemolecular orbitaloxidationpeptide structureprotein aminoacid sequencethioethertoolundergraduate studentvectorvibration
项目摘要
Project Abstract. Mononuclear nonheme iron (mnhFe) enzymes perform an array of chemically diverse
reactions that are vital to many different aspects of human health including: antibiotic biosynthesis, production
of key metabolites, and DNA repair. Thus, the misregulation and dysfunction of mnhFe enzymes have been
implicated in a number of disorders including neurodegeneration, cancers, diabetes, and cardiovascular
diseases. A large class of mnhFe enzymes contains a reduced Fe(II) ion that activates dioxygen, forming a highly
reactive FeIII-O2– species. Once formed, this FeIII-O2– intermediate can promote a large number of different
reactions leading to an enormous diversity in chemical reactivity. Despite the surprising similarities in active-site
(and sometimes substrate) structures, each enzyme promotes a highly specific reaction and yields a highly
specific product. The factors leading to such high reaction specificity from these similar active-site structures are
not fully understood. The overarching goal of the work proposed herein is to understand how the FeIII-O2–
intermediate in two mnhFe enzymes, cysteine dioxygenase (CDO) and isopenicillin-N-synthase (IPNS), can
selectively promote two vastly different reactions on structurally similar substrates: sulfur oxygenation (CDO) vs
C-H atom abstraction (IPNS).
Both CDO and IPNS modify a thiol-containing substrate once it is coordinated to the iron-center. We hypothesize
that the differential reactivity in these two enzymes is promoted by the orientation of the nominal S(3p)-type
orbital of the coordinated substrate, which will turn on or off a thermodynamically favored S-based oxygenation
reaction. To explore this hypothesis, we will prepare a library of structurally related metallopeptides that will
promote either CDO- or IPNS-like chemistries. The major difference between these peptides will be the
orientation of the S(3p)-type orbital relative to the vector of attack of the superoxo ligand of the FeIII-O2–
intermediate. Because the geometric and electronic structures of these peptides will all be nearly identical, all
differences in reactivity will be attributable to the S(3p) orbital orientation.
This research makes use of a large number of tools encountered in bioinorganic chemistry, thus providing an
excellent training platform for undergraduate researchers. In addition to biomimietic metallopeptide design and
synthesis, these systems will be subjected to mechanistic, spectroscopic (electronic absorption, EPR, (M)CD,
X-ray absorption, vibrational and Mössbauer spectroscopies), and high-level computational studies. The use of
metalloenzyme mimics in our investigations is especially noteworthy; few studies have been performed where
insight into specific biochemical processes are revealed through metallopeptide based metalloenzyme mimics.
Therefore, completion of this project will not only reveal interesting aspects of mnhFe biochemistry, but will also
expand the limits of investigations concerning metallopeptide based metalloenzyme mimics.
项目摘要。单核非血红素铁(mnhFe)酶具有一系列不同的化学性质
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 }}
Jason M Shearer其他文献
Jason M Shearer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('Jason M Shearer', 18)}}的其他基金
Metallopeptide Based Mimics of Mononuclear Nonheme Iron Enzymes: Understanding Enzymatic Reactivity Using Designed Metallopeptides
基于金属肽的单核非血红素铁酶模拟物:使用设计的金属肽了解酶反应性
- 批准号:
10797337 - 财政年份:2021
- 资助金额:
$ 39.44万 - 项目类别:
Change of Institution: The Influence of Cysteinate Protonation in Nickel Containing Metalloenzymes
制度变迁:半胱氨酸质子化对含镍金属酶的影响
- 批准号:
9825169 - 财政年份:2016
- 资助金额:
$ 39.44万 - 项目类别:
The Influence of Cysteinate Protonation in Nickel Containing Metalloenzymes
半胱氨酸质子化对含镍金属酶的影响
- 批准号:
9170625 - 财政年份:2016
- 资助金额:
$ 39.44万 - 项目类别:
PROBING THE INFLUENCE OF ARGININE METHYLATION ON THE MODULATION OF BIOMOLECULAR
探讨精氨酸甲基化对生物分子调节的影响
- 批准号:
8360611 - 财政年份:2011
- 资助金额:
$ 39.44万 - 项目类别:
PROBING THE INFLUENCE OF ARGININE METHYLATION ON THE MODULATION OF BIOMOLECULAR
探讨精氨酸甲基化对生物分子调节的影响
- 批准号:
8168233 - 财政年份:2010
- 资助金额:
$ 39.44万 - 项目类别:
PROBING THE INFLUENCE OF ARGININE METHYLATION ON THE MODULATION OF BIOMOLECULAR
探讨精氨酸甲基化对生物分子调节的影响
- 批准号:
7959721 - 财政年份:2009
- 资助金额:
$ 39.44万 - 项目类别:
Substrate Modification at Redox Active Copper Centers
氧化还原活性铜中心的基材改性
- 批准号:
6585096 - 财政年份:2003
- 资助金额:
$ 39.44万 - 项目类别:
Substrate Modification at Redox Active Copper Centers
氧化还原活性铜中心的基材改性
- 批准号:
6709365 - 财政年份:2003
- 资助金额:
$ 39.44万 - 项目类别:
相似海外基金
Bone-Adipose Interactions During Skeletal Anabolism
骨骼合成代谢过程中骨-脂肪相互作用
- 批准号:
10590611 - 财政年份:2022
- 资助金额:
$ 39.44万 - 项目类别:
Bone-Adipose Interactions During Skeletal Anabolism
骨骼合成代谢过程中的骨-脂肪相互作用
- 批准号:
10706006 - 财政年份:2022
- 资助金额:
$ 39.44万 - 项目类别:
Bone-Adipose Interactions During Skeletal Anabolism
骨骼合成代谢过程中骨-脂肪相互作用
- 批准号:
10368975 - 财政年份:2021
- 资助金额:
$ 39.44万 - 项目类别:
BCCMA: Foundational Research to Act Upon and Resist Conditions Unfavorable to Bone (FRACTURE CURB): Combined long-acting PTH and calcimimetics actions on skeletal anabolism
BCCMA:针对和抵抗不利于骨骼的条件的基础研究(遏制骨折):长效 PTH 和拟钙剂联合作用对骨骼合成代谢的作用
- 批准号:
10365254 - 财政年份:2021
- 资助金额:
$ 39.44万 - 项目类别:
Bone-Adipose Interactions During Skeletal Anabolism
骨骼合成代谢过程中骨-脂肪相互作用
- 批准号:
10202896 - 财政年份:2021
- 资助金额:
$ 39.44万 - 项目类别:
BCCMA: Foundational Research to Act Upon and Resist Conditions Unfavorable to Bone (FRACTURE CURB): Combined long-acting PTH and calcimimetics actions on skeletal anabolism
BCCMA:针对和抵抗不利于骨骼的条件的基础研究(遏制骨折):长效 PTH 和拟钙剂联合作用对骨骼合成代谢的作用
- 批准号:
10531570 - 财政年份:2021
- 资助金额:
$ 39.44万 - 项目类别:
Dissecting molecular mechanisms implicated in age- and osteoarthritis-related decline in anabolism in articular cartilage
剖析与年龄和骨关节炎相关的关节软骨合成代谢下降有关的分子机制
- 批准号:
10541847 - 财政年份:2019
- 资助金额:
$ 39.44万 - 项目类别:
Dissecting molecular mechanisms implicated in age- and osteoarthritis-related decline in anabolism in articular cartilage
剖析与年龄和骨关节炎相关的关节软骨合成代谢下降有关的分子机制
- 批准号:
10319573 - 财政年份:2019
- 资助金额:
$ 39.44万 - 项目类别:
Dissecting molecular mechanisms implicated in age- and osteoarthritis-related decline in anabolism in articular cartilage
剖析与年龄和骨关节炎相关的关节软骨合成代谢下降有关的分子机制
- 批准号:
10062790 - 财政年份:2019
- 资助金额:
$ 39.44万 - 项目类别:
Promotion of NAD+ anabolism to promote lifespan
促进NAD合成代谢以延长寿命
- 批准号:
DE170100628 - 财政年份:2017
- 资助金额:
$ 39.44万 - 项目类别:
Discovery Early Career Researcher Award