Divergence of Carboxylate-Bridged Diiron Enzymes for Natural Product Biosynthesis
Divergence of Carboxylate-Bridged Diiron Enzymes for Natural Product Biosynthesis
批准号:
10283095
负责人:
Thomas M Makris
金额:
$30.17万
依托单位国家:
美国
项目类别:
财政年份:
2019
资助国家:
美国
项目状态:
已结题
起止时间:
2019-09-20 至 2023-06-30
关键词:
Acyl Carrier ProteinAddressAffectAlkane 1-monooxygenaseAlkenesAnabolismAntibioticsArchitectureBiochemicalBiochemical ReactionBiologyCarbonChemicalsChemistryComplexCritical PathwaysCytochrome P450Cytochrome aDecarboxylationDioxygenEnzymesEvolutionExhibitsFatty AcidsFolic AcidFundingGenerationsGeneticGeometryGrantHalogensHemeHemerythrinHistidineHydrogenHydroxylationIronKineticsLaboratoriesLeadLigandsLigationLinkMembraneMetabolismMethane hydroxylaseMolecularMononuclearNatural ProductsOutcomeOxidesOxygenPathogenicityPathway interactionsProteinsReactionRoleScaffolding ProteinSideSiteStructureWorkcarboxylatecatalystchemical reactioncofactordesaturaseflexibilityhalogenationinterestlensmetalloenzymemicrobialoxidationpathogenic bacteriapharmacophoreprogramsprotein structurescaffoldtool
中文摘要
双核铁酶(DI)利用羧酸和组氨酸配位的辅因子来影响
具有挑战性的生物化学反应。DI的公认角色最近
扩大到包括几个重要的天然产物生物合成途径,包括
在病原菌中产生叶酸,通过卤素调节抗生素效力
安装,并通过碳-碳键合成必需的次生代谢产物
断裂为了理解一个非常相似的辅因子和结构核心
可以执行如此不同的功能,我们建议研究三个新发现的DI,
几乎相同的配位基序和整体结构支架,但协调化学,
这些方法从根本上不同于彼此,也不同于经过充分研究的DI,
进行底物的氧化。拟议的工作将利用一系列光谱,
动力学和遗传学工具,以确定蛋白质,底物和辅因子的关键位点,
这些不同的活动。DI功能重编程的结构基础
将为合成新的药效团和分子生物学提供生物化学模板。
微生物增殖和致病性的关键途径的基础。
英文摘要
Dinuclear iron enzymes (DIs) utilize a carboxylate- and histidine-coordinated cofactor to affect
synthetically challenging biochemical reactions. The recognized roles for DIs have recently
expanded to include several important natural product biosynthetic pathways, including the
generation of folate in pathogenic bacteria, the modulation of antibiotic potency via halogen
installation, and the synthesis of essential secondary metabolites through carbon-carbon bond
scission. To understand the molecular basis for how a very similar cofactor and structural core
can perform such diverse functions, we propose to study three newly discovered DIs that contain
nearly identical coordination motifs and overall structural scaffolds, but orchestrate chemistry in
ways that fundamentally differ from both each other and from well-studied DIs that instead
perform the oxygenation of substrates. The proposed work will utilize an array of spectroscopic,
kinetic, and genetic tools to identify key sites of the protein, substrate, and cofactor that enable
such disparate activities. An elucidation of the structural basis for DI functional reprogramming
will provide a biochemical template for the synthesis of new pharmacophores and the molecular
basis for pathways that are critical for microbial proliferation and pathogenicity.
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Divergence of Carboxylate-Bridged Diiron Enzymes for Natural Product Biosynthesis
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批准号:10304210
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项目类别:
-
资助金额:$30.17万
-
财政年份:2019
-
负责人:Thomas M Makris
-
依托单位:
Divergence of Carboxylate-Bridged Diiron Enzymes for Natural Product Biosynthesis
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批准号:10581314
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项目类别:
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资助金额:$19.26万
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财政年份:2019
-
负责人:Thomas M Makris
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依托单位:
海外基金