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Mechanism of Taurine: Alpha-Ketoglutarate Dioxygenase

牛磺酸的作用机制：α-酮戊二酸双加氧酶

基本信息

批准号：
9117618
负责人：
JOSEPH M BOLLINGER
金额：
$ 36.35万
依托单位：
PENNSYLVANIA STATE UNIVERSITY, THE
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-01-01 至 2018-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9117618
关键词：
Alcohols Anabolism Antibiotics Antifungal Antibiotics Antiviral Agents Area Binding Biomimetics Caffeine Carbapenems Carbon Carbon Dioxide Carboxylic Acids Chemicals Chemistry Cleaved cell Complex Connective Tissue Coupled Coupling DNA Data Detection Deuterium Dioxygen Dioxygenases Drug Targeting Electrons Enzymes Epoxy Compounds Event Exhibits Family Formaldehyde Formates Fosfomycin Genetic Materials Genetic Transcription Glycols Grant Herbicides Human Hydrogen Hydrogen Bonding Hydrogen Peroxide Hypoxia Iron Isotopes Ketones Kinetics Label Measurement Mediating Methane Methods Microbe Mixed Function Oxygenases Mononuclear Natural Products Nature Outcome Oxidants Oxidases Oxygen Oxygenases Pathway interactions Peroxidases Play Process Proteins Publishing Reaction Role Scheme Side Signal Transduction Soil Solvents Source Structure Taurine Testing Variant Work abstracting adduct alpha ketoglutarate analog anticancer activity bioactive natural products cofactor combinatorial dehydrogenation design enzyme substrate epoxidase fascinate ferryl iron frontier innovation inositol oxygenase isopenicillin N member methyl group methylphosphonate migration oxidation phosphinothricin phosphonate product development response stoichiometry success tissue repair

项目摘要

Mononuclear non-heme-iron (MNH-Fe) enzymes activate O2 for a stunning array of biomedically, agriculturally, and environmentally important oxidation reactions. Our past decade's work, supported (in part) by this grant, established the intermediacy of iron(IV)-oxo (ferryl) complexes in the reactions of seven different MNH-Fe enzymes. Five of these complexes generate substrate radicals by abstracting hydrogen (H•) from unactivated aliphatic carbons, initiating formation of new C-O, C- Cl/Br, and C-S bonds. Energized by our recent success in rationalizing the divergent outcomes mediated by the (halo)ferryl complexes in the α-ketoglutarate(αKG)-dependent aliphatic hydroxylases and halogenases, we now aim to understand even more complex ferryl-mediated transformations, including those exhibited by the enzymes: (1) hydroxypropylphosponate epoxidase (HppE), which catalyzes the 1,3-dehydrogenation of an alcohol to an epoxide, using hydrogen peroxide as the oxidant, in the biosynthesis of the antibiotic, fosfomycin; (2) carbapenem synthase (CarC), which uses one or more tyrosyl radical in concert with the presumptive ferryl complex to promote stereoinversion of a chiral carbon and desaturation of a C-C bond two atoms removed from the stereocenter, reportedly in a single O2 activation event, to produce the core of an important class of antibiotics; and (3) 2-hydroxyethylphosponate (2-HEP) dioxygenase (HEPD) and methylphosphonate synthase (MPnS), a pair of related enzymes that use ferryl complexes to cleave the C-C bond of 2- HEP in distinct 4-e- oxidation reactions, producing a precursor to the herbicide phosphinothricin (HEPD) and a major store of oceanic methane (MPnS). Our past studies on myo-inositol oxygenase and isopenicillin N synthase demonstrated a fundamentally distinct manifold for enzymatic O2 and C- H activation, involving H• abstracting FeIII-superoxo complexes. This manifold obviates the requirement for a reducing co-substrate (e.g., αKG), enabling four-electron (4-e-) oxidations. HEPD and MPnS are likely also to employ this manifold on the pathways to their ferryl intermediates, a hypothesis that we will test here. We will elucidate the mechanisms of these fascinating enzymes to develop an integrated understanding of their complex oxidation chemistry.

Monoclonal非血红素铁（MNH-Fe）酶激活O2用于一系列令人惊叹的生物医学，农业上和环境上重要的氧化反应。我们过去十年的工作， (in部分）通过这一授权，建立了铁（IV）-氧代（铁酰基）配合物在反应中的中间体七种不同的MNH-Fe酶。这些复合物中的五种通过以下方式产生底物自由基：从未活化的脂肪族碳中夺取氢（H·），引发新C-O、C-的形成 Cl/Br和C-S键。我们最近成功地将不同的结果合理化，在α-酮戊二酸（αKG）依赖性脂肪族羟化酶中由（卤代）铁基复合物介导和卤化酶，我们现在的目标是了解更复杂的铁介导的转化，包括由以下酶显示的那些：（1）羟丙基磷酸环氧酶（HppE），其催化醇的1，3-脱氢为环氧化物，使用过氧化氢作为氧化剂，在抗生素磷霉素的生物合成中;（2）碳青霉烯合酶（CarC），使用一个或多个酪氨酰基自由基与假定的铁酰基复合物协同作用，手性碳的立体转化和C-C键的去饱和，从手性碳中除去两个原子，立体中心，据报道，在一个单一的O2激活事件，以产生一个重要的一类的核心，抗生素;和（3）2-羟乙基膦酸（2-HEP）双加氧酶（HEPD）和甲基膦酸酯合成酶（MPnS），一对相关的酶，其使用铁基复合物来切割2-氨基-3-甲基-4-（2-氨基-3-甲基-4-氧代）-3-甲基-4-氧代- HEP在不同的4-e-氧化反应中，产生除草剂膦丝菌素的前体（HEPD）和海洋甲烷（MPnS）的主要储存。肌醇加氧酶的研究进展和异青霉素N合酶证明了酶的O2和C- H活化，涉及H·提取FeIII-超氧配合物。该歧管避免了对还原性共底物的要求（例如，αKG），使四电子（4-e-）氧化。HEPD 和MPnS也可能在其铁基中间体的途径上使用这种歧管，我们将在这里测试的假设。我们将阐明这些迷人的酶的机制，发展其复杂的氧化化学的综合理解。

项目成果

期刊论文数量（15）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Cryoreduction of the NO-adduct of taurine:alpha-ketoglutarate dioxygenase (TauD) yields an elusive {FeNO}(8) species.

牛磺酸：α-酮戊二酸双加氧酶 (TauD) 的 NO 加合物的冷冻还原产生难以捉摸的 {FeNO}(8) 物种。

DOI：
10.1021/ja909715g
发表时间：
2010
期刊：
Journal of the American Chemical Society
影响因子：
15
作者：
Ye,Shengfa;Price,JohnC;Barr,EricW;Green,MichaelT;BollingerJr,JMartin;Krebs,Carsten;Neese,Frank
通讯作者：
Neese,Frank

Direct nitration and azidation of aliphatic carbons by an iron-dependent halogenase.

DOI：
10.1038/nchembio.1438
发表时间：
2014-03
期刊：
NATURE CHEMICAL BIOLOGY
影响因子：
14.8
作者：
Matthews, Megan L.;Chang, Wei-chen;Layne, Andrew P.;Miles, Linde A.;Krebs, Carsten;Bollinger, J. Martin, Jr.
通讯作者：
Bollinger, J. Martin, Jr.

Evidence for the slow reaction of hypoxia-inducible factor prolyl hydroxylase 2 with oxygen.

DOI：
10.1111/j.1742-4658.2010.07804.x
发表时间：
2010-10
期刊：
The FEBS journal
影响因子：
0
作者：
Flashman E;Hoffart LM;Hamed RB;Bollinger JM Jr;Krebs C;Schofield CJ
通讯作者：
Schofield CJ

O-H Activation by an Unexpected Ferryl Intermediate during Catalysis by 2-Hydroxyethylphosphonate Dioxygenase.

DOI：
10.1021/jacs.6b12147
发表时间：
2017-02-08
期刊：
Journal of the American Chemical Society
影响因子：
15
作者：
Peck SC;Wang C;Dassama LM;Zhang B;Guo Y;Rajakovich LJ;Bollinger JM Jr;Krebs C;van der Donk WA
通讯作者：
van der Donk WA

Experimental Correlation of Substrate Position with Reaction Outcome in the Aliphatic Halogenase, SyrB2.