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Heme-Dependent Chemistry in Aromatic Oxidation

芳香族氧化中血红素依赖性化学

基本信息

批准号：
10819008
负责人：
Aimin Liu
金额：
$ 6.53万
依托单位：
UNIVERSITY OF TEXAS SAN ANTONIO
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-08-01 至 2026-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10819008
关键词：
Acids Affect Amino Acids Anabolism Antibiotics Antineoplastic Agents Aromatic Compounds Binding Biochemistry Biogenesis Biological Biological Process Catabolism Catalysis Cations Chemicals Chemistry Crystallography Development Dioxygenases Distal Drug Design Electron Spin Resonance Spectroscopy Environment Enzymes Family Funding Generations Genetic Goals Health Heme Hemeproteins Histidine Human Hydrogen Peroxide Hydroxylation In Situ Isotope Labeling Kinetics Knowledge Lead Learning Ligation Metabolism Mixed Function Oxygenases Molecular Monitor Natural Products Outcome Oxidants Oxidation-Reduction Oxygen Oxygenases Parents Pathway interactions Pharmacologic Substance Play Porphyrins Process Property Protein Engineering Proteins Quinones Reaction Regulation Research Project Grants Roentgen Rays Role Rotation Site Source Specificity Spectrum Analysis Structure System Temperature Testing Time Tryptophan Tyrosine Visit Work analog anti-cancer antimicrobial drug base catalyst chemical reaction cofactor design dopaquinone drug development drug discovery enzyme mechanism heme a insight member millisecond natural antimicrobial novel oxidation pyrroline recruit scaffold secondary metabolite structural determinants thioether x-ray free-electron laser

项目摘要

Abstract of the Parent Research Project Heme-containing enzymes are ubiquitous, contributing to various processes and catalyzing a vast array of oxidative chemistries. Histidine-ligated heme enzymes, such as the heme-dependent aromatic oxygenase (HDAO) superfamily, can use either molecular oxygen or hydrogen peroxide to oxidize their substrates. What is currently not understood are the molecular factors that engender these enzymes with their respective specificities, i.e., after generation of the critical active oxidant, how is a single reaction type catalyzed? The answer to this question will broaden our fundamental understanding of enzyme catalysis, de novo enzyme design, and protein engineering. This application focuses on the structural and mechanistic characterization of three aromatic-oxidizing enzymes of the HDAO superfamily involved in natural product and antimicrobial drug biosynthesis, including antibiotics with a pyrroline moiety or a core quinone structure. These enzymes play essential roles in the biosynthetic pathway of secondary metabolites found in many biologically active natural products and pharmaceutical lead compounds. Our primary goal is to understand the key factors that govern their hydroxylation mechanisms and their differing strategies to form oxidizing intermediates with these enzymes. We have utilized a broad spectrum of approaches to probe the intricate molecular details of these enzyme mechanisms using noncanonical amino acids, substrate analogs, time-resolved UV-vis and EPR spectroscopies, kinetics, and isotope-labeling studies, and we have been successful in trapping on-pathway reaction intermediates in crystallo. The proposed work will test our hypotheses regarding i) how the heme-based oxidant is generated, ii) how oxygen is directed to the substrate, and iii) unravel the structural factors that affect catalysis. The outcome of the proposed studies is an in-depth understanding of these three related catalytic systems to aid the development of scaffolds for rational drug design and discovery processes.

母研究项目摘要含血红素的酶是普遍存在的，有助于各种过程和催化大量的氧化化学反应。组氨酸连接的血红素酶，如血红素依赖性芳香族血红素酶，加氧酶（HDAO）超家族，可以使用分子氧或过氧化氢来氧化它们的印刷受体.目前尚不清楚的是产生这些酶的分子因素，它们各自的特性，即，关键活性氧化剂生成后，类型催化的？这个问题的答案将拓宽我们对酶的基本理解催化、从头酶设计和蛋白质工程。该应用程序侧重于结构三种芳香族氧化酶的HDAO超家族参与的机制表征在天然产物和抗微生物药物生物合成中，包括具有吡咯啉部分或核心醌结构。这些酶在次生代谢物的生物合成途径中起着重要作用在许多具有生物活性的天然产物和药物先导化合物中发现的代谢物。我们主要目标是了解控制其羟基化机制的关键因素及其不同的策略与这些酶形成氧化中间体。我们利用了广泛的一系列的方法来探测这些酶机制的复杂分子细节，非规范氨基酸，底物类似物，时间分辨UV-vis和EPR光谱，动力学，和同位素标记的研究，我们已经成功地在捕获的途径反应晶体中间体。拟议的工作将测试我们的假设，关于i）如何基于血红素氧化剂的产生，ii）氧气如何被引导到基底，以及iii）解开结构因素，影响催化作用。拟议研究的结果是深入了解这三个相关的催化系统，以帮助开发合理的药物设计和发现过程的支架。

项目成果

期刊论文数量（37）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Radical Trapping Study of the Relaxation of bis-Fe(IV) MauG.

双-Fe(IV) MauG 弛豫的自由基捕获研究。

DOI：
发表时间：
2018
期刊：
Reactive oxygen species (Apex, N.C.)
影响因子：
0
作者：
Davis,Ian;Koto,Teruaki;Liu,Aimin
通讯作者：
Liu,Aimin

Probing Ligand Exchange in the P450 Enzyme CYP121 from Mycobacterium tuberculosis: Dynamic Equilibrium of the Distal Heme Ligand as a Function of pH and Temperature.

DOI：
10.1021/jacs.7b08911
发表时间：
2017-12-06
期刊：
Journal of the American Chemical Society
影响因子：
15
作者：
Fielding AJ;Dornevil K;Ma L;Davis I;Liu A
通讯作者：
Liu A

Observing 3-hydroxyanthranilate-3,4-dioxygenase in action through a crystalline lens

通过晶状体观察 3-羟基邻氨基苯甲酸-3,4-双加氧酶的作用

DOI：
10.1073/pnas.2005327117
发表时间：
2020
期刊：
Proceedings of the National Academy of Sciences
影响因子：
0
作者：
Wang, Yifan;Liu, Kathy Fange;Yang, Yu;Davis, Ian;Liu, Aimin
通讯作者：
Liu, Aimin

Heme Binding to HupZ with a C-Terminal Tag from Group A Streptococcus.

DOI：
10.3390/molecules26030549
发表时间：
2021-01-21
期刊：
Molecules (Basel, Switzerland)
影响因子：
0
作者：
Traore ES;Li J;Chiura T;Geng J;Sachla AJ;Yoshimoto F;Eichenbaum Z;Davis I;Mak PJ;Liu A
通讯作者：
Liu A

Reassignment of the human aldehyde dehydrogenase ALDH8A1 (ALDH12) to the kynurenine pathway in tryptophan catabolism