权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Heme-Dependent Chemistry in Tyrosine Oxidation

酪氨酸氧化中血红素依赖性化学

基本信息

批准号：
10799188
负责人：
Aimin Liu
金额：
$ 8.33万
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/10799188
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 Pathway interactions Pharmacologic Substance Play Porphyrins Process Property Protein Engineering Proteins Quinones Reaction Regulation 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

Heme-Dependent Chemistry in Aromatic Oxidation Abstract 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.

芳香氧化中血红素依赖性化学