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: 10201144
• 负责人: Jason M Shearer
• 金额: $ 39.44万
• 依托单位: TRINITY UNIVERSITY
• 依托单位国家: 美国
• 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: https://reporter.nih.gov/project-details/10201144
• 关键词: Active Sites; Anabolism; Antibiotics; Biochemical Process; Biochemistry; Bioinorganic Chemistry; Biological; Cardiovascular Diseases; Chemicals; Chemistry; Computing Methodologies; Cysteine; Cysteine dioxygenase; DNA Repair; Data; Diabetes Mellitus; Dioxygen; Disease; Elements; Environment; Enzymes; Event; Functional disorder; Goals; Health; Human; Hydrocarbons; Hydrogen; Hydroxylation; Infrastructure; Institution; Investigation; Ions; Iron; Laboratories; Libraries; Ligands; Literature; Malignant Neoplasms; Metabolic Pathway; Minor; Mononuclear; Mossbauer Spectroscopy; Nerve Degeneration; Pathway interactions; Penicillins; Peptides; Play; Positioning Attribute; Production; Reaction; Research; Research Personnel; Roentgen Rays; Role; Series; Site; Specificity; Structure; Sulfhydryl Compounds; Sulfur; System; Therapeutic; Thermodynamics; Training; Work; absorption; adduct; base; computer studies; cysteine sulfinic acid; design; electronic structure; experience; geometric structure; human disease; insight; interest; isopenicillin N; metalloenzyme; molecular orbital; oxidation; peptide structure; protein aminoacid sequence; thioether; tool; undergraduate student; vector; vibration

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