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Biosynthesis of Several Oxyvinylglycine Nonproteinogenic Amino Acids Bearing Unusual Alkoxyamine Bonds

几种带有异常烷氧基胺键的氧乙烯甘氨酸非蛋白氨基酸的生物合成

基本信息

批准号：
10752052
负责人：
Joshua Ray Turek-Herman
金额：
$ 6.87万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-08-01 至 2026-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10752052
关键词：
Agrochemicals Amino Acids Anabolism Anti-Bacterial Agents Antibiotics Attenuated Bacteria Binding Biochemical Bioinformatics Biological Assay Breathing C-terminal Cells Chemicals Dependence Drug Compounding Drug Industry Enzyme Inhibition Enzymes Ethers Ethylenes Exhibits Family member Gene Cluster Genetic Germination Goals Guanidines Heme Herbicides Homoserine Imino Acids In Vitro Industrialization Iron Medicine Metabolism Metals Methods N hydroxylation N-terminal Natural Compound Natural Products Nucleosides Oxygen Oxygenases Pathway interactions Pharmaceutical Preparations Pharmacologic Substance Plant Growth Regulators Plants Property Pseudomonas fluorescens Pyridoxal Phosphate Reaction Recombinants Reporting Role Source Streptozocin Structure Symbiosis Synthesis Chemistry System Virulence bactericide carboxylate carboxylation chemotherapy cofactor enol enzyme mechanism experimental study feeding functional group member metalloenzyme microorganism secondary metabolite small molecule small molecule inhibitor stable isotope unnatural amino acids vinyl ether

项目摘要

Project Summary Natural products serve crucial roles in the pharmaceutical industry as drugs or leads for drug compounds. Generated through secondary metabolism, these molecules impact the virulence, symbiosis, and survival of microorganisms. The nonproteinogenic oxyvinylglycine amino acids are an interesting class of secondary metabolites characterized by the presence of a vinyl oxygen moiety. Members of this class, such as 4-(2’- aminoethoxy)vinylglycine (AVG), are known to arrest germination in plants by inhibiting the pyridoxal 5’- phosphate (PLP)-dependent enzyme 1-aminocyclopropane-1-carboxylate (ACC) synthase.2 While the biosynthesis of vinyl ether-bearing oxyvinylglycine nonproteinogenic amino acids including AVG has been explored, the formation of other members of the family with alternative functional groups remains undetermined. 4-Formylaminooxyvinylglycine (FVG), an oxyvinylglycine containing an N–O bond, was reported to have duel herbicidal and bactericidal activity.3,4 The gvg biosynthetic gene cluster in Pseudomonas fluorescens strain WH6 is responsible for the biosynthesis of FVG and the related compounds guanidinooxyvinylglycine (GOVG) and aminooxyvinylglycine (AOVG) though the exact biosynthetic mechanism remains unclear.5,6 In this proposal I will determine the biosynthetic pathways responsible for the formation of FVG, GOVG, and AOVG. I will use a combination of feeding experiments and in vitro biochemical assays to determine the substrate and product of each enzyme along the biosynthetic pathway of these three nonproteinogenic amino acids. The vinyl alkoxyamine is unusual in amino acids, therefore I will characterize the enzyme responsible for N–O bond construction and determine its chemical mechanism. These studies will facilitate the bioinformatic discovery of similar oxyvinylglycine nonproteinogenic amino acids. Moreover, characterization of the iron-dependent enzyme responsible for N–O bond formation will facilitate its use in a synthetic context to expand the repertoire of oxidative biocatalysts.

项目总结