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Biosynthesis of hypermodified gaunosines.

超修饰鸟苷的生物合成。

基本信息

批准号：
7937367
负责人：
Valerie A de Crecy-Lagard
金额：
$ 7.5万
依托单位：
UNIVERSITY OF FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-30 至 2010-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7937367
关键词：
7-deazaguanine 7-deazaguanosine Amino Acids Anabolism Anti-Bacterial Agents Archaea Bacillus subtilis Bacteria Biochemical Biochemistry Bioinformatics Biological Factors Biological Process Biology Biopterin Cell physiology Chemicals Chemistry Classification Codon Nucleotides Comparative Genomic Analysis Complex DNA Sequence Enzyme Gene Enzymes Eukaryota Event Evolution Exhibits Family Folate GTP Cyclohydrolase GTP Cyclohydrolase I Genes Genetic Genetic Code Genome Genomics Guanosine Triphosphate In Vitro Link Metabolism Methods Microbial Physiology Modification Molecular Nitriles Nucleic Acids Nucleoside Q Nucleosides Organism Orthologous Gene Oxidoreductase Pathway interactions Pharmacologic Substance Physiological Positioning Attribute Process Prokaryotic Cells RNA Role Streptomyces Structure Testing Toyocamycin Transfer RNA Translations Tubercidin Validation Work Workplace antineoplastic antibiotics archaeosine comparative functional/structural genomics gene conservation genome sequencing in vivo insight interest microorganism novel pathogen sangivamycin stem tumor

项目摘要

Project Summary. The post-transcriptional processing of transfer RNA (tRNA) involves a number of functionally distinct events essential for tRNA maturation. The phenomenon of nucleoside modification is perhaps the most remarkable of these events, and results in a wealth of structural changes to the canonical nucleosides. Two of the most remarkable modified nucleosides found in tRNA are the 7-deazaguanosine derivatives queuosine and archaeosine, which have putative roles in translation and RNA stabilization, respectively. While evolutionarily related, these nucleosides are segregated within separate Domains; queuosine is ubiquitous among Bacteria and Eukarya, while archaeosine is only present in the Archaea. The 7-deazapurine structure in general is widespread in biology, where it is found in a variety of natural products such as the antitumor antibiotics toyocamycin,sangivamycin, and tubercidin from Streptomyces. The biosynthetic pathways to these deazapurines are poorly understood, a fact that has stymied functional studies. The availability of hundreds of sequenced genomes now allows the identification of genes and pathways using a comparative genomics approach. This approach was used to discover five new enzymes in the de novo biosynthesis of queuosine and archaeosine, and potentially of other 7-deazapurine metabolites. Notably, this pathway is limited to prokaryotes, and some of these newly discovered enzymes appear to catalyze chemistry unprecedented in biology. The long-term objectives of this project are to , elucidate the biosynthesis and metabolism of 7-deazapurines in prokaryotes. The specific aims of this proposal are 1) to elucidate the role of these new enzymes in the early steps in the queuosine and archaeosine biosynthetic pathways leading to the formation of the common precursor 7-cyano-7- deazaguanine, 2) to initiate studies into the broader metabolism of these modified nucleosides, and 3) to investigate the mechanism and structure of one of these enzymes, a novel nitrile oxidoreductase. This proposal brings an ensemble of bioinformatic, genetic, biochemical, and chemical approaches to the problem of elucidating the biosynthesis of 7-deazaguanine modified nucleosides. The study of this new pathway and the constituent enzymes will provide unprecedented access to elucidating the biology of 7-deazapurine metabolism and its manipulation. Relevance. The pathway to 7-deazapurines is unique to microorganisms, and many of the constitute enzymes are potentially new antibacterial targets. Furthermore, one of the enzymes is a novel nitrile oxidoreductase that may have applications in industrial biocatalysis.

项目总结。转运RNA （tRNA）的转录后加工涉及许多