. 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.
| Harrison, Katherine J; Crécy-Lagard, Valérie de; Zallot, Rémi (2018) Gene Graphics: a genomic neighborhood data visualization web application. Bioinformatics 34:1406-1408 |
| Yuan, Yifeng; Hutinet, Geoffrey; Valera, Jacqueline Gamboa et al. (2018) Identification of the minimal bacterial 2'-deoxy-7-amido-7-deazaguanine synthesis machinery. Mol Microbiol 110:469-483 |
| Boccaletto, Pietro; Machnicka, Magdalena A; Purta, Elzbieta et al. (2018) MODOMICS: a database of RNA modification pathways. 2017 update. Nucleic Acids Res 46:D303-D307 |
| Zallot, Rémi; Yuan, Yifeng; de Crécy-Lagard, Valérie (2017) The Escherichia coli COG1738 Member YhhQ Is Involved in 7-Cyanodeazaguanine (preQ?) Transport. Biomolecules 7: |
| Paranagama, Naduni; Bonnett, Shilah A; Alvarez, Jonathan et al. (2017) Mechanism and catalytic strategy of the prokaryotic-specific GTP cyclohydrolase-IB. Biochem J 474:1017-1039 |
| Edvardson, Simon; Prunetti, Laurence; Arraf, Aiman et al. (2017) tRNA N6-adenosine threonylcarbamoyltransferase defect due to KAE1/TCS3 (OSGEP) mutation manifest by neurodegeneration and renal tubulopathy. Eur J Hum Genet 25:545-551 |
| Bon Ramos, Adriana; Bao, Lide; Turner, Ben et al. (2017) QueF-Like, a Non-Homologous Archaeosine Synthase from the Crenarchaeota. Biomolecules 7: |
| Hutinet, Geoffrey; Swarjo, Manal A; de Crécy-Lagard, Valérie (2017) Deazaguanine derivatives, examples of crosstalk between RNA and DNA modification pathways. RNA Biol 14:1175-1184 |
| Zallot, Rémi; Ross, Robert; Chen, Wei-Hung et al. (2017) Identification of a Novel Epoxyqueuosine Reductase Family by Comparative Genomics. ACS Chem Biol 12:844-851 |
| Nairn, Brittany L; Lonergan, Zachery R; Wang, Jiefei et al. (2016) The Response of Acinetobacter baumannii to Zinc Starvation. Cell Host Microbe 19:826-36 |
Showing the most recent 10 out of 48 publications
