Queuosine (Q) is the only tRNA modification that can be salvaged, linking nutrition to translation. In eukaryotes salvage is the only Q synthesis route and the precursor base queuine (q) is provided by the diet or the gut microflora and directly inserted in target tRNAs. Around 50% of the gut microbiota model species are predicted to be auxotrophs and must salvage a Q precursor. In general, bacterial Q salvage enzymes are very poorly characterized, particularly in Gram-positive bacteria that are prevalent in the gut and oral microbiome. This project focuses on discovering and characterizing Q salvage enzymes as well as novel Q synthesis and Q degradation enzymes in bacteria associated with the human host. We will also explore in detail the physiological role of Q in the major oral pathogen Streptococcus mutans as preliminary results suggest a role of Q and/or Q precursors in biofilm formation, competence and virulence. The goal of Aim 1 is to experimentally characterize two main families of transporters predicted to salvage Q precursors: the YhhQ/COG1738 family and the Energy-Coupling Factor (ECF) substrate specificity families (QueT/QtrT). Indeed, these families are not iso-functional, and members seem to diverge, depending on the species, on the ability to transport different Q precursors.
Aim 2 focuses on the biochemical characterization of the novel Q synthesis enzyme QueH that catalyzes the last step of biosynthesis through an unprecedented reaction. In both Aims 1 and 2, we will also hunt for ?missing? components in Q metabolism such as missing transporters in prevalent gut microbiome bacteria such as Brevibacteria and potential Q catabolism genes.
The final aim will explore the role of Q synthesis genes in S. mutans testing the hypothesis that they could have important roles in regulation of competence. The proposed research is significant because the microbiota is a key source for the queuine micronutrient, hence fully characterizing the bacterial Q synthesis, salvage and degradation pathways in human associated bacteria is a requirement to fully understand and model the competition dynamics for this key resource. In addition, because of the importance of S. mutans in dental caries progression, understanding the molecular basis for the observed importance of Q synthesis genes in competence will increase our understanding of key component of how this organism competes with others in its oral microbiome niche.
In human queuine, the precursor of the Queuosine (Q) tRNA modification is emerging as an important micronutrient or longevity vitamin. As the microbiota is a key queuine source, fully characterizing the bacterial Q synthesis, salvage and degradation pathways in human associated bacteria is a requirement to model the competition dynamics for this key resource. In addition, because of the key role of Streptococcus mutans in dental caries development, understanding the molecular basis for the observed importance of Q synthesis in competence and biofilm formation will increase our understanding of how this organism competes with others in its oral microbiome niche.
| 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 |
| Zallot, Rémi; Harrison, Katherine J; Kolaczkowski, Bryan et al. (2016) Functional Annotations of Paralogs: A Blessing and a Curse. Life (Basel) 6: |
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