Bacterial Xanthine Dehydrogenase Regulators

Abstract

Bacteria are resilient organisms that tend to evolve rapidly in order to acquire abilities to survive in a constantly changing environment. Transcriptional regulators play a vital role in regulating the function of various essential proteins of the cell. The gene encoding Xanthine Dehydrogenase Regulator (XdhR), a transcriptional regulator, is divergently oriented to the gene cluster (xdhABC) encoding Xanthine Dehydrogenase (Xdh) protein in Streptomyces coelicolor, Agrobacterium tumefaciens and Ralstonia solanacearum. Xdh participates in purine salvage pathway in converting adenine to guanine. My research here is aimed at identifying the novel function of Xdh and XdhR in the above mentioned bacteria. XdhR binds to the intergenic region between xdhR and the xdhABC gene cluster in all these bacteria. The small molecules GTP and ppGpp are ligands of S. coelicolor XdhR, and intergenic DNA-XdhR binding is attenuated in the presence of these ligands. Gene expression studies in S. coelicolor reveal that xdhB gene expression is induced during stationary phase and stringent response. The accumulation of (p)ppGpp is highest during stationary phase and stringent response. Therefore, this study sets forth a model in which XdhR responds to cellular levels of GTP and (p)ppGpp to ensure production of Xdh, which biases purine salvage pathway towards generation of guanine for maintaining GTP levels in order to sustain (p)ppGpp synthesis during starvation and stringent conditions. The signaling molecules ppGpp and c-di-GMP are both ligands of XdhR from A. tumefaciens and R. solanacearum, attenuating binding of the XdhR proteins to their respective gene promoters. It is shown that (p)ppGpp accumulates during stationary phase in A. tumefaciens, and that xdhB expression is repressed when Xdh activity is inhibited, consistent with guanosine nucleotides being ligands for XdhR. The secondary messenger c-di-GMP has been attributed to signal exopolysaccharide production and biofilm formation in several pathogenic bacteria. The findings of this research suggest that XdhR plays an important role during starvation and biofilm formation in A. tumefaciens and R. solanacearum. Since XdhR is identified to play a critical role during starvation, exopolysaccharide production and biofilm formation in bacteria, this protein could act as a potential drug target for curtailing bacterial infections.