Investigating the evolutionary history of the biosynthetic gene cluster for the cytotoxic purine analog, 6-thioguanine.

The aim of this study was to explore the distribution and evolution of the biosynthetic gene cluster that directs the synthesis of 6-thioguanine, a purine antimetabolite that has applications as a chemotherapeutic, and has been studied for anti-inflammatory, antibacterial, and antiviral properties. Some bacteria, like members of the genus Erwinia, carry the ycfRABCD operon that directs the synthesis of 6-thioguanine. To explore its evolution, we surveyed for the presence of the cluster across all bacteria available in the public databases, and identified two distinct configurations of the gene cluster. One configuration is found exclusively within the Erwiniaceae and the Yersiniaceae (Gammaproteobacteria), and the second, which carries an additional gene, is found within members of the Alpha- and Betaproteobacteria. We found that the genomic location of ycf operon is conserved across divergent bacteria, with phylogenetic and %GC analyses suggesting that the cluster is evolutionarily old and vertically inherited. In some lineages, the cluster has been lost, while in others it has been acquired horizontally from distantly related groups. Maintenance of the cluster across diverse bacterial species suggests multiple roles for 6-thioguanine in the general ecology of these species.