When deprived of the essential trace nutrient zinc, bacteria are known to adapt by increasing the intracellular concentration of zinc through transport or by lowering the zinc quota of the cell through the use of zinc-independent back-up proteins. These mechanisms were discovered by functional and computational analyses of Zur regulons. A recent computational analysis of Zur regulons from newly sequenced genomes suggested the existence of genes in addition to those presently known that may be involved in the adaptive response to zinc-depletion. Of these novel genes the role of COG0523 genes and paralogs of zinc-dependent proteins are investigated and discussed.

COG0523 proteins are, like the nickel chaperones of the UreG and HypB families, part of the G3E family of GTPases, strongly suggesting a link to metallocenter biosynthesis. Even though the first COG0523-encoding gene, cobW, was identified almost 20 years ago, little is known concerning the function of this ubiquitous family. Therefore, a phylogenomic study of the COG0523 family was performed, leading to the separation of the family into fifteen subgroups. To further probe the function of the COG0523 family, yeiR from Escherichia coli was chosen to test the apparent link between some COG0523 genes and zinc homeostasis. This previously uncharacterized gene was found to be involved in survival during EDTA or cadmium challenge and was linked to optimal growth during zinc-depletion.

In addition to the canonical DksA protein, the Pseudomonas aeruginosa genome encodes a closely-related paralog DksA2 that lacks the Zn-finger motif and whose gene was predicted to be regulated by Zur. A study on the role of dksA2 and verification of its regulation by zinc and Zur was performed. dksA2 was found to be able to functionally substitute for the canonical dksA, in vivo. Expression was repressed by the presence of exogenous zinc, deletion of Zur resulted in constitutive expression, and Zur bound specifically to the upstream region of dksA2. This data suggests that DksA2 plays a role in zinc homeostasis and serves as a back-up copy of the canonical zinc-dependent DksA in zinc-poor environments.