Evolutionary relationship between the bacterial HPr kinase and the ubiquitous PEP‐carboxykinase: expanding the P‐loop nucleotidyl transferase superfamily

Similarities between protein three‐dimensional structures can reveal evolutionary and functional relationships not apparent from sequence comparison alone. Here we report such a similarity between the metabolic enzymes histidine phosphocarrier protein kinase (HPrK) and phosphoenolpyruvate carboxykinase (PCK), suggesting that they are evolutionarily related. Current structure classifications place PCK and other P‐loop containing nucleotidyl‐transferases into different folds. Our comparison of both HPrK and PCK to other P‐loop containing proteins reveals that all share a common structural motif consisting of an αβ segment containing the P‐loop flanked by an additional β‐strand that is adjacent in space, but far apart along the sequence. Analysis also shows that HPrK/PCK differ from other P‐loop containing structures no more than they differ from each other. We thus suggest that HPrK and PCK should be classified with other P‐loop containing proteins, and that all probably share a common ancestor that probably contained a simple P‐loop motif with different protein segments being added or lost over the course of evolution. We used the structure‐based sequence alignment containing residues specific to HPrK/PCK to identify additional members of this P‐loop containing family.