Structural and evolutionary analysis unveil functional adaptations in the promiscuous behavior of serum albumins.

Promiscuous activities have been related to the capacity to catalyze reactions different from those a protein has evolved to sustain. In this work, we rethought the serum albumin's promiscuous behavior using evolutionary and structural analysis. We found that the cross aldol condensation of acetone and p-formylbenzonitrile is a promiscuous reaction conserved in humans serum albumin and in closely related albumins from other mammals. Evolutionary analysis indicates that the residues involved in this promiscuous reaction are evolving under positive selection, an evolutionary pattern indicating a putative functional adaptation. Also, key residues are located in an evolutionary conserved cavity connected with the protein surface with an also conserved tunnel and mutations involving these residues are described in human diseases. Overall, our results suggest that albumin could have evolved to sustain a still unknown biological function among the many others it maintains. Our results could contribute to better characterize the serum albumin family and raise questions about the evolution of protein promiscuity and function.