Catalytic promiscuity in Pseudomonas aeruginosa arylsulfatase as an example of chemistry-driven protein evolution

► Catalytic promiscuity can potentially play an important role in enzyme evolution. ► We theoretically probed the highly promiscuous arylsulfatase from P. aeruginosa. ► The enzyme tightens all transition states, particularly for the native reaction. ► An active site lysine with depressed pKa appears to be a “specificity switch”. ► The molecular basis for the promiscuity appears to be purely electrostatic.