Cascading proton transfers are a hallmark of the catalytic mechanism of SAM-dependent methyltransferases.

The S-adenosyl methionine (SAM)-dependent methyltransferases attach a methyl group to the deprotonated methyl lysine using SAM as a donor. An intriguing, yet unanswered, question is how the deprotonation takes place. PRDM9 with well-defined enzyme activity is a good representative of the methyltransferase family to study the deprotonation and subsequently the methyl transfer. Our study has found that the pKa of Tyr357 is low enough to make it an ideal candidate for proton abstraction from the methyl lysine. The partially deprontonated Tyr357 is able to change its H-bond pattern thus bridging two proton tunneling states and providing a cascading proton transfer. We have uncovered a new catalytic mechanism for the deprotonation of the methyl lysine in methyltransferases.