Human DNMT1 transition state structure.

摘要: Human DNA methyltransferase 1 (DNMT1) maintains the epigenetic state of by replicating CpG methylation signatures from parent to daughter strands, producing heritable patterns through cell divisions. The proposed catalytic mechanism DNMT1 involves nucleophilic attack Cys(1226) cytosine (Cyt) C6, methyl transfer S-adenosyl-l-methionine (SAM) Cyt C5, and proton abstraction C5 form methylated in DNA. Here, we report subangstrom geometric electrostatic structure major transition (TS) reaction catalyzed human DNMT1. Experimental kinetic isotope effects were used guide quantum mechanical calculations solve TS structure. Methyl occurs after step is chemically rate-limiting for Electrostatic potential maps compared ground states, providing electronic basis interactions between protein reactants at TS. Understanding demonstrates possibility using similar analysis gain insight into complex reactions modifications.