![]() Thus, when structure 4.1 is positioned in the active site it should trigger formation of covalent adduct shown as the structure 4.2. The structure 4.1 is supposed to mimic the transition from structures 2.1 to 2.2. We have decided to target this reversible step with a mechanism-based suicide inhibitor. Following the methyltransfer step (steps 2.1–2.2), there is a reversible target base elimination step (steps 3.1–3.2). Kinetic and QM/MM studies showed that the formation of the covalent adduct intermediate is a reversible step unless the reaction is driven forward by the rate-limiting irreversible methyltransfer step ( Svedruzic and Reich, 2004, 2005a Yang et al., 2013). The enzyme can form unstable covalent adduct intermediate when conjugated aromatic bonds in the target base ring are positioned in asymmetric active site between polar amino acids (steps 1.1–1.2). In case of human and mouse enzymes the active site is composed of conserved Arg 1310, Arg 1312, Glu1266, and Cys 1126 residues (step 1.1). ![]() The catalysis is initiated when the aromatic target base ring is posited in the active site cavity (step 1.1). The catalysis consists of three main steps. The catalytic mechanism of bacterial and mammalian cytosine-C5 DNA methyltransferase has been described in detail in the last 40 years in different crystal structures, enzyme kinetics studies, enzyme substrate binding studies, and QM/MM studies ( Santi and Hardy, 1987 Song et al., 2011, 2012 Svedruzic and Reich, 2004, 2005a Yang et al., 2013 Zhou et al., 2002). Catalytic mechanism of DNA methyltransferase DNMT1.
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