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Figure 1.
Figure 1. The reaction pathway of C5 MTases in the presence
and in the absence of mechanism-based inhibitors. (a) The
reaction pathway for all C5 MTases involves the transfer of the
labile methyl group from S-adenosyl- Image -methionine (AdoMet)
to the 5 position of the cytosine ring, proceeds through a
covalent intermediate at position C6.[14] The nucleophilic
attack upon the C6 position of cytosine drives the subsequent
acquisition of the labile methyl group from AdoMet. (Note, the
protonation status of Glu119 in M.HhaI[36]). (b) The inhibition
by FdC. Following covalent complex formation and methyl
transfer, the analogue remains bound to the active-site Cys,
since abstraction of F cannot be achieved. (c) The inhibition by
AzaC. Following covalent complex formation at a C6 with enhanced
reactivity, slow methyl transfer may take place, but there is no
H at C5 to abstract and the covalent complex persists. (d) The
inhibition by zebularine. Following covalent complex formation
at a C6 with enhanced reactivity as with AzaC, facilitated
deamination at C4 cannot proceed, [33] since the amino moiety is
absent from the analogue. Note that the water molecule nearest
to the C4 atom is 3.6 Å away and the water molecule
nearest to the C5 atom is 3.3 Å away.
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