Ten M.HhaI residues were replaced with alanine to probe the importance of distal protein elements to substrate/cofactor binding, methyl transfer, and product release. The substitutions, ranging from 6-20 Å from the active site were evaluated by thermodynamic analysis, pre-steady and steady-state kinetics, to obtain K_d^AdoMet, K_d^DNA, k_cat/K_m^DNA, k_cat, and k_{methyltransfer} values. For the wild-type M.HhaI, product release steps dominate catalytic turnover while the 4-fold faster internal microscopic constant k_{methyltransfer} presents an upper limit. The methyl transfer reaction has ΔH^‡ and ΔS^‡ values of 10.3 kcal/mol and -29.4 cal/(mol K), respectively, consistent with a compressed transition state similar to that observed in the gas phase. Although the ten mutants remained largely unperturbed in methyl transfer, long-range effects influencing substrate/cofactor binding and product release were observed. Positive enhancements were seen in Asp⁷³Ala, which showed a 25-fold improvement in AdoMet affinity and in Val²⁸²Ala, which showed a 4-fold improvement in catalytic turnover. Based on an analysis of the positional probability within the C⁵-cytosine DNA methyltransferase family we propose that certain conserved distal residues may be important in mediating long-range effects.