Consisting of more than 11,000 members distributed over five families, the tautomerase superfamily (TSF) is a large collection of proteins with diverse biological functions. While a lot of attention has been given to individual TSF enzymes, a majority remain structurally and functionally uncharacterized. Given its large size, studying a representative member of each family offers a viable approach for extracting mechanistic insights applicable to the entire superfamily. In this study, cis-3-chloroacrylic acid dehalogenase (cis-CaaD), 5-carboxymethyl-2-hydroxymuconate isomerase (CHMI), malonate semialdehyde decarboxylase (MSAD), and 4-oxalocrotonate tautomerase (4-OT) were referenced against the well-studied macrophage migration inhibitory factor (MIF) and D-dopachrome tautomerase (D-DT) using triplicate 1 μs molecular dynamics (MD) simulations for a total of 18 μs. Through root mean square fluctuation (RMSF) measurements and correlation analyses comparisons to previous crystallographic structures, we reveal key mechanistic insights that promote understanding of the catalytic activities in TSF. Collectively, our findings from these functionally diverse TSF proteins provide key information on allosteric coupling, long-range intra- and intersubunit communications as well as structure-activity relationships that enable new studies in the superfamily.