Inhibition of fucosyltransferase VII by gallic acid and its derivatives

Gallic acid (GA) and several gallate derivatives were identified as inhibitors of fucosyltransferase VII (FucT VII). The inhibition by GA and (−)-epigallocatechin gallate (EGCG) is time-dependent and irreversible. GA and EGCG showed inhibition with IC50 of 60 and 700 nM, respectively, after pre-incubation with FucT VII in the presence of MnCl2. Absence of MnCl2 results in significantly weaker inhibition. Complexation of Mn2+ with GA, EGCG, and gallate esters was observed. Such complexation, however, is not rate-limiting for the inhibition of FucT VII. Therefore, time-dependent inhibition of fucosyltransferases by GA and EGCG is likely due to the slow inactivation by the inhibitors or Mn–inhibitor complex. Although Mg2+ or Ca2+ can replace Mn2+ for FucT VII activation, none forms a complex with GA or EGCG and hence results in weaker inhibition of FucT VII. GA and EGCG also inhibit FucT IV and α2,3-(N)-sialyltransferase in the low micromolar range. The structure–function divergence could be observed, as EGCG, but not GA or gallate esters, inhibits Zn2+ containing metalloproteases such as TNFα convertase, matrix metalloproteases 2 and 7.