Elaboration of a general strategy for inhibition of myo-inositol 1-phosphate synthase: active site interactions of analogues possessing oxidized reaction centers

The mechanism of inhibition of myo-inositol 1-phosphate (MIP) synthase by myo-2-inosose 1-phosphate at pH 7.2 was determined by examining the structural features for active site binding in myo-2-inosose 1-phosphate and the contribution of its keto form to these interactions. 2-Deoxy-myo-inositol 1-phosphate (dMIP) was used to evaluate the impact of removing the oxidized reaction center of the enzyme. dMIP reduced its inhibitor potency by 47-fold. Meanwhile, dihydroxyacetone phosphate inhibited MIP synthase activity at 700 muMolar at pH 7.2. These results suggest that active site interactions are essential in inhibiting MIP synthase.