Human UDP-α-d-glucose 6-dehydrogenase (hUGDH) forms a hexamer that catalyzes the NAD(+)-dependent oxidation of UDP-α-d-glucose (UDG) to produce UDP-α-d-glucuronic acid. Mammalian UGDH displays hysteresis (observed as a lag in progress curves), indicating that the enzyme undergoes a slow transition from an inactive to an active state. Here we show that hUGDH is sensitive to product inhibition during the lag. The inhibition results in a systematic decrease in steady-state velocity and makes the lag appear to have a second-order dependence on enzyme concentration. Using transient-state kinetics, we confirm that the lag is in fact due to a substrate and cofactor-induced isomerization of the enzyme. We also show that the cofactor binds to the hUGDH:UDG complex with negative cooperativity. This suggests that the isomerization may be related to the formation of an asymmetric enzyme complex. We propose that the hysteresis in hUGDH is the consequence of a functional adaptation; by slowing the response of hUGDH to sudden increases in the flux of UDG, the other biochemical pathways that use this important metabolite (i.e., glycolysis) will have a competitive edge.