Figure 1.

Reaction scheme emphasizing the conformation of the distal histidine, H55, in response to binding of the substrate, 2,4,6-TXP, and inhibitor, 4-XP. (a) Active enzyme: DHP with TXP substrate bound external to the heme pocket. The protein is 6cHS (aquo) with the distal H55 in a closed position. (b) When an inhibitor (4-XP) binds in the internal pocket of DHP, H₂O is displaced (5cHS) and the distal H55 is pushed to the open position. The resulting conformation leads to inactivation of the enzyme. (c) Addition of H₂O₂ leads to the formation of compound ES (39), the high-valent iron-oxo protein (Tyr) radical intermediate, which can lead to formation of the product 2,6-DXQ by two-electron oxidation. Compound ES cannot be formed in the inhibitor-bound state because the Fe^III site is blocked by 4-XP binding in the distal cavity. (d) In the resting state of DHP the distal histidine exists in two conformations, known as open (black) and closed (gray). H₂O is bound to the heme iron only in the closed conformation.