Inhibition of Histidine Ammonia Lyase by Heteroaryl‐alanines and Acrylates

Histidine ammonia lyase (HAL) catalyzes the elimination of ammonia from the substrate to form ( E )‐urocanate. The interaction between HAL and acrylic acids or alanines substituted with heteroaryl groups in the β ‐position was investigated. These proved to be strong competitive inhibitors when the heteroaryl groups were furanyl, thiophenyl, benzofuranyl, and benzothiophenyl, carrying the alanyl or acrylic side chains either in 2 or 3 positions, with K i values between 18 and 139 μ M . The exception was (furan‐3‐yl)alanine which was found to be inert. Tryptophan and 1‐methyltryptophan, as well as the corresponding acrylates (=prop‐2‐enoates), are strong mixed inhibitors of HAL. Theoretically, L ‐histidine can be dissected into 4‐methyl‐1 H ‐imidazole and glycine. Whereas these two compounds separately are only very weak inhibitors of HAL, equimolar amounts of both show a K i value of 1.7±0.09 m M which is to be compared with the K m value of 15.6 m M for the normal reaction. We conclude that 5‐methyl‐1 H ‐imidazole and glycine mimic the substrate and occupy the active site of HAL in a similar orientation.