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 beta-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 microM. 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-1H-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 mM which is to be compared with the K(m) value of 15.6 mM for the normal reaction. We conclude that 5-methyl-1H-imidazole and glycine mimic the substrate and occupy the active site of HAL in a similar orientation.
Katona
Adrian
A
Institute of Organic Chemistry, University of Karlsruhe, Richard-Willstätter-Allee, D-76128 Karlsruhe.
Toşa
Monica Ioana
MI
Paizs
Csaba
C
Rétey
János
J
D000179:Acrylates / Q000737:chemistry* / Q000494:pharmacology*; D000409:Alanine / Q000737:chemistry* / Q000494:pharmacology*; D005998:Glycine / Q000494:pharmacology; D006638:Histidine Ammonia-Lyase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D007700:Kinetics; D015394:Molecular Structure; D016958:Pseudomonas putida / Q000187:drug effects / Q000201:enzymology
D000179:Acrylates; D006638:Histidine Ammonia-Lyase; C036658:acrylic acid; D000409:Alanine; D005998:Glycine