Tetrazole isosteres of biologically active acids and their effects on enzymes.
A number of tetrazole analogs of carboxylic substrates and inhibitors have been tested. Lactic and pyruvic tetrazoles were found to be competitive inhibitors of rabbit muscle L-lactate dehydrogenase in both the pyruvate reduction and the lactate oxidation reactions (Ki's of 0.04 M and 0.08 M D,L-lactic tetrazole and 0.02 M and 0.035 M pyruvic tetrazole, respectively). Lactic tetrazole is a non-competitive inhibitor of yeast L-lactate dehydrogenase (Ki = 0.10 M D,L-lactic tetrazole) while pyruvic tetrazole is predominantly competitive (Ki = 0.15 M). Alanine tetrazole is a poorer substrate than alanine for D-amino acid oxidase. It also acts as weak inhibitor. Benzoic tetrazole is a substrate-competitive inhibitor of D-amino acid oxidase (Ki = 0.7 mM) and is also a stronger ethanol-competitive inhibitor than benzoic acid (Ki = 0.03 M) of liver alcohol dehydrogenase. In all the substrates and inhibitors tested, substitution of a tetrazole ring for a carboxylic group has resulted in decreased binding, presumably due to a dilution of the negative charge density and the larger size of the tetrazoyl anion.
Kraus
J L
JL
Laboratoire de Chimie Biomoléculaire Unité Inserm U322, Faculté des Sciences de Luminy, Marseille, France.
Faury
P
P
Charvet
A S
AS
Camplo
M
M
D000409:Alanine / Q000378:metabolism / Q000494:pharmacology*; D000426:Alcohol Dehydrogenase / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D001565:Benzoates / Q000494:pharmacology; D019817:Benzoic Acid; D002264:Carboxylic Acids / Q000378:metabolism / Q000494:pharmacology*; D003605:D-Amino-Acid Oxidase / Q000037:antagonists & inhibitors / Q000378:metabolism; D004952:Esters; D007700:Kinetics; D007770:L-Lactate Dehydrogenase / Q000037:antagonists & inhibitors; D009132:Muscles / Q000201:enzymology; D010084:Oxidation-Reduction; D010088:Oxidoreductases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011773:Pyruvates / Q000494:pharmacology; D019289:Pyruvic Acid; D011817:Rabbits; D013056:Spectrophotometry, Ultraviolet; D013777:Tetrazoles / Q000378:metabolism / Q000494:pharmacology*
D001565:Benzoates; D002264:Carboxylic Acids; D004952:Esters; D011773:Pyruvates; D013777:Tetrazoles; D019289:Pyruvic Acid; D019817:Benzoic Acid; D010088:Oxidoreductases; D000426:Alcohol Dehydrogenase; D007770:L-Lactate Dehydrogenase; D003605:D-Amino-Acid Oxidase; D000409:Alanine