Tetrazole isosteres of biologically active acids and their effects on enzymes

Res Commun Chem Pathol Pharmacol. 1994 Feb;83(2):209-22.

Abstract

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.

MeSH terms

  • Alanine / metabolism
  • Alanine / pharmacology*
  • Alcohol Dehydrogenase / antagonists & inhibitors
  • Alcohol Dehydrogenase / metabolism
  • Animals
  • Benzoates / pharmacology
  • Benzoic Acid
  • Carboxylic Acids / metabolism
  • Carboxylic Acids / pharmacology*
  • D-Amino-Acid Oxidase / antagonists & inhibitors
  • D-Amino-Acid Oxidase / metabolism
  • Esters
  • Kinetics
  • L-Lactate Dehydrogenase / antagonists & inhibitors
  • Muscles / enzymology
  • Oxidation-Reduction
  • Oxidoreductases / antagonists & inhibitors
  • Oxidoreductases / metabolism*
  • Pyruvates / pharmacology
  • Pyruvic Acid
  • Rabbits
  • Spectrophotometry, Ultraviolet
  • Tetrazoles / metabolism
  • Tetrazoles / pharmacology*

Substances

  • Benzoates
  • Carboxylic Acids
  • Esters
  • Pyruvates
  • Tetrazoles
  • Pyruvic Acid
  • Benzoic Acid
  • Oxidoreductases
  • Alcohol Dehydrogenase
  • L-Lactate Dehydrogenase
  • D-Amino-Acid Oxidase
  • Alanine