Synthesis of analogues of 5-aminolaevulinic acid and inhibition of 5-aminolaevulinic acid dehydratase1

Abstract

Syntheses are described of several analogues of 5-aminolaevulinic acid (ALA), which are potential inhibitors of ALA dehydratase (porphobilinogen synthase), an early enzyme of tetrapyrrole biosynthesis. Most of the analogues are relatively weak competitive inhibitors of the enzyme from Bacillus subtilis or irreversible inhibitors due to multiple alkylation of the enzyme but the 3-oxa and 3-thia analogues are potent mechanism-based inhibitors which inactivate, by acylation of a nucleophilic residue, probably the active-site lysine residue. The kinetics of the inactivation by 3-thiaALA have implications for the mechanism of the enzymic reaction.