Alternative Microbial Routes to Homoserine Activation and Sulfuration: Critical Steps in Methionine Biosynthesis

Background: Methionine is a sulfur-containing amino acid that is synthesized via a branch point in the aspartate metabolic pathway. S-adenosyl methionine is subsequently synthesized from methionine, and plays a critical role in the transfer of methyl groups to various biomolecules, including DNA, proteins and small-molecule secondary metabolites. The branch point that leads to the synthesis of methionine and S-adenosyl methionine starts with the activation of the hydroxyl group of homoserine.

Species Variation: The mode of activation of homoserine differs from plants to microorganisms, as well as within different microbial systems. At this point, depending on the species, at least three different activation routes have been identified. In addition, the route of sulfur assimilation in these systems can also vary from species to species.

Enzymology: Homoserine acyl transferases catalyze the primary routes to homoserine activation in microbes, and these enzymes are members of the α/β hydrolase superfamily. While the two different families of homoserine acyl transferases use the same kinetic and chemical mechanisms to catalyze this related reaction, they do so by using significantly different overall structures, as well as subtle differences in their closely related active site structures.

Conclusion: Since this pathway produces metabolites that play a number of critical biochemical roles in microorganisms, and because of the complete absence of related enzymes in mammals, the enzymes in this pathway represent novel targets for future antibiotic drug development.