Partners in crime: Structure-function studies on chorismate mutases and their associated enzymes

Abstract

Aromatic amino acids are essential building blocks for proteins. Humans lack enzymes that produce aromatic amino acids, thus they must consume them with their diet. In contrast, plants, bacteria and fungi are capable of de novo synthesis of aromatic amino acids, including the essential amino acids phenylalanine and tryptophan. Enzymes involved in the biosynthesis of aromatic amino acids are very promising drug targets, to fight bacterial and fungal infections or plant parasitosis. This PhD thesis is concerned with the study of chorismate mutase (CM), a fundamental metabolic enzyme. CM is often found associated to other enzymes from the same biosynthetic pathway, which regulate its activity. This work reports the structure of chorismate mutases from several bacteria, including human pathogens Mycobacterium tuberculosis and Pseudomonas aeruginosa, and novel bifunctional chorismate mutases from non-pathogenic bacteria. We shed light on their activity and regulation, including the mode of interaction with associated enzymes, laying the foundation for the discovery of new drugs.