Functional investigation of the antitubercular drug target Decaprenylphosphoryl-β-D-ribofuranose-2-epimerase DprE1/DprE2 complex

Abstract

Tuberculosis (TB) is one of the leading causes of death worldwide, due to a single pathogen, Mycobacterium tuberculosis. To eradicate TB, management of drug-resistant strains is fundamental, therefore, the identification and characterization of drug targets is pivotal. In this work we aim at describing the relationships with the well-known drug target DprE1 and DprE2, working in association for the biosynthesis of the arabinogalactan precursor, essential component of mycobacterial cell wall. We demonstrated that the enzymes behave as a stable heterodimeric complex, once co-expressed into the same system. This complex showed improved catalytic properties, compared to the singularly expressed enzymes, demonstrating that co-expression is fundamental to achieve the proper folding of the active sites. Our results represent an important step forward in deciphering the functional properties of these enzymes, and lay the foundations for structural studies, useful for development of more specific inhibitors helpful to contrast the spreading of drug-resistant strains.

Keywords: Decaprenylphosphoryl-D-2-keto erythropentose reductase DprE2; Decaprenylphosphoryl-β-d-ribose 2′-oxidase DprE1; Heterodimeric complex; M. smegmatis; M. tuberculosis.