Tuberculosis (TB) remains the leading cause of mortality due to a single bacterial pathogen, Mycobacterium tuberculosis. The reemergence of TB as a potential public health threat, the high susceptibility of human immunodeficiency virus-infected persons to the disease, the proliferation of multi-
drug-resistant strains (MDR-TB) and, more recently, of extensively
drug resistant isolates (
XDR-TB) have created a need for the development of new
antimycobacterial agents. Amongst the several
proteins and/or
enzymes to be studied as potential targets to develop novel drugs against M.
tuberculosis, the
enzymes of the
shikimate pathway are attractive targets because they are essential in algae, higher plants, bacteria, and fungi, but absent from mammals. The mycobacterial
shikimate pathway leads to the biosynthesis of chorismate, which is a precursor of
aromatic amino acids,
naphthoquinones,
menaquinones, and
mycobactins. Here we report the structural studies by homology modeling and circular dichroism spectroscopy of the
shikimate dehydrogenase from M.
tuberculosis (MtSDH), which catalyses the fourth step of the
shikimate pathway. Our structural models show that the MtSDH has similar structure to other
shikimate dehydrogenase structures previously reported either in presence or absence of
NADP, despite the low amino acid sequence identity. The circular dichroism spectra corroborate the secondary structure content observed in the MtSDH models developed. The
enzyme was stable up to 50 degrees C presenting a cooperative unfolding profile with the midpoint of the unfolding temperature value of approximately 63-64 degrees C, as observed in the unfolding experiment followed by circular dichroism. Our MtSDH structural models and circular dichroism data showed small conformational changes induced by
NADP binding. We hope that the data presented here will assist the rational design of
antitubercular agents.