The World Health Organization reports that two million people are dying each year from tuberculosis, and one-third of the world’s population is infected with the causative bacterium, Mycobacterium tuberculosis. Metabolic pathways that are common to other organisms frequently have aspects that are peculiar to M. tuberculosis. Such is the case for ribose metabolism. Ribose, particularly in the form of ribose-5-phosphate, is essential to the synthesis of nucleotides and a number of important cofactors such as ATP and NAD⁺. Additionally, this pathway oxidizes glucose and under certain conditions can completely oxidize glucose to CO₂ and water. Enzymes that function primarily in the reductive direction utilize the NADP⁺/NADPH cofactor pair as co-factors as opposed to oxidative enzymes that utilize the NAD⁺/NADH cofactor pair. The pentose phosphate pathway has both an oxidative and a non-oxidative arm. The oxidation steps, utilizing glucose-6-phosphate as the substrate, occur at the beginning of the pathway and are the reactions that generate NADPH. Model building of the enzymes of oxidative arm, glucose-6-phosphate dehydrogenase, 6-phosphogluconolactonase and 6-phosphogluconate dehydrogenase were carried out using the program Parmodel, which is a web server for automated modeling and protein structural assessment. Parmodel runs a parallelized version of MODELLER. We have constructed three-dimensional models by comparative molecular modeling, and these models are further assessed by Procheck and Verify-3D. The models present good correlations with its templates, and the possible interactions between the structural NADP⁺ and substrate in glucose-6-phosphate dehydrogenase, and in 6-phosphogluconate dehydrogenase are considered. In glucose-6-phosphate dehydrogenase, the first enzyme, the tetramer interface remains the flexibility in the predominantly hydrophilic dimer-dimer interactions, as observed in the template. In 6-phosphogluconate dehydrogenase, the third enzyme, each subunit of the dimer conserves the three domains: the domain of NADP⁺, the domain of the dimer interface and the C-terminal domain. These three-dimensional structures can help in the understanding of the action mechanisms of this essential pathway in M. tuberculosis.