Journal of Bacteriology & Parasitology

Novel mechanistic models for target reactions in Mycobacterium tuberculosis DNA synthesis pathway

3^rd International Congress on Bacteriology and Infectious Diseases

August 04-06, 2015 Valencia, Spain

Parag A Deshpande

Posters-Accepted Abstracts: J Bacteriol Parasitol

Abstract:

Orotidine 5’-monophosphate (OMP) is an important intermediate observed during the de novo synthesis pathway of DNA
of Mycobacterium tuberculosis. It is synthesized by the reaction of α-D-5-phosphoribosyl-1-pyrophosphate (PRPP) and
orotate (OA) with the help of Orotatephosphoribosyltransferases (OPRT) and is consumed to yield the nucleotide uridine
5’-monophosphate (UMP) using Orotidine 5’-phosphate decarboxylase (ODCase). These two reactions are popular targets for
inhibition to check the growth of Mycobacterium tuberculosis. Therefore, a detailed understanding of kinetics and mechanism
of these reactions is important as the inhibition of these reactions in organisms like Mycobacterium tuberculosis can have
implications on development of drugs for cure of tuberculosis.There are several issues concerning the mechanism of the reactions
which remain unresolved till date and require attention. Experimental studies have been carried outprobing the mechanism of
these reactions. Surprisingly, different studies either report different mechanisms for the reaction which are not in agreement
or the mechanisms are suspected tobe organism-dependent thereby making the mechanisms of the reactions doubtful. For
every new observation made for these reactions, a series of kinetic studies and tests of different kinetic models are to be done
every time. We have developed generic mechanistic models for the activity of OPRT and ODCase for catalyzing the reactions.
We propose a detailed reaction pathway for OMP formation and consumption which encompass the features of various key
mechanisms. The models were rigorously tested with kinetic data reported in the literature derived from different organisms and
our unified mechanisms were able to successfully describe all the test data without any additional assumption. The models will
prove to be valuable for assessment of experimental kinetic studies without making any reference to the organism from which
the enzymes have been derived.