Metabolic Control Analysis of Reaction Catalysed by Chalcone Synthase to Inhibit Complex Lipid Formation in Mycobacterium tuberculosis

Abstract

Tuberculosis is among the deadliest diseases occurring worldwide killing almost 2 million of people every year and the number increases every year. The drugs and medications used for treatment become ineffective due to the development of resistance in the causative pathogen, M. tuberculosis towards the drugs. This has led to the development of new approaches to study the diseases from different views. Chalcone Synthase is an enzyme involved in the flavonoid biosynthetic pathway occurring in plants and in certain bacterial species including M. tuberculosis. The enzyme is responsible for lipid biosynthesis in bacterial cell wall of M. tuberculosis. This study describes the kinetic behaviour of reaction; Chalcone Synthase catalyzes the first reaction in flavonoid biosynthesis and needs a certain threshold concentration of substrates for reaction to proceed. In this study, the steady state concentration of substrates is predicted by simulation experiment using Gepasi tool. Initial concentrations of substrates in M. tuberculosis are 4.78*10-2 mMol for p-coumaroyl-CoA and 2.23*10-7 mMol for malonyl-CoA, are taken as input which are essential for synthesis of Naringenin chalcone and release of CoA. This concentration was used to simulate the reaction. Simulation results show that after 5.00 seconds, at equilibrium constant J(R1) 0.000000e mM*ml/s, initial and final concentrations of all the five components become 1.000000 mM, at 0.000 mM reaction rate. Low and stable concentrations of products were obtained during steady state analysis which is 1.157721 mM for both Naringenin chalcone and Coenzyme. The work brings a relevant approach about the possibility of the inactivation of mycobacterial growth by reducing mycolic acid synthesis in the cell wall of mycobacterium and provides basis for new strategy to design vaccine or drug against the pathogen.