Đang chuẩn bị nút TẢI XUỐNG, xin hãy chờ
Tải xuống
The cobalamin–dependent cytosolic enzyme, methionine synthase (EC.2.1.1.13), catalyzes the remethylation of homocysteine to methionine using 5-methyltetrahydrofolate as the methyl donor. The products of this remethylation – methionine and tetrahydrofolate – participate in the active methionine and folate pathways. | ỊFEBS Journal Inhibition of cobalamin-dependent methionine synthase by substituted benzo-fused heterocycles Elizabeth C. Banks1 Stephen W. Doughty2 Steven M. Toms1 Richard T. Wheelhouse1 and Anna Nicolaou1 1 Schoolof Pharmacy University of Bradford UK 2 Schoolof Pharmacy Centre for Biomolecular Sciences University of Nottingham UK Keywords benzimidazole benzothiadiazole inhibition methionine synthase molecular modelling Correspondence A. Nicolaou Schoolof Pharmacy University of Bradford Richmond Road Bradford BD7 1DP UK Fax 44 1274 235600 Tel 44 1274 234717 E-mail a.nicolaou@bradford.ac.uk Present address Faculty of Health and Biological Sciences Schoolof Pharmacy University of Nottingham Malaysia Campus Jalan Broga 43500 Semenyih Selangor DarulEhsan Malaysia Received 14 July 2006 revised 7 November 2006 accepted 9 November 2006 doi 10.1111 j.1742-4658.2006.05583.x The cobalamin-dependent cytosolic enzyme methionine synthase EC.2.1.1.13 catalyzes the remethylation of homocysteine to methionine using 5-methyltetrahydrofolate as the methyl donor. The products of this remethylation - methionine and tetrahydrofolate - participate in the active methionine and folate pathways. Impaired methionine synthase activity has been implicated in the pathogenesis of anaemias cancer and neurological disorders. Although the need for potent and specific inhibitors of methionine synthase has been recognized there is a lack of such agents. In this study we designed synthesized and evaluated the inhibitory activity of a series of substituted benzimidazoles and small benzothiadiazoles. Kinetic analysis revealed that the benzimidazoles act as competitive inhibitors of the rat liver methionine synthase whilst the most active benzothiadiazole IC50 80 pM exhibited characteristics of uncompetitive inhibition. A model of the methyltetrahydrofolate-binding site of the rat liver methionine synthase was constructed docking experiments were designed to elucidate in greater detail the binding mode
