tailieunhanh - Báo cáo khoa học: Structural and thermodynamic insights into the binding mode of five novel inhibitors of lumazine synthase from Mycobacterium tuberculosis

Recently published genomic investigations of the human pathogenMyco-bacterium tuberculosishave revealed that genes coding the proteins involved in riboflavin biosynthesis are essential for the growth of the organism. Because the enzymes involved in cofactor biosynthesis pathways are not present in humans, they appear to be promising candidates for the develop-ment of therapeutic drugs. | ễFEBS Journal Structural and thermodynamic insights into the binding mode of five novel inhibitors of lumazine synthase from Mycobacterium tuberculosis 1 2 1. 3 2 2 Ekaterina Morgunova Boris Illarionov Thota Sambaiah Ilka Haase Adelbert Bacher Mark Cushman3 Markus Fischer2 and Rudolf Ladenstein1 1 Karolinska Institute NOVUM Centre for StructuralBiochemistry Huddinge Sweden 2 Lehrstuhl fur Organische Chemie und Biochemie Technische Universitat Munchen Garching Germany 3 Department of MedicinalChemistry and Molecular Pharmacology and the Purdue Cancer Center Schoolof Pharmacy and Pharmaceutical Sciences Purdue University West Lafayette IN USA Keywords crystal structure inhibition lumazine synthase Mycobacterium tuberculosis Correspondence E. Morgunova Karolinska Institutet Department of Bioscience and Nutrition Centre for Structural Biochemistry S-14157 Huddinge Sweden Fax 46 8 6089290 Tel 46 8 608177 E-mail Received 26 June 2006 revised 23 August 2006 accepted 23 August 2006 doi Recently published genomic investigations of the human pathogen Mycobacterium tuberculosis have revealed that genes coding the proteins involved in riboflavin biosynthesis are essential for the growth of the organism. Because the enzymes involved in cofactor biosynthesis pathways are not present in humans they appear to be promising candidates for the development of therapeutic drugs. The substituted purinetrione compounds have demonstrated high affinity and specificity to lumazine synthase which catalyzes the penultimate step of riboflavin biosynthesis in bacteria and plants. The structure of M. tuberculosis lumazine synthase in complex with five different inhibitor compounds is presented together with studies of the binding reactions by isothermal titration calorimetry. The inhibitors showed the association constants in the micromolar range. The analysis of the structures demonstrated the specific features of the binding of .