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Structural and thermodynamic insights into the binding mode of five novel inhibitors of lumazine synthase from Mycobacterium tuberculosis
Author(s) -
Morgunova Ekaterina,
Illarionov Boris,
Sambaiah Thota,
Haase Ilka,
Bacher Adelbert,
Cushman Mark,
Fischer Markus,
Ladenstein Rudolf
Publication year - 2006
Publication title -
the febs journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 204
eISSN - 1742-4658
pISSN - 1742-464X
DOI - 10.1111/j.1742-4658.2006.05481.x
Subject(s) - isothermal titration calorimetry , mycobacterium tuberculosis , biochemistry , biosynthesis , enzyme , cofactor , biology , transferase , chemistry , stereochemistry , tuberculosis , medicine , pathology
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 different inhibitors. The comparison of the structures and binding modes of five different inhibitors allows us to propose the ribitylpurinetrione compounds with C4–C5 alkylphosphate chains as most promising leads for further development of therapeutic drugs against M. tuberculosis .