tailieunhanh - Báo cáo khoa học: Identification and characterization of an inhibitor specific to bacterial NAD+-dependent DNA ligases

S100 proteins and annexins both constitute groups of Ca 2+ -binding pro-teins, each of which comprises more than 10 members. S100 proteins are small, dimeric, EF-hand-type Ca 2+ -binding proteins that exert both intra-cellular and extracellular functions. | ễFEBS Journal Identification and characterization of an inhibitor specific to bacterial NAD -dependent DNA ligases Timothy I. Meier Dalai Yan Robert B. Peery Kelly A. McAllister Chris Zook Sheng-Bin Peng and Genshi Zhao Lilly Research Laboratories Eli Lilly and Company Indianapolis IN USA Keywords antibiotics DNA ligase DNA replication ligase inhibitor Streptococcus pneumoniae Correspondence G. Zhao Lilly Research Laboratories Eli Lilly and Company Cancer Research DC0434 Lilly Corporate Center Indianapolis IN 46285 0434 USA Fax 1 317 276 1414 Tel 1 317 276 2040 E-mail Zhao_Genshi@ Received 10 July 2008 revised 12 August 2008 accepted 22 August 2008 doi DNA ligases are the enzymes essential for DNA replication repair and recombination in all organisms. The bacterial DNA ligases involved in DNA replication require NAD for activity but eukaryotic and viral DNA ligases require ATP. Because of their essential nature unique structures and widespread existence in nature bacterial DNA ligases represent a class of valuable targets for identifying novel and selective antibacterial agents. In this study we cloned and expressed the ligA gene from Streptococcus pneumoniae and characterized this ligA-encoded NAD -dependent DNA ligase. We then screened small molecule chemical libraries using a biochemical assay and identified a new small molecule with a structure of 2 4-diamino-7-dimethylamino-pyrimido 4 5-d pyrimidine. We show that this small molecule is a specific inhibitor of bacterial NAD -dependent DNA ligases. Biochemical studies show that this molecule inhibits NAD -depen-dent DNA ligases but not ATP-dependent enzymes. The molecule inhibits NAD -dependent DNA ligases competitively with respect to NAD and specifically inhibits enzyme adenylation but not DNA adenylation or ligation. Labeling studies establish that this molecule inhibits the incorporation of thymidine into DNA and that overexpression of DNA ligase in the cell .

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