crystal structure of the 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase？dihydropteroate synthase bifunctional enzyme from francisella tularensis晶体结构的6-hydroxymethyl-7 8-dihydropterin pyrophosphokinase dihydropteroate合酶双功能酶从土拉杆菌内.pdf

Crystal Structure of the 6-Hydroxymethyl-7,8- Dihydropterin PyrophosphokinaseNDihydropteroate Synthase Bifunctional Enzyme from Francisella tularensis 1¤a 2 1¤b 1 3 Charles W. Pemble IV , Perdeep K. Mehta , Smriti Mehra , Zhenmei Li , Amanda Nourse , Richard E. Lee4*, Stephen W. White1,5* 1 Department of Structural Biology, St. Jude Children’s Research Hospital, Memphis, Tennessee, United States of America, 2 Department of Information Sciences, St. Jude Children’s Research Hospital, Memphis, Tennessee, United States of America, 3 The Hartwell Center, St. Jude Children’s Research Hospital, Memphis, Tennessee, United States of America, 4 Chemical Biology and Therapeutics, St. Jude Children’s Research Hospital, Memphis, Tennessee, United States of America, 5 Department of Molecular Sciences, University of Tennessee Health Science Center, Memphis, Tennessee, United States of America Abstract The 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase (HPPK) and dihydropteroate synthase (DHPS) enzymes catalyze sequential metabolic reactions in the folate biosynthetic pathway of bacteria and lower eukaryotes. Both enzymes represent validated targets for the development of novel anti-microbial therapies. We report herein that the genes which encode FtHPPK and FtDHPS from the biowarfare agent Francisella tularensis are fused into a single polypeptide. The potential of simultaneously targeting both modules with pterin binding inhibitors prompted us to characterize the molecular details of the multifunctional complex. Our high resolution crystallographic analyses reveal the structural organization between FtHPPK and FtDHPS which are tethe