Crystal structure of 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase, a potential target for the development of novel antimicrobial agents

摘要: Abstract Background: Folate cofactors are essential for life. Mammals derive folates from their diet, whereas most microorganisms must synthesize de novo . Enzymes of the folate pathway therefore provide ideal targets development antimicrobial agents. 6-Hydroxymethyl-7,8-dihydropterin pyrophosphokinase (HPPK) catalyzes transfer pyrophosphate ATP to 6-hydroxymethyl-7,8-dihydropterin (HP), first reaction in biosynthetic pathway. Results: The crystal structure HPPK Escherichia coli has been determined at 1.5 A resolution with a crystallographic R factor 0.182. molecule novel three-layered α β fold that creates valley approximately 26 long, 10 wide and deep. active center is located substrate-binding sites have identified aid NMR spectroscopy. HP-binding site one end valley, near Asn55, sandwiched between two aromatic sidechains. ATP-binding other valley. adenine base positioned Leu111 ribose triphosphate extend across reach vicinity HP. Conclusions: provides framework elucidate structure/function relationships enzyme analyze mechanisms pyrophosphoryl transfer. Furthermore, this work may prove useful structure-based design new