Structure and dynamics of 6-Hydroxymethyl-6,8-dihydropterin pyrophosphokinase
Folates are essential or life. Unlike mammals, most microorganisms must synthesize folates de novo. 6-Hydroxymethyl-7,8-dihydropterin pyrophosphokinase (HPPK) catalyzes pyrophosphoryl transfer from ATP to 6-hydroxymethyl-7,8-dihydropterin (HP), the first reaction in folate pathway, and therefore, is an ideal target for developing novel antimicrobial agents. Because of its small size and high thermal stability. E, coli HPPK is also an excellent model enzyme for studying the mechanisms of enzymatic pyrophosphoryl transfer. We have determined the crystal structures at HPPK in the unligated form and in complex with HP, two Mg2+ ions, and AMPCPP (nn ATP analog that inhibits the enzymatic reaction), Comparison of the two crystal structures reveals dramatic conformational changes of three flexible loops and many side chains and possible roles of the active sire residues. (C) 2001 hy Elsevier Science Inc.
pyrophosphokinase folate hppk antimicrobial agent conformation change pterin protein flexibility nmr spectroscopy x-ray crystallography