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Title: Structure and Activity of Yersinia pestis 6-hydroxymethyl-7,8-dihydropterin Pyrophosphokinase as a Novel Target for the Development of Antiplague Therapeutics

Abstract

6-Hydroxymethyl-7,8-dihydropterin pyrophosphokinase (HPPK) is a key enzyme in the folate-biosynthetic pathway and is essential for microorganisms but absent from mammals. HPPK catalyzes Mg2+-dependent pyrophosphoryl transfer from ATP to 6-hydroxymethyl-7,8-dihydropterin (HP). Previously, three-dimensional structures of Escherichia coli HPPK (EcHPPK) have been determined at almost every stage of its catalytic cycle and the reaction mechanism has been established. Here, the crystal structure of Yersinia pestis HPPK (YpHPPK) in complex with HP and an ATP analog is presented together with thermodynamic and kinetic characterizations. The two HPPK molecules differ significantly in a helix-loop area ([alpha]2-Lp3). YpHPPK has lower affinities than EcHPPK for both nucleotides and HP, but its rate constants for the mechanistic steps of both chemical transformation and product release are comparable with those of EcHPPK. Y. pestis, which causes plague, is a category A select agent according to the Centers for Disease Control and Prevention (CDC). Therefore, these structural and biochemical data are valuable for the design of novel medical countermeasures against plague.

Authors:
; ; ; ; ; ; ; ; ;
Publication Date:
Research Org.:
Brookhaven National Laboratory (BNL) National Synchrotron Light Source
Sponsoring Org.:
Doe - Office Of Science
OSTI Identifier:
959550
Report Number(s):
BNL-82536-2009-JA
TRN: US201016%%694
DOE Contract Number:
DE-AC02-98CH10886
Resource Type:
Journal Article
Resource Relation:
Journal Name: Acta Crystallographica Section D: Biological Crystallography; Journal Volume: 63
Country of Publication:
United States
Language:
English
Subject:
36 MATERIALS SCIENCE; CRYSTAL STRUCTURE; DESIGN; DISEASES; ENZYMES; ESCHERICHIA COLI; KINETICS; MAMMALS; MICROORGANISMS; NUCLEOTIDES; REACTION KINETICS; TARGETS; THERMODYNAMICS; TRANSFORMATIONS; national synchrotron light source

Citation Formats

Blaszczyk,J., Li, Y., Cherry, S., Alexandratos, J., Wu, Y., Shaw, G., Tropea, J., Waugh, D., Yan, H., and Ji, X. Structure and Activity of Yersinia pestis 6-hydroxymethyl-7,8-dihydropterin Pyrophosphokinase as a Novel Target for the Development of Antiplague Therapeutics. United States: N. p., 2007. Web. doi:10.1107/S0907444907047452.
Blaszczyk,J., Li, Y., Cherry, S., Alexandratos, J., Wu, Y., Shaw, G., Tropea, J., Waugh, D., Yan, H., & Ji, X. Structure and Activity of Yersinia pestis 6-hydroxymethyl-7,8-dihydropterin Pyrophosphokinase as a Novel Target for the Development of Antiplague Therapeutics. United States. doi:10.1107/S0907444907047452.
Blaszczyk,J., Li, Y., Cherry, S., Alexandratos, J., Wu, Y., Shaw, G., Tropea, J., Waugh, D., Yan, H., and Ji, X. Mon . "Structure and Activity of Yersinia pestis 6-hydroxymethyl-7,8-dihydropterin Pyrophosphokinase as a Novel Target for the Development of Antiplague Therapeutics". United States. doi:10.1107/S0907444907047452.
@article{osti_959550,
title = {Structure and Activity of Yersinia pestis 6-hydroxymethyl-7,8-dihydropterin Pyrophosphokinase as a Novel Target for the Development of Antiplague Therapeutics},
author = {Blaszczyk,J. and Li, Y. and Cherry, S. and Alexandratos, J. and Wu, Y. and Shaw, G. and Tropea, J. and Waugh, D. and Yan, H. and Ji, X.},
abstractNote = {6-Hydroxymethyl-7,8-dihydropterin pyrophosphokinase (HPPK) is a key enzyme in the folate-biosynthetic pathway and is essential for microorganisms but absent from mammals. HPPK catalyzes Mg2+-dependent pyrophosphoryl transfer from ATP to 6-hydroxymethyl-7,8-dihydropterin (HP). Previously, three-dimensional structures of Escherichia coli HPPK (EcHPPK) have been determined at almost every stage of its catalytic cycle and the reaction mechanism has been established. Here, the crystal structure of Yersinia pestis HPPK (YpHPPK) in complex with HP and an ATP analog is presented together with thermodynamic and kinetic characterizations. The two HPPK molecules differ significantly in a helix-loop area ([alpha]2-Lp3). YpHPPK has lower affinities than EcHPPK for both nucleotides and HP, but its rate constants for the mechanistic steps of both chemical transformation and product release are comparable with those of EcHPPK. Y. pestis, which causes plague, is a category A select agent according to the Centers for Disease Control and Prevention (CDC). Therefore, these structural and biochemical data are valuable for the design of novel medical countermeasures against plague.},
doi = {10.1107/S0907444907047452},
journal = {Acta Crystallographica Section D: Biological Crystallography},
number = ,
volume = 63,
place = {United States},
year = {Mon Jan 01 00:00:00 EST 2007},
month = {Mon Jan 01 00:00:00 EST 2007}
}