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Title: Structure of the Type III Pantothenate Kinase from Bacillus Anthracis at 2.0 A Resolution: Implications for Coenzyme A-Dependent Redox Biology

Abstract

Coenzyme A (CoASH) is the major low-molecular weight thiol in Staphylococcus aureus and a number of other bacteria; the crystal structure of the S. aureus coenzyme A-disulfide reductase (CoADR), which maintains the reduced intracellular state of CoASH, has recently been reported [Mallett, T.C., Wallen, J.R., Karplus, P.A., Sakai, H., Tsukihara, T., and Claiborne, A. (2006) Biochemistry 45, 11278-89]. In this report we demonstrate that CoASH is the major thiol in Bacillus anthracis; a bioinformatics analysis indicates that three of the four proteins responsible for the conversion of pantothenate (Pan) to CoASH in Escherichia coli are conserved in B. anthracis. In contrast, a novel type III pantothenate kinase (PanK) catalyzes the first committed step in the biosynthetic pathway in B. anthracis; unlike the E. coli type I PanK, this enzyme is not subject to feedback inhibition by CoASH. The crystal structure of B. anthracis PanK (BaPanK), solved using multiwavelength anomalous dispersion data and refined at a resolution of 2.0 {angstrom}, demonstrates that BaPanK is a new member of the Acetate and Sugar Kinase/Hsc70/Actin (ASKHA) superfamily. The Pan and ATP substrates have been modeled into the active-site cleft; in addition to providing a clear rationale for the absence of CoASH inhibition, analysismore » of the Pan-binding pocket has led to the development of two new structure-based motifs (the PAN and INTERFACE motifs). Our analyses also suggest that the type III PanK in the spore-forming B. anthracis plays an essential role in the novel thiol/disulfide redox biology of this category A biodefense pathogen.« less

Authors:
; ; ; ; ; ; ; ;
Publication Date:
Research Org.:
Brookhaven National Laboratory (BNL) National Synchrotron Light Source
Sponsoring Org.:
Doe - Office Of Science
OSTI Identifier:
930265
Report Number(s):
BNL-80958-2008-JA
Journal ID: ISSN 0006-2960; TRN: US200822%%1433
DOE Contract Number:
DE-AC02-98CH10886
Resource Type:
Journal Article
Resource Relation:
Journal Name: Biochemistry; Journal Volume: 46; Journal Issue: 11
Country of Publication:
United States
Language:
English
Subject:
36 MATERIALS SCIENCE; ACETATES; ATP; BACILLUS; BACTERIA; BIOCHEMISTRY; BIOLOGY; COENZYMES; CONVERSION; CRYSTAL STRUCTURE; DATA; DISPERSIONS; ENZYMES; ESCHERICHIA COLI; FEEDBACK; INHIBITION; INTERFACES; OXIDOREDUCTASES; PHOSPHOTRANSFERASES; PROTEINS; PYRIDYLAZONAPHTHOL; RESOLUTION; SACCHAROSE; STAPHYLOCOCCUS; SUBSTRATES; THIOLS; WEIGHT; national synchrotron light source

Citation Formats

Nicely,N., Parsonage, D., Paige, C., Newton, G., Fahey, R., Leonardi, R., Jackowski, S., Mallett, T., and Claiborne, A. Structure of the Type III Pantothenate Kinase from Bacillus Anthracis at 2.0 A Resolution: Implications for Coenzyme A-Dependent Redox Biology. United States: N. p., 2007. Web. doi:10.1021/bi062299p.
Nicely,N., Parsonage, D., Paige, C., Newton, G., Fahey, R., Leonardi, R., Jackowski, S., Mallett, T., & Claiborne, A. Structure of the Type III Pantothenate Kinase from Bacillus Anthracis at 2.0 A Resolution: Implications for Coenzyme A-Dependent Redox Biology. United States. doi:10.1021/bi062299p.
Nicely,N., Parsonage, D., Paige, C., Newton, G., Fahey, R., Leonardi, R., Jackowski, S., Mallett, T., and Claiborne, A. Mon . "Structure of the Type III Pantothenate Kinase from Bacillus Anthracis at 2.0 A Resolution: Implications for Coenzyme A-Dependent Redox Biology". United States. doi:10.1021/bi062299p.
@article{osti_930265,
title = {Structure of the Type III Pantothenate Kinase from Bacillus Anthracis at 2.0 A Resolution: Implications for Coenzyme A-Dependent Redox Biology},
author = {Nicely,N. and Parsonage, D. and Paige, C. and Newton, G. and Fahey, R. and Leonardi, R. and Jackowski, S. and Mallett, T. and Claiborne, A.},
abstractNote = {Coenzyme A (CoASH) is the major low-molecular weight thiol in Staphylococcus aureus and a number of other bacteria; the crystal structure of the S. aureus coenzyme A-disulfide reductase (CoADR), which maintains the reduced intracellular state of CoASH, has recently been reported [Mallett, T.C., Wallen, J.R., Karplus, P.A., Sakai, H., Tsukihara, T., and Claiborne, A. (2006) Biochemistry 45, 11278-89]. In this report we demonstrate that CoASH is the major thiol in Bacillus anthracis; a bioinformatics analysis indicates that three of the four proteins responsible for the conversion of pantothenate (Pan) to CoASH in Escherichia coli are conserved in B. anthracis. In contrast, a novel type III pantothenate kinase (PanK) catalyzes the first committed step in the biosynthetic pathway in B. anthracis; unlike the E. coli type I PanK, this enzyme is not subject to feedback inhibition by CoASH. The crystal structure of B. anthracis PanK (BaPanK), solved using multiwavelength anomalous dispersion data and refined at a resolution of 2.0 {angstrom}, demonstrates that BaPanK is a new member of the Acetate and Sugar Kinase/Hsc70/Actin (ASKHA) superfamily. The Pan and ATP substrates have been modeled into the active-site cleft; in addition to providing a clear rationale for the absence of CoASH inhibition, analysis of the Pan-binding pocket has led to the development of two new structure-based motifs (the PAN and INTERFACE motifs). Our analyses also suggest that the type III PanK in the spore-forming B. anthracis plays an essential role in the novel thiol/disulfide redox biology of this category A biodefense pathogen.},
doi = {10.1021/bi062299p},
journal = {Biochemistry},
number = 11,
volume = 46,
place = {United States},
year = {Mon Jan 01 00:00:00 EST 2007},
month = {Mon Jan 01 00:00:00 EST 2007}
}