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Logo of jbcThe Journal of Biological Chemistry
 
J Biol Chem. 2014 January 31; 289(5): 2825.
PMCID: PMC3908414

Figuring out How a Deoxyribonucleoside Triphosphate Triphosphohydrolase Functions in a Pathogenic Bacterium♦

Mechanisms of Allosteric Activation and Inhibition of the Deoxyribonucleoside Triphosphate Triphosphohydrolase from Enterococcus faecalis

♦ See referenced article, J. Biol. Chem. 2014, 289, 2815–2824

Enterococcus faecalis is a common, life-threatening pathogen that gets picked up in hospitals. The bacterium undergoes frequent mutations, giving rise to antibiotic-resistant forms. To better understand E. faecalis pathogenicity and adaptation to antibiotics, a team led by Jinwoo Ahn at the University of Pittsburgh School of Medicine and Wayne F. Anderson at the Northwestern University Feinberg School of Medicine studied EF1143, a triphosphohydrolase that acts on deoxyribonucleoside triphosphates (dNTPs) and is involved in maintaining the correct levels of dNTPs in cells. The investigators carried out enzymatic analyses on EF1143 and solved its crystal structure bound to dGTP and dTTP. Their data helped to clarify previous studies and show that tetrameric EF1143 has secondary allosteric sites that lie next to the main dGTP-binding regulatory sites. dGTP binding in the main sites has to happen before other dNTPs can dock and undergo hydrolysis. “The presence of a particular dNTP in the second site either enhances or inhibits the dNTPase activity of EF1143,” say the authors. “Our results provide the first mechanistic insight into dNTP-mediated regulation of dNTPase activity.”

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Model of dNTP-dependent allosteric regulation of EF1143 catalysis. dGTP binds to each of four primary allosteric sites (Intermediate). Binding of either dTTP or dGTP at the two secondary allosteric sites, adjacent to the primary site, results in an inhibited form by closing the catalytic site (×), whereas binding of dATP or dCTP at the same secondary sites activates the enzyme (○).


Articles from The Journal of Biological Chemistry are provided here courtesy of American Society for Biochemistry and Molecular Biology