Enhanced complexity and catalytic efficiency in the hydrolysis of phosphate diesters by rationally designed helix-loop-helix motifs.

Enhanced complexity and catalytic efficiency in the hydrolysis of phosphate diesters by rationally designed helix-loop-helix motifs. Research Abstract Details 

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Enhanced complexity and catalytic efficiency in the hydrolysis of phosphate diesters by rationally designed helix-loop-helix motifs. Abstract Text:

HJ1, a 42-residue peptide that folds into a helix-loop-helix motif and dimerizes to form a four-helix bundle, successfully catalyzes the cleavage of "early stage" DNA model substrates in an aqueous solution at pH 7.0, with a rate enhancement in the hydrolysis of heptyl 4-nitrophenyl phosphate of over three orders of magnitude over that of the imidazole-catalyzed reaction, k(2)(HJ1)/k(2)(Im) = 3135. The second-order rate constant, k(2)(HJ1) was determined to be 1.58x10(-4) M(-1) s(-1). The catalyst successfully assembles residues that in a single elementary reaction step are capable of general-acid and general-base catalysis as well as transition state stabilization and proximity effects. The reactivity achieved with the HJ1 polypeptide, rationally designed to catalyze the hydrolysis of phosphodiesters, is based on two histidine residues flanked by four arginines and two adjacent tyrosine residues, all located on the surface of a helix-loop-helix motif. The introduction of Tyr residues close to the catalytic site improves efficiency, in the cleavage of activated aryl alkyl phosphates as well as less activated dialkyl phosphates. HJ1 is also effective in the cleavage of an RNA-mimic substrate, uridine-3'-2,2,2-trichloroethyl phosphate (leaving group pK(a) = 12.3) with a second-order rate constant of 8.23x10(-4) M(-1) s(-1) in aqueous solution at pH 7.0, some 500 times faster than the reaction catalyzed by imidazole, k(2)(HJ1)/k(2)(Im) = 496.

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Enhanced complexity and catalytic efficiency in the hydrolysis of phosphate diesters by rationally designed helix-loop-helix motifs. Journal Published:

PUBLICATION TYPE: Research Support, Non-U.S. Gov

Journal: Chembiochem : a European journal of chemical biolo

VOLUME: 9

Page Numbers: 1975-84

Journal Abbreviation: Chembiochem

ISSN: 1439-7633

DAY: 11

MONTH: Aug

YEAR: 2008

Enhanced complexity and catalytic efficiency in the hydrolysis of phosphate diesters by rationally designed helix-loop-helix motifs. Information

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LANGUAGE: eng

NlmUniqueID: 100937360

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Grant and Affiliation Information for Enhanced complexity and catalytic efficiency in the hydrolysis of phosphate diesters by rationally designed helix-loop-helix motifs.

AFFILIATION: Department of Applied Chemistry, Public University of Navarra, 31006 Pamplona, Navarra, Spain. jrazk@unavarra.es

Country: Germany

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MEDLINETA: Chembiochem

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