Tyrosyl DNA-phosphodiesterase I (Tdp1) is a DNA repair enzyme conserved across eukaryotes that catalyzes the hydrolysis of the phosphodiester bond between the tyrosine residue of topoisomerase I and the 3' phosphate of DNA. Tdp1 is an important drug target in anticancer therapy. The atomic level details of the mechanism of Tyrosyl DNA-phosphodiesterase I (Tdp1) is proposed and analyzed using a fully quantum mechanical, geometrically-constrained model. The structural basis for the computational model is the vanadate-inhibited crystal structure of human Tdp1 (PDB Code = 1RFF). Density Functional Theory (DFT) is used to acquire thermodynamic and kinetic data along the catalytic pathway, including the phosphoryl transfer and subsequent hydrolysis. Located transition states and intermediates along the reaction coordinate suggest an associative phosphoryl transfer mechanism with five-coordinate phosphorane intermediates. The possibility of �substrate reorganization� is explored, and comparisons to computed results obtained in our investigation of Streptomyces sp. Strain PMF Phospholipase D [J. Am. Chem. Soc. 2013 , 135, 13764] are discussed.

Phosphoryl transfers of tyrosyl DNA-phosphodiesterase I: A quantum mechanical �cluster model� study

247th National Meeting (2014)

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