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      Product release mechanism and the complete enzyme catalysis cycle in yeast cytosine deaminase (yCD): A computational study.

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          Abstract

          Yeast cytosine deaminase (yCD) is critical in gene-directed enzyme prodrug therapy as it catalyzes the hydrolytic deamination of cytosine. The product (uracil) release process is considered as rate-limiting in the whole enzymatic catalysis and includes the cleavage of the uracil-metal bond and the delivery of free uracil out of the reactive site. Herein extensive combined random acceleration molecular dynamics (RAMD) and molecular dynamics (MD) simulations coupled with the umbrella sampling technique have been performed to study the product transport mechanism. Five channels have been identified, and the thermodynamic and dynamic characterizations for the two most favorable channels have been determined and analyzed. The free energy barrier for the most beneficial pathway is about 13kcal/mol and mainly results from the cleavage of hydrogen bonds between the ligand uracil and surrounding residues Asn51, Glu64, and Asp155. The conjugated rings of Phe114 and Trp152 play gating and guiding roles in the product delivery via π⋯π van der Waals interactions with the product. Finally, the full cycle of the enzymatic catalysis has been determined, making the whole process computationally more precise.

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          Author and article information

          Journal
          Biochim. Biophys. Acta
          Biochimica et biophysica acta
          Elsevier BV
          0006-3002
          0006-3002
          May 03 2017
          Affiliations
          [1 ] The Key Laboratory of Natural Medicine and Immuno-Engineering, Henan University, Kaifeng 475004, China. Electronic address: zhaoyuan@henu.edu.cn.
          [2 ] The Key Laboratory of Natural Medicine and Immuno-Engineering, Henan University, Kaifeng 475004, China.
          [3 ] State Key Laboratory of Chemical Resource Engineering, Institute of Materia Medica, College of Science, Beijing University of Chemical Technology, Beijing 100029, China.
          [4 ] The Key Laboratory of Natural Medicine and Immuno-Engineering, Henan University, Kaifeng 475004, China. Electronic address: wcjsxq@henu.edu.cn.
          [5 ] Department of Chemistry, Western Michigan University, Kalamazoo, MI 49008, USA.
          Article
          S1570-9639(17)30083-3
          10.1016/j.bbapap.2017.05.001
          28478051
          c00b4ef9-cd6c-4ac9-9fca-5256394ca2b3
          History

          MM MD,Product release mechanism,RAMD MD,Umbrella sampling,Yeast cytosine deaminase

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