A Quantum Mechanical/Molecular Mechanical Study on the Catalysis of the Pyridoxal 5′-Phosphate-Dependent Enzyme l-Serine Dehydratase

Zheng Zhao and Haiyan Liu*
School of Life Sciences, and Hefei National Laboratory for Physical Sciences at the Microscale, University of Science and Technology of China (USTC), Hefei, Anhui, 230027, China
J. Phys. Chem. B, 2008, 112 (41), pp 13091–13100
DOI: 10.1021/jp802262m
Publication Date (Web): September 24, 2008
Copyright © 2008 American Chemical Society
* To whom correspondence should be addressed. E-mail: hyliu@ustc.edu.cn.

Abstract

The catalytic mechanism of a pyridoxal 5′-phosphate-dependent enzyme, l-serine dehydratase, has been investigated using ab initio quantum mechanical/molecular mechanical (QM/MM) methods. New insights into the chemical steps have been obtained, including the chemical role of the substrate carboxyl group in the Schiff base formation step and a proton-relaying mechanism involving the phosphate of the cofactor in the β-hydroxyl-leaving step. The latter step is of no barrier and follows sequentially after the elimination of the α-proton, leading to a single but sequential α, β-elimination step. The rate-limiting transition state is specifically stabilized by the enzyme environment. At this transition state, charges are localized on the substrate carboxyl group, as well as on the amino group of Lys41. Specific interactions of the enzyme environment with these groups are able to lower the activation barrier significantly. One major difficulty associated with studies of complicated enzymatic reactions using ab initio QM/MM models is the appropriate choices of reaction coordinates. In this study, we have made use of efficient semiempirical models and pathway optimization techniques to overcome this difficulty.

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History

  • Published In Issue October 16, 2008
  • Article ASAPSeptember 24, 2008
  • Received: March 14, 2008
    Revised: June 19, 2008

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