New insights into the mechanism of the Schiff base formation catalyzed by type I dehydroquinate dehydratase from <Emphasis Type="Italic">S. enterica</Emphasis> |
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Authors: | Qi?Pan Email author" target="_blank">Yuan?YaoEmail author Email author" target="_blank">Ze-Sheng?LiEmail author |
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Institution: | (1) Academy of Fundamental and Interdisciplinary Science, Harbin Institute of Technology, Harbin, 150080, People’s Republic of China;(2) Department of Orthopaedic, The First Affiliated Hospital of Harbin Medical University, Harbin, 150080, People’s Republic of China;(3) Key Laboratory of Cluster Science of Ministry of Education, School of Chemistry, Beijing Institute of Technology, No. 5 Yard, Zhong Guan Cun South Street, Beijing, 100081, People’s Republic of China; |
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Abstract: | The Schiff base formation catalyzed by type I dehydroquinate dehydratase (DHQD) from Salmonella enterica has been studied by molecular docking, molecular dynamics simulation, and quantum chemical calculations. The substrate locates
stably a similar position as the Schiff base intermediate observed in the crystal structure and forms strong hydrogen bonds
with several active site residues. This binding mode is different from that of several other Schiff base enzymes. Then, the
quantum chemical model has been constructed and the fundamental reaction pathways have been explored by performing quantum
chemical calculation. The energy barrier of the previously proposed reaction pathway is calculated to be 30.7 kcal/mol, which
is much higher than the experimental value of 14.3 kcal/mol of the whole dehydration reaction by type I DHQD from S. enterica. It means that this pathway is not favorable in energy. Therefore, a new and unexpected reaction pathway has been investigated
with the favorable and reasonable energy barrier of 12.1 kcal/mol. The complicated role of catalytic His143 residue has also
been elucidated that it mediates two proton transfers to facilitate the reaction. Moreover, the similarity and the difference
between these two reaction pathways have been analyzed in detail. The new structural and mechanistic insights may direct the
design of the inhibitors of type I dehydroquinate dehydratase as non-toxic antimicrobials, antifungals, and herbicides. |
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