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Catalytic mechanism of type C sialidase from Streptococcus pneumoniae: from covalent intermediate to final product

  • Jing Xiong
  • Chunchun Zhang
  • Dingguo Xu
Original Paper

Abstract

Streptococcus pneumoniae is a Gram-positive human pathogenic bacterium, which is the main cause of pneumonia and meningitis in children and the elderly. Three sialidases (or neuraminidases) encoded from Streptococcus pneumoniae could catalyze the cleavage of sialic acid linkages. This mechanism is directly connected with infection, apoptosis, and signaling, and usually considered to be one of the critical virulence factors. Type C neuraminidase (NanC) is unique because its primary product of Neu5Ac2en is considered to be an inhibitor to the other two sialidases. Experimentally, there are two different pathways for the formation mechanism of Neu5Ac2en catalyzed by NanC. In this work, a combined quantum mechanical and molecular mechanical approach was employed in all calculations. Starting from the covalent sialylated intermediate, we first examined the reaction to Neu5Ac2en and found the reaction prefers a direct proton abstraction mechanism rather than the water mediated proton abstraction mechanism. Free energy profiles can confirm that Neu5Ac2en is the major product of NanC. Functional roles of some important residues were also investigated, e.g., D315 acts as the proton acceptor during the formation of Neu5Ac2en, while the general base for the hydrolytic reaction to Neu5Ac. This study can facilitate the understanding of the catalytic mechanism of NanC and has the potential to aid in future inhibitor design studies.

Keywords

QM/MM Sialidase C Catalytic mechanism PMF 

Notes

Acknowledgments

This work was funded by the National Key Research and Development Program (No. 2016YFB0700801) and the National Natural Science Foundation of China (No. 21473117). Some of the results described in this work were obtained on the Supercomputing Center of Chinese Academy of Science.

Supplementary material

894_2018_3822_MOESM1_ESM.docx (1.2 mb)
Supporting information 1 Distances between C3 of Neu5Ac unit and the carboxylate group of D315 in the CI complex (covalently sialylated enzyme intermediate); The endocyclic torsion angles for Neu5Ac unit of the CI and two products of Neu5Ac2en and Neu5Ac. B3LYP/MM single point free energy correction strategy. RMSD for the backbone atoms of the CI complex in classical MD simulation. Distance between the oxygen atom of this water molecule and C3 along the simulation time. (DOCX 1270 kb)

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.MOE Key Laboratory of Green Chemistry & Technology, College of ChemistrySichuan UniversityChengduPeople’s Republic of China
  2. 2.School of PharmacyChengdu Medical CollegeChengduPeople’s Republic of China
  3. 3.Analytical&Testing CenterSichuan UniversityChengduPeople’s Republic of China

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