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Simulation of structural and functional properties of mevalonate diphosphate decarboxylase (MVD)

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Abstract

Mevalonate 5-diphosphate decarboxylase (MVD) is an important enzyme in the mevalonate pathway catalyzing the ATP-dependent decarboxylation of mevalonate 5-diphosphate (MDP) to yield isopentynyl diphosphate (IPP) which is an ubiquitous precursor for isoprenoids and sterols. Although there are studies to show the involvement of certain amino acid residues in MVD activity, the structure and the function of the active site is yet to be investigated. Therefore the objectives of this study were to elucidate the active site of Saccharomyces cerevisiae MVD (scMVD) using a molecular docking and simulation-based approach. The Cartesian coordinates of scMVD retrieved from the PDB database were used in the docking procedure. 3D atomic coordinates of MDP, ATP and an inhibitor trifluoromevalonate (TFMDP) were generated using Gaussian 98. ATP, MDP and TFMDP were docked into the potential active site identified by sequence analyses using Hex 4.2. The complexes obtained from docking procedure were subjected to 1.5 ns simulation by GROMACS 3.2. Investigation of complexes revealed that Ala15, Lys18, Ser121 & Ser155; Lys22, Ser153 & Ser155 and Tyr19, Ser121, Ser153, Gly154 & Thr209 of MVD are within hydrogen bond forming distances of MDP, ATP and TFMDP, respectively indicating their possible involvement in active site formation through H-bond formation. The presence of a water molecule between the carboxyl group of Asp302, a previously characterized active site residue and C3 region of MDP at a distance of 3 Å suggests that deprotonation of the hydroxyl of the C3 takes place via a water molecule. Conjunction with reported crucial catalytic activity of Ser121 of MVD and our finding of the presence of this residue in hydrogen bond forming distance to MDP suggests that this hydrogen bond helps in proper orienting of MDP for phosphorylation /decarboxylation. We further suggest that the reported greater RMS deviation of Pro79- Leu mutated MVD with respect to native MVD of temperature sensitive mutant phenotype of S. cerevisiae is due to partial unfolding of MVD as a result of mutation. Finally, this study provides a tantalizing glimpse about hitherto unknown structural and functional properties of the active site of MVD.

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Acknowledgments

We acknowledge the Department of Chemistry, University of Colombo, Sri Lanka for providing us with computer facilities and software for this work. We thank scientists who worked on MVD and published in scientific journals or deposited their data in publicly available databases. We further thank the scientists who developed Molecular Biology Software programs and Bioinformatics tools used in this study and also Dr. N.V. Chandrasekharan, Department of Chemistry, University of Colombo, Sri Lanka, for critical reading of the manuscript.

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  1. Department of Chemistry, Faculty of Science, University of Colombo, Colombo, 00300, Sri Lanka

    Samantha Weerasinghe & Ranil Samantha Dassanayake

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  1. Samantha Weerasinghe
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  2. Ranil Samantha Dassanayake
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Correspondence to Ranil Samantha Dassanayake.

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Weerasinghe, S., Samantha Dassanayake, R. Simulation of structural and functional properties of mevalonate diphosphate decarboxylase (MVD). J Mol Model 16, 489–498 (2010). https://doi.org/10.1007/s00894-009-0561-7

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  • DOI: https://doi.org/10.1007/s00894-009-0561-7

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