Simulation of structural and functional properties of mevalonate diphosphate decarboxylase (MVD).
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 A 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 Pro(79)- 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.
Weerasinghe
Samantha
S
Department of Chemistry, University of Colombo, Colombo, 00300, Sri Lanka.
Samantha Dassanayake
Ranil
R
D001224:Aspartic Acid / Q000378:metabolism; D055162:Biocatalysis; D002262:Carboxy-Lyases / Q000737:chemistry* / Q000378:metabolism*; D006860:Hydrogen Bonding; D008798:Mevalonic Acid / Q000031:analogs & derivatives / Q000737:chemistry; D056004:Molecular Dynamics Simulation; D009154:Mutation / Q000235:genetics; D017433:Protein Structure, Secondary; D012441:Saccharomyces cerevisiae / Q000201:enzymology*; D020539:Sequence Analysis, Protein; D013816:Thermodynamics; D013997:Time Factors
D001224:Aspartic Acid; C046285:5-diphosphomevalonic acid; D002262:Carboxy-Lyases; C022503:pyrophosphomevalonate decarboxylase; D008798:Mevalonic Acid