Molecular characterization of farnesyl pyrophosphate synthase from Bacopa monniera by comparative modeling and docking studies |
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Authors: | Rishi Kishore Vishwakarma Krunal Arvind Patel Prashant Sonawane Somesh Singh Ruby Uma Kumari Dinesh Chandra Agrawal Bashir Mohammad Khan |
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Institution: | Plant Tissue Culture Division, National Chemical Laboratory, Dr. Homi Bhabha Road, Pune-411 008, Maharashtra, India;$Authors equally contributed |
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Abstract: | Farnesyl pyrophosphate synthase (FPS; EC 2.5.1.10) is a key enzyme in isoprenoid biosynthetic pathway and provides precursors
for the biosynthesis of various pharmaceutically important metabolites. It catalyzes head to tail condensation of two isopentenyl
pyrophosphate molecules with dimethylallyl pyrophosphate to form C15 compound farnesyl pyrophosphate. Recent studies have
confirmed FPS as a molecular target of bisphosphonates for drug development against bone diseases as well as pathogens.
Although large numbers of FPSs from different sources are known, very few protein structures have been reported till date. In the
present study, FPS gene from medicinal plant Bacopa monniera (BmFPS) was characterized by comparative modeling and docking.
Multiple sequence alignment showed two highly conserved aspartate rich motifs FARM and SARM (DDXXD). The 3-D model of
BmFPS was generated based on structurally resolved FPS crystal information of Gallus gallus. The generated models were validated
by various bioinformatics tools and the final model contained only α-helices and coils. Further, docking studies of modeled BmFPS
with substrates and inhibitors were performed to understand the protein ligand interactions. The two Asp residues from FARM
(Asp100 and Asp104) as well as Asp171, Lys197 and Lys262 were found to be important for catalytic activity. Interaction of
nitrogen containing bisphosphonates (risedronate, alendronate, zoledronate and pamidronate) with modeled BmFPS showed
competitive inhibition; where, apart from Asp (100, 104 and 171), Thr175 played an important role. The results presented here
could be useful for designing of mutants for isoprenoid biosynthetic pathway engineering well as more effective drugs against
osteoporosis and human pathogens.AbbreviationsIPP - Isopentenyl Pyrophosphate,
DMAPP - Dimethylallyl Pyrophosphate,
GPP - Geranyl Pyrophosphate,
FPP - FPPFarnesyl Pyrophosphate,
DOPE - Discrete Optimized Protein Energy,
BmFPS - Bacopa monniera Farnesyl Pyrophosphate Synthase,
RMSD - Root Mean square Deviation,
OPLS-AA - Optimized Potentials for Liquid Simulations- All Atom,
FARM - First Aspartate Rich Motif,
SARM - Second Aspartate Rich Motif. |
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Keywords: | Bacopa monniera Bisphosphonates Comparative modeling and docking Farnesyl pyrophosphate synthase |
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