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.
Highlights
Farnesyl pyrophosphate synthase (FPS; EC 2.5.1.10) is an important chain elongation enzyme of the terpenoid biosynthetic pathway and belongs to the E-family of the prenyltransferases [1]
We modeled three dimensional structure of BmFPS based on comparative modeling approach to establish a basis for its biological role and interaction properties
The final energy estimation was done with Glide score (GScore) and a best orientation was taken as the output for a particular ligand
Summary
Farnesyl pyrophosphate synthase (FPS; EC 2.5.1.10) is an important chain elongation enzyme of the terpenoid biosynthetic pathway and belongs to the E-family of the prenyltransferases [1]. We modeled three dimensional structure of BmFPS based on comparative modeling approach to establish a basis for its biological role and interaction properties. Molecular interactions with substrates and inhibitors were studied by docking simulations, which could certainly provide mechanistic insight in development of mutants for better understanding of reaction mechanisms These structural studies will give an authoritative approach to study catalysis mechanism of BmFPS and its potential use for pathway engineering in plants for altered medicinal value and to develop the drugs for bone related disease and to inhibit the growth of different disease causative agents. Docking studies of BmFPS model with substrates and inhibitors The structure data files (SDF) of the substrates and inhibitors (ligands) were obtained from the PubChem database. The interactions of the ligands with protein were visualized and the figures were formed using PyMOL 1.3
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