Title

Authors

Affiliation

Plant Tissue Culture Division, National Chemical Laboratory, Dr. Homi Bhabha Road, Pune-411 008, Maharashtra, India.

Email

bm.khan@ncl.res.in; *Corresponding author

Article Type

Hypothesis

Date

Received October 17, 2012; Accepted October 26, 2012; Published November 13, 2012

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. 

Keywords

Bacopa monniera, Bisphosphonates, Comparative modeling and docking, Farnesyl pyrophosphate synthase.

Abbreviations

IPP- Isopentenyl Pyrophosphate, DMAPP- Dimethylallyl Pyrophosphate, GPP- Geranyl Pyrophosphate, FPP- Farnesyl 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.

Citation

Vishwakarma et al.  Bioinformation 8(22): 1075-1081 (2012)
 

Edited by

P Kangueane

ISSN

0973-2063

Publisher

Biomedical Informatics

License

This is an Open Access article which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. This is distributed under the terms of the Creative Commons Attribution License.