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Updated: Jul 14, 2026
07:35
Overexpression and Purification of Human Cis-prenyltransferase in Escherichia coli
Published on: August 3, 2017
Bisphosphonates target multiple sites in both cis- and trans-prenyltransferases
Rey-Ting Guo1, Rong Cao, Po-Huang Liang
1Taiwan International Graduate Program, Institute of Biological Chemistry, Core Facility for Protein Crystallography, Academia Sinica, Taipei 115, Taiwan.
Summary
Bisphosphonates inhibit geranylgeranyl diphosphate synthase (GGPPS) and undecaprenyl diphosphate synthase (UPPS), expanding their known drug targets beyond farnesyl diphosphate synthase (FPPS). This reveals novel binding sites and modes for potential antibacterial therapies.
Area of Science:
- Biochemistry
- Structural Biology
- Pharmacology
Background:
- Bisphosphonate drugs are primarily known to inhibit farnesyl diphosphate synthase (FPPS).
- FPPS inhibition leads to decreased prenylation of small GTPases, impacting cellular processes.
- Cis-prenyltransferases like UPPS are potential targets for novel antibacterial therapies.
Purpose of the Study:
- To investigate the inhibitory effects of bisphosphonates on geranylgeranyl diphosphate synthase (GGPPS) and undecaprenyl diphosphate synthase (UPPS).
- To elucidate the structural basis of bisphosphonate binding to GGPPS and UPPS.
- To explore novel therapeutic strategies targeting prenyltransferases.
Main Methods:
- X-ray crystallography was employed to determine the structures of GGPPS- and UPPS-inhibitor complexes.
- Analysis of bisphosphonate binding sites within GGPPS and UPPS.
- Comparison of binding modes across different prenyltransferase enzymes.
Main Results:
- Some bisphosphonates were found to inhibit GGPPS and UPPS, in addition to the known FPPS inhibition.
- Ten structures revealed three distinct bisphosphonate-binding sites in GGPPS, involving substrate and product/inhibitor sites.
- Five structures identified four bisphosphonate-binding sites in UPPS, demonstrating diverse binding interactions.
Conclusions:
- Bisphosphonates exhibit a broader inhibitory spectrum against prenyltransferases than previously understood.
- The determined structures provide the first insights into GGPPS- and UPPS-bisphosphonate complexes.
- These findings open avenues for developing new antibacterial agents targeting UPPS and other prenyltransferases.
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