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Updated: Dec 7, 2025

Screening for Thermotoga maritima Membrane-Bound Pyrophosphatase Inhibitors
Published on: November 23, 2019
A guanidinium-based inhibitor of a type I isopentenyl diphosphate isomerase
Walid M Abdelmagid1, Niusha Mahmoodi1, Martin E Tanner1
1Department of Chemistry, University of British Columbia, 2036 Main Mall, Vancouver, British Columbia V6T 1Z1, Canada.
Abstract:
An inhibitor bearing a phosphinylphosphonate group appended to a guanidinium functionality was designed to inhibit enzymes that generate carbocations from dimethylallyl diphosphate. When tested against human farnesyl diphosphate synthase the inhibitor bound with high micromolar affinity and did not bind more tightly than an isosteric inhibitor lacking the guanidinium functionality. When tested against the Type I isopentenyl diphosphate:dimethylallyl diphosphate isomerase from Escherichia coli, the inhibitor bound with a Ki value of 120 nM, which was 400 times greater than its isosteric counterpart. This strategy of inhibition was much more effective with an enzyme that generates a carbocation that is not stabilized by both resonance and ion pairing, presumably because there is more evolutionary pressure on the enzyme to stabilize the cation.
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