A guanidinium group is an effective mimic of the tertiary carbocation formed by isopentenyl diphosphate isomerase.

Basic Information

ID: ALA5223115

Journal: Bioorg Med Chem Lett

Title: A guanidinium group is an effective mimic of the tertiary carbocation formed by isopentenyl diphosphate isomerase.

Authors: Zhuang Z, Li M, Tanner ME.

Abstract: Type I isopentenyl diphosphate isomerase is a metal-dependent enzyme that generates a tertiary carbocation intermediate during catalysis. This study describes an inhibitor (2-guanidinoethyl(dihydroxyphosphorylmethyl)phosphinate) of the isomerase that bears a guanidinium as a carbocation mimic and a phosphinylphosphonate as a non-hydrolyzable metal binding functionality. Inhibition kinetics show that the compound acts in a competitive manner with a K_i value of 129 nM (K_M,IPP/K_i = 27). An analogous inhibitor bearing a tertiary ammonium as the carbocation mimic was 50-fold less potent, suggesting that the planar guanidinium is a more effective carbocation mimic. Inhibitors bearing an acylated methanesulfonamide or a hydroxamate group in place of the pyrophosphate inhibited the enzyme at millimolar concentrations indicating that the isomerase is highly specific for binding to the diphosphate portion of the intermediate.

CiteXplore: 36064124

DOI: 10.1016/j.bmcl.2022.128971

Patent ID: ┄

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