RESUMO
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 Ki value of 129 nM (KM,IPP/Ki = 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.
Assuntos
Compostos de Amônio , Difosfatos , Guanidina/farmacologia , Hemiterpenos/química , Isomerases , Cinética , Compostos OrganofosforadosRESUMO
Tubulin polyglycylation is a posttranslational modification that occurs primarily on the axonemes of flagella and cilia and has been shown to be essential for proper sperm motility. Inhibitors of both the initiase and elongase ligases (TTLL8 and TTLL10) are shown to inhibit tubulin glycylation in the low micromolar range.