Inhibition of glutamate racemase by substrate–product analogues

Synthesis and Biological Applications of Phosphinates and Derivatives

“…In this perspective, Pal and Bearne reported cyclic phosphinic acid 211, analogues of natural glutamate substrate, as modest and partial noncompetitive inhibitors of glutamate racemase from Fusobacterium nucleatum (FnGR) [143]. Phosphinane 211 was prepared through a six-step sequence starting from hypophosphorous acid (Scheme 41) [143]. After transformation into silyl phosphonite by treatment with trismethoxy(propyl)silane, a Michael addition afforded H-phosphinic acid 212 in 62% yield.…”

“…Glutamate racemase (GR) is the enzyme controlling the stereoconversion of L-glutamate into D-enantiomer. In this perspective, Pal and Bearne reported cyclic phosphinic acid 211, analogues of natural glutamate substrate, as modest and partial noncompetitive inhibitors of glutamate racemase from Fusobacterium nucleatum (FnGR) [143]. Phosphinane 211 was prepared through a six-step sequence starting from hypophosphorous acid (Scheme 41) [143].…”

“…The inhibitory properties of phosphinane 211 were evaluated against FnGR [143]. With a K i value of 24.1 AE 3.8 mM, compound 211 was considered as a modest inhibitor of FnGR.…”

Changes in quaternary structure cause a kinetic asymmetry of glutamate racemase‐catalyzed homocysteic acid racemization

“…In general, GRs exhibit restricted substrate specificity with respect to the charge distribution and side chain length of the potential substrate . These observations are in accord with the incommodious nature of the active site and specific electrostatic interactions observed in crystal structures of GRs with bound substrate or inhibitors . Since l ‐homocysteine sulfinate was shown to be a substrate for GRs from B. subtilis and Pediococcus pentosaceus , we explored the ability of Fn GR to utilize the Glu analog HCA as a substrate and compared the results with those obtained for Bs GR.…”

“…Primarily, two strategies for developing GR inhibitors have been described. First, a variety of Glu analogs have been successfully developed as inhibitors , and second, inhibitors that bind at allosteric sites have been discovered . Because of the importance of GR as an antibacterial target, the development of alternative inhibition strategies remains an important goal.…”