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

Glutamate racemases ( GR ) catalyze the racemization of d ‐ and l ‐glutamate and are targets for the development of antibiotics. We demonstrate that GR from the periodontal pathogen Fusobacterium nucleatum ( Fn GR ) catalyzes the racemization of d ‐homocysteic acid ( d ‐ HCA ), while l ‐ HCA is a poor substrate. This enantioselectivity arises because l ‐ HCA perturbs Fn GR 's monomer–dimer equilibrium toward inactive monomer. The inhibitory effect of l ‐ HCA may be overcome by increasing the total Fn GR concentration or by adding glutamate, but not by blocking access to the active site through site‐directed mutagenesis, suggesting that l ‐ HCA binds at an allosteric site. This phenomenon is also exhibited by GR from Bacillus subtilis , suggesting that enantiospecific, “substrate”‐induced dissociation of oligomers to form inactive monomers may furnish a new inhibition strategy.