Capturing the free energy of transition state stabilization: insights from the inhibition of mandelate racemase.

ABSTRACT: Mandelate racemase (MR) catalyses the Mg²⁺-dependent interconversion of (R)- and (S)-mandelate. To effect catalysis, MR stabilizes the altered substrate in the transition state (TS) by approximately 26 kcal mol^-1 (-ΔG_tx), such that the upper limit of the virtual dissociation constant of the enzyme-TS complex is 2 × 10^-19 M. Designing TS analogue inhibitors that capture a significant amount of ΔG_tx for binding presents a challenge since there are a limited number of protein binding determinants that interact with the substrate and the structural simplicity of mandelate constrains the number of possible isostructural variations. Indeed, current intermediate/TS analogue inhibitors of MR capture less than or equ

SUBMITTER: Bearne SL 

PROVIDER: S-EPMC9835602 | biostudies-literature | 2023 Feb

REPOSITORIES: biostudies-literature