Comment on binding affinity determines substrate specificity and enables discovery of substrates for N-Myristoyltransferases
Résumé
Establishing the protein posttranslational modification (PTM) landscape at the proteome scale relies
on the target specificity of the relevant enzyme catalysts. Su et al. (ACS Catal, 2021:14877) proposed
that “the kcat/Km value is not the best parameter to determine the in vivo substrate specificity of an
enzyme. Instead, the binding affinities of substrates are more important for determining the substrate
specificity of enzymes in a physiological setting”. The authors extended their conclusions to any
“substrate pairs for enzymes that catalyze PTM”. This study provides a springboard for the discussion
of the relative merits of different approaches used to identify protein modification targets. My point of
view is that the specificity constant kcat/Km remains a highly relevant parameter for defining specificity,
while knowledge of the catalytic mechanism - including limiting and synergistic steps - is crucial for
reliable data interpretation. Enzyme catalysis and specificity cannot be reduced solely to the formation
of an encountered complex that makes the reaction between two partners more likely. I highlight how
reactants promote conformational changes that significantly contribute to the final specificity and
whose impact can only be assessed using kinetic approaches. There is also a need to integrate data with
in vivo availability of each competing substrate, and protein data resources must be regularly updated
to validate any PTM discovery. These conclusions apply to the substrate specificity of any catalyst.
Origine : Fichiers produits par l'(les) auteur(s)