No abstract

To explore the impact of globally incorporated fluorinated aromatic analogs on functional proteins, we investigate the effects of the monofluorinated phenylalanine analogs para‐fluorophenylalanine (pFF), meta‐fluorophenylalanine (mFF), and ortho‐fluorophenylalanine (oFF) on the stability, activity and specificity of the histone acetyltransferase (HAT) protein, tGCN5. We selected this set of fluorinated amino acids because each analog bears the same overall polarity and size while altering the direction of the dipole and side chain shape. Our experiments demonstrate a positional effect of single fluorine substitution on tGCN5 in which pFF provides minimal perturbance to structure and activity followed by mFF and oFF. Surprisingly, all monofluorophenylalanines lead to an enhanced selectivity for the target histone H3 relative to the non‐histone p53 substrate. Based on these results, tGCN5 labeled with pFF appears to maintain stability and function, while improving its specificity for its target histone H3 substrate.