Alpha-ketoglutarate-dependent oxygenases functionalize complex biomolecules, including proteins. Their chemical reactivity parallels that of the P450 enzymes in many ways, suggesting that engineering the oxygenases could lead to novel chemistry. In the case of the enzyme factor inhibiting HIFα (FIH), engineering this enzyme to perform non-natural modifications would lead to bio-orthogonal labels for proteins. Herein we report the anion dependent substrate hydroxylation by FIH variants, in initial efforts to achieve non-natural peptide modification. Our results indicate that FIH can be engineered to bind exogenous anions and perform anion-selective hydroxylation chemistry, achieving the preliminary steps necessary for alternate rebound chemistry.

Engineering the alpha-ketoglutarate oxygenase FIH for alternate rebound chemistry

253rd National Meeting (2017)

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