Substrate Conformation Regulates Aromatic C-H Vs C-F Bond Activation in Heme-Dependent Tyrosine Hydroxylase

Warispreet Singh, Sonia Gomes Dos Santos, Shalini Yadav, Gary Black, Kshatresh Dutta Dubey

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1 Citation (Scopus)


A recently discovered heme-dependent enzyme tyrosine hydroxylase (TyrH) offers a green approach for functionalizing the high-strength C-H and C-F bonds in aromatic compounds. However, there is ambiguity regarding the nature of the oxidant (compound 0 or compound I) involved in activating these bonds. Herein, using comprehensive molecular dynamics (MD) simulations and hybrid quantum mechanical/molecular mechanical calculations, we reveal that it is compound I (Cpd I) that acts as the primary oxidant involved in the functionalization of both C-F and C-H bonds. The energy barrier for C-H and C-F activation using compound 0 (Cpd 0) as an oxidant was very high, indicating that Cpd 0 cannot be an oxidant. Consistent with the previous experimental finding, our simulation shows two different conformations of the substrate, where one orientation favors the C-H activation, while the other conformation prefers the C-F activation. As such, our mechanistic study shows that nature utilizes just one oxidant, that is, Cpd I, but it is the active site conformation that decides whether it selects C-F or C-H functionalization which may resemble involvement of two different oxidants.

Original languageEnglish
Pages (from-to)1577-1587
Number of pages11
Issue number10
Early online date24 Apr 2023
Publication statusPublished - 16 May 2023

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