TY - JOUR
T1 - Substrate Conformation Regulates Aromatic C-H Vs C-F Bond Activation in Heme-Dependent Tyrosine Hydroxylase
AU - Singh, Warispreet
AU - Gomes Dos Santos, Sonia
AU - Yadav, Shalini
AU - Black, Gary
AU - Dubey, Kshatresh Dutta
N1 - Funding information: K.D.D. acknowledges the Department of Biotechnology, Govt. of India for the Ramalingamswami re-entry research grant (BT/RLF/Re-entry/10/2017). W.S., S.F.G.S., and G.W.B. acknowledge the support of Research England’s Expanding Excellence in England (E3) Fund.
PY - 2023/5/16
Y1 - 2023/5/16
N2 - 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.
AB - 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.
KW - Catalytic Domain
KW - Heme/chemistry
KW - Molecular Dynamics Simulation
KW - Oxidants/chemistry
KW - Tyrosine 3-Monooxygenase
UR - http://www.scopus.com/inward/record.url?scp=85156143217&partnerID=8YFLogxK
U2 - 10.1021/acs.biochem.3c00087
DO - 10.1021/acs.biochem.3c00087
M3 - Article
C2 - 37092990
SN - 0006-2960
VL - 62
SP - 1577
EP - 1587
JO - Biochemistry
JF - Biochemistry
IS - 10
ER -