TY - JOUR
T1 - QM/MM Calculations Reveal the Important Role of α-Heteroatom Substituents in Controlling Selectivity of Mononuclear Nonheme HppE-Catalyzed Reactions
AU - Lu, Jiarui
AU - Wang, Binju
AU - Shaik, Sason
AU - Lai, Wenzhen
N1 - Publisher Copyright:
© 2020 American Chemical Society.
PY - 2020/8/21
Y1 - 2020/8/21
N2 - The nonheme iron enzyme, (S)-2-hydroxypropylphosphonate [(S)-2-HPP] epoxidase (HppE), uses H2O2 as the oxidizing cosubstrate to catalyze the epoxidation of (S)-2-HPP to fosfomycin, as well as other oxidative processes (including dehydrogenation and 1,2-phosphono-migration) of structural isomers of its native substrate. The HppE-catalyzed 1,2-phosphono-migration of (R)-1-HPP, which involves the pro-R hydrogen abstraction from C2, was proposed to proceed via the formation of a C2 carbocation intermediate. Here, we show that such an intermediate does not transpire during the reaction. The reorientation of the singly occupied orbital at the C2-radical center, through out-of-plane torsion of the P-C1-C2-C3 dihedral angle, triggers the phosphono-migration and precludes the attack of the Fe-bound OH on the C2 radical (hydroxylation) as well as the C2-O coupling (epoxidation). For the substrate (1R)-1-hydroxyl-2-aminopropyl phosphonate, the lone-pair electrons on the amino group enable a fast proton-coupled electron transfer process, wherein the proton transfer from the amino group to phosphonate is coupled to the electron transfer from the C2 radical to the iron center, leading to a C2-iminium cation rather than the phosphono-migration. Finally, the C2-iminium intermediate is converted to a ketone product and NH3. These results demonstrate that the α-heteroatom substituent is vital for the generation of the cationic species, as well as the selectivity control in the HppE-catalyzed reactions.
AB - The nonheme iron enzyme, (S)-2-hydroxypropylphosphonate [(S)-2-HPP] epoxidase (HppE), uses H2O2 as the oxidizing cosubstrate to catalyze the epoxidation of (S)-2-HPP to fosfomycin, as well as other oxidative processes (including dehydrogenation and 1,2-phosphono-migration) of structural isomers of its native substrate. The HppE-catalyzed 1,2-phosphono-migration of (R)-1-HPP, which involves the pro-R hydrogen abstraction from C2, was proposed to proceed via the formation of a C2 carbocation intermediate. Here, we show that such an intermediate does not transpire during the reaction. The reorientation of the singly occupied orbital at the C2-radical center, through out-of-plane torsion of the P-C1-C2-C3 dihedral angle, triggers the phosphono-migration and precludes the attack of the Fe-bound OH on the C2 radical (hydroxylation) as well as the C2-O coupling (epoxidation). For the substrate (1R)-1-hydroxyl-2-aminopropyl phosphonate, the lone-pair electrons on the amino group enable a fast proton-coupled electron transfer process, wherein the proton transfer from the amino group to phosphonate is coupled to the electron transfer from the C2 radical to the iron center, leading to a C2-iminium cation rather than the phosphono-migration. Finally, the C2-iminium intermediate is converted to a ketone product and NH3. These results demonstrate that the α-heteroatom substituent is vital for the generation of the cationic species, as well as the selectivity control in the HppE-catalyzed reactions.
KW - 2-His-1-carboxylate
KW - nonheme
KW - peroxidase
KW - phosphono-migration
KW - QM/MM
UR - http://www.scopus.com/inward/record.url?scp=85091418402&partnerID=8YFLogxK
U2 - 10.1021/acscatal.0c01803
DO - 10.1021/acscatal.0c01803
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AN - SCOPUS:85091418402
SN - 2155-5435
VL - 10
SP - 9521
EP - 9532
JO - ACS Catalysis
JF - ACS Catalysis
IS - 16
ER -