TY - JOUR
T1 - An assessment of the reaction energetics for cytochrome P450-mediated reactions
AU - Higgins, Lee Ann
AU - Korzekwa, Kenneth R.
AU - Rao, Streedhara
AU - Shou, Magong
AU - Jones, Jeffrey P.
N1 - Funding Information:
This research was supported by the National Institute of Health, Grants ES06062 and ES09122.
PY - 2001/1/1
Y1 - 2001/1/1
N2 - Regioselectivity is used to determine the absolute energetic differences for four different reactions catalyzed by P450. Abstraction of a hydrogen from a benzylic carbon containing a chlorine has a 1.0 kcal/mol lower barrier than abstraction from a simple benzylic carbon, which in turn is 0.4 to 0.9 kcal/mol lower than abstraction from the methyl group of an aromatic ether and 0.1 to 0.6 kcal/mol easier than aromatic hydroxylation. Isotope effects are used to determine if the enzyme-substrate complexes leading to each product, from a given substrate, are in rapid equilibrium. For all enzymes isotopically sensitive branching is observed from the benzylic carbon upon deuterium incorporation at that position to each of the other positions, indicating that each product arises from the same active oxygen species. The energetic differences determined experimentally are accurately reproduced by theoretical hydrogen atom abstractions at both the AM1 semiempirical and DFT levels of theory.
AB - Regioselectivity is used to determine the absolute energetic differences for four different reactions catalyzed by P450. Abstraction of a hydrogen from a benzylic carbon containing a chlorine has a 1.0 kcal/mol lower barrier than abstraction from a simple benzylic carbon, which in turn is 0.4 to 0.9 kcal/mol lower than abstraction from the methyl group of an aromatic ether and 0.1 to 0.6 kcal/mol easier than aromatic hydroxylation. Isotope effects are used to determine if the enzyme-substrate complexes leading to each product, from a given substrate, are in rapid equilibrium. For all enzymes isotopically sensitive branching is observed from the benzylic carbon upon deuterium incorporation at that position to each of the other positions, indicating that each product arises from the same active oxygen species. The energetic differences determined experimentally are accurately reproduced by theoretical hydrogen atom abstractions at both the AM1 semiempirical and DFT levels of theory.
UR - http://www.scopus.com/inward/record.url?scp=0034779948&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0034779948&partnerID=8YFLogxK
U2 - 10.1006/abbi.2000.2147
DO - 10.1006/abbi.2000.2147
M3 - Article
C2 - 11361021
AN - SCOPUS:0034779948
SN - 0003-9861
VL - 385
SP - 220
EP - 230
JO - Archives of Biochemistry and Biophysics
JF - Archives of Biochemistry and Biophysics
IS - 1
ER -