Drug metabolism by cytochrome p450 enzymes: what distinguishes the pathways leading to substrate hydroxylation over desaturation?
Cytochrome P450 enzymes are highly versatile biological catalysts in our body that react with a broad range of substrates. Key functions in the liver include the metabolism of drugs and xenobiotics. One particular metabolic pathway that is poorly understood relates to the P450 activation of aliphatic groups leading to either hydroxylation or desaturation pathways. A DFT and QM/MM study has been carried out on the factors that determine the regioselectivity of aliphatic hydroxylation over desaturation of compounds by P450 isozymes. The calculations establish multistate reactivity patterns, whereby the product distributions differ on each of the spin-state surfaces; hence spin-selective product formation was found. The electronic and thermochemical factors that determine the bifurcation pathways were analysed and a model that predicts the regioselectivity of aliphatic hydroxylation over desaturation pathways was established from valence bond and molecular orbital theories. Thus, the difference in energy of the OH versus the OC bond formed and the π-conjugation energy determines the degree of desaturation products. In addition, environmental effects of the substrate binding pocket that affect the regioselectivities were identified. These studies imply that bioengineering P450 isozymes for desaturation reactions will have to include modifications in the substrate binding pocket to restrict the hydroxylation rebound reaction.
College of Environmental and Resource Sciences, Zhejiang University, Yuhangtang Road 866, Hangzhou 310058 (China).
Li
L
Ji
Manchester Institute of Biotechnology and School of Chemical Engineering and Analytical Science, The University of Manchester, 131 Princess Street, Manchester M1 7DN (UK).
Abayomi S
AS
Faponle
Manchester Institute of Biotechnology and School of Chemical Engineering and Analytical Science, The University of Manchester, 131 Princess Street, Manchester M1 7DN (UK).
Matthew G
MG
Quesne
Manchester Institute of Biotechnology and School of Chemical Engineering and Analytical Science, The University of Manchester, 131 Princess Street, Manchester M1 7DN (UK).
Mala A
MA
Sainna
College of Environmental and Resource Sciences, Zhejiang University, Yuhangtang Road 866, Hangzhou 310058 (China).
Jing
J
Zhang
Inorganic Chemistry, Department of Chemistry and Pharmacy, University of Erlangen-Nuremberg, Egerlandstrasse 1, 91058 Erlangen (Germany).
Alicja
A
Franke
Department of Applied Physics, School for Physical Sciences, Babasaheb Bhimrao Ambedkar University, Vidya Vihar, Rai Bareilly Road, Lucknow 226 025 (India).
Devesh
D
Kumar
Inorganic Chemistry, Department of Chemistry and Pharmacy, University of Erlangen-Nuremberg, Egerlandstrasse 1, 91058 Erlangen (Germany).|Faculty of Chemistry, Jagiellonian University, Ingardena 3, 30-060 Krakow (Poland).
Rudi
R
van Eldik
College of Environmental and Resource Sciences, Zhejiang University, Yuhangtang Road 866, Hangzhou 310058 (China). wliu@zju.edu.cn.
Weiping
W
Liu
Manchester Institute of Biotechnology and School of Chemical Engineering and Analytical Science, The University of Manchester, 131 Princess Street, Manchester M1 7DN (UK). sam.devisser@manchester.ac.uk.
Sam P
SP
de Visser
D055162:Biocatalysis; D003577:Cytochrome P-450 Enzyme System / Q000737:chemistry / Q000378:metabolism*; D006900:Hydroxylation; D011789:Quantum Theory; D013816:Thermodynamics; D015262:Xenobiotics / Q000737:chemistry / Q000378:metabolism*
D015262:Xenobiotics; D003577:Cytochrome P-450 Enzyme System
compound I; density functional calculations; enzyme catalysis; oxygen atom transfer; reaction mechanisms