TY - JOUR
T1 - Cooperative properties of cytochromes P450
AU - Denisov, Ilia G.
AU - Frank, Daniel J.
AU - Sligar, Stephen G.
N1 - Funding Information:
We gratefully acknowledge Y. V. Grinkova, Dr. M. McLean, Dr. B. Baas, and other members of the Sligar laboratory for their important contribution and useful discussions. Previous and continuing collaborations with a number of laboratories, including G. K. Ackers, W. M. Atkins, D. R. Davydov, J. R. Halpert, E. F. Johnson, J. R. Kincaid, P. J. Mak, A. Nath, I. Schlichting, and M. R. Waterman are acknowledged. Our research is supported by grants from the National Institutes of Health GM31756 and 33737.
PY - 2009/11
Y1 - 2009/11
N2 - Cytochromes P450 form a large and important class of heme monooxygenases with a broad spectrum of substrates and corresponding functions, from steroid hormone biosynthesis to the metabolism of xenobiotics. Despite decades of study, the molecular mechanisms responsible for the complex non-Michaelis behavior observed with many members of this superfamily during metabolism, often termed 'cooperativity', remain to be fully elucidated. Although there is evidence that oligomerization may play an important role in defining the observed cooperativity, some monomeric cytochromes P450, particularly those involved in xenobiotic metabolism, also display this behavior due to their ability to simultaneously bind several substrate molecules. As a result, formation of distinct enzyme-substrate complexes with different stoichiometry and functional properties can give rise to homotropic and heterotropic cooperative behavior. This review aims to summarize the current understanding of cooperativity in cytochromes P450, with a focus on the nature of cooperative effects in monomeric enzymes.
AB - Cytochromes P450 form a large and important class of heme monooxygenases with a broad spectrum of substrates and corresponding functions, from steroid hormone biosynthesis to the metabolism of xenobiotics. Despite decades of study, the molecular mechanisms responsible for the complex non-Michaelis behavior observed with many members of this superfamily during metabolism, often termed 'cooperativity', remain to be fully elucidated. Although there is evidence that oligomerization may play an important role in defining the observed cooperativity, some monomeric cytochromes P450, particularly those involved in xenobiotic metabolism, also display this behavior due to their ability to simultaneously bind several substrate molecules. As a result, formation of distinct enzyme-substrate complexes with different stoichiometry and functional properties can give rise to homotropic and heterotropic cooperative behavior. This review aims to summarize the current understanding of cooperativity in cytochromes P450, with a focus on the nature of cooperative effects in monomeric enzymes.
KW - Allosteric effects
KW - Cooperativity
KW - Drug-drug interactions
KW - P450
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U2 - 10.1016/j.pharmthera.2009.05.011
DO - 10.1016/j.pharmthera.2009.05.011
M3 - Review article
C2 - 19555717
AN - SCOPUS:69249241970
VL - 124
SP - 151
EP - 167
JO - Pharmacology and Therapeutics, Part A: Chemotherapy, Toxicology and
JF - Pharmacology and Therapeutics, Part A: Chemotherapy, Toxicology and
SN - 0163-7258
IS - 2
ER -