1998
DOI: 10.1021/bi9715627
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Abstract: Some cytochrome P450 catalyzed reactions show atypical kinetics, and these kinetic processes can be grouped into five categories: activation, autoactivation, partial inhibition, substrate inhibition, and biphasic saturation curves. A two-site model in which the enzyme can bind two substrate molecules simultaneously is presented which can be used to describe all of these observed kinetic properties. Sigmoidal kinetic characteristics were observed for carbamazepine metabolism by CYP3A4 and naphthalene metabolism… Show more

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Cited by 474 publications
(493 citation statements)
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“…Initial "space-filling" models proposed that the large substrate-binding pocket of microsomal drug metabolizing cytochromes P450 sometimes requires more than one substrate molecule to assure a productive binding orientation of at least one of them [1][2][3][4][5][6][7][8][9]. However, this hypothesis fails to explain the entire body of observations obtained with cytochrome P450 3A4 (CYP3A4), the principal human drug-metabolizing enzyme [10].…”
Section: Introductionmentioning
confidence: 99%
“…Initial "space-filling" models proposed that the large substrate-binding pocket of microsomal drug metabolizing cytochromes P450 sometimes requires more than one substrate molecule to assure a productive binding orientation of at least one of them [1][2][3][4][5][6][7][8][9]. However, this hypothesis fails to explain the entire body of observations obtained with cytochrome P450 3A4 (CYP3A4), the principal human drug-metabolizing enzyme [10].…”
Section: Introductionmentioning
confidence: 99%
“…There are three prevailing models of cooperativity for cytochrome P450s (CYPs): the multisubstrate binding site model [11][12][13], the peripheral effector binding site model [14][15][16], and the conformational heterogeneity model [17][18][19]. With the multi-substrate binding model, multiple substrates are bound at unproductive binding sites within the active site that can modulate the apparent K m , k cat and V max of substrate that transiently occupies a metabolically productive position.…”
Section: Introductionmentioning
confidence: 99%
“…CYP3A4 has been modeled with two [11,12,14,15,[24][25][26], three [16,[27][28][29], and more ligand [13] binding sites. Since the x-ray crystal structures of CYP3A4 and P450 eryF have at most 2 ligands bound simultaneously [20,23], the data in this study were modeled with two ligand binding sites.…”
Section: Introductionmentioning
confidence: 99%
“…The most prominent examples of these phenomena are observed with P450 3A4 (CYP3A4), and studies of cooperativity of this enzyme are of considerable importance in elucidating the mechanisms of drug metabolism and drug-drug interactions in humans [7]. The proposed models for the cooperativity in cytochromes P450 involve multiple substrate molecules in one large binding pocket [8][9][10]. Direct physical evidence for the presence of two ketoconazole molecules in the CYP3A4 active site was provided very recently by x-ray crystallography [11].…”
Section: Introductionmentioning
confidence: 99%
“…Direct physical evidence for the presence of two ketoconazole molecules in the CYP3A4 active site was provided very recently by x-ray crystallography [11]. Inherent in most of the models is the assumption that a loose fit of a single substrate molecule requires the binding of a second ligand for efficient binding and/or catalysis [9,10,12], although recent evidence for effector-induced conformational rearrangements has emerged from our laboratory and others [13][14][15]. Strong support for an important conformational transition in P450 function is provided by several recent x-ray crystal structures of mammalian P450 enzymes including CYP3A4, which have revealed considerable flexibility [11,[16][17][18].…”
Section: Introductionmentioning
confidence: 99%