Cytochrome P450 reductase interaction

Enzymology and Stoichiometry A depiction of the thermodynamic analysis of substrate, P450, and NADPH cytochrome P450 reductase interactions is shown in Figure 8.13. 

Kenaan C, Zhang H, Shea EV, Hollenberg PE (2011) Uneovering the role of hydrophobic residues in cyto-ehrome P450-cytochrome P450 reductase interactions. Biochemistry 50 3957 3967... 

NADPH controls the protein interaction properties of human cytochrome P450 reductase. Biochemistry, 45 (5), 1421-1434. 

D. Active Site Environment Human HO-1 Crystal Structure Interaction with Cytochrome P450 Reductase Gaseous Ligands... 

For most drugs, oxidative biotransformation is performed primarily by the mixed-function oxidase enzyme system, which is present predominantly in the smooth endoplasmic reticulum of the liver. This system comprises (1) the enzyme NADPH cytochrome P450 reductase (2) cytochrome P450, a family of heme-containing proteins that catalyze a variety of oxidative and reductive reactions and (3) a phospholipid bilayer that facilitates interaction between the two proteins. Important exceptions to this rule are ethyl alcohol and caffeine, which are oxidatively metabolized by enzymes primarily present in the soluble, cytosolic fraction of the liver. 

Brimfield, A.A., Novak, M.J., Mancebo, A.M., Gallagher, B.S., Arroyo, M. (2006). The detection of free radical formation from the interaction of sulfur mustard with NADPH-cytochrome P450 reductase. Toxicologist 90 391. 

Mao, W., Rupasinghe, S.G., Zangerl, A.R., Berenbaum, M.R. and Schuler, M.A. (2007) Allelic variation in the Depressaria pastinacella CYP6AB3 protein enhances metabolism of plant allelochemicals by altering a proximal surface residue and potential interactions with cytochrome P450 reductase. /. Biol. Chem., 282,10544—52. 

NADPH cytochrome P450 reductase, an enzyme containing which a complex flavoenzyme that contains two flavins, one electron is first intramolecularly transferred from FAD to FMN, before the reaction with cytochrome P450 takes place. With FNR, NADP+ first has to bind to the oxidized form, before the very fast one-electron transfer from the specifically interacting reduced ferredoxin (Fdred) occurs (8). Subsequent dissociation of the oxidized ferredoxin (Fdox) is rate-limiting in catalysis. The enzyme semiquinone-NADP" complex then reacts with another reduced ferredoxin molecule to yield the flavin hydroquinone state. In the final steps of the catalytic cycle, the NADP+ is reduced and the NADPH dissociates ... 

Einarson TR, Metge CJ, Iskedjian M, Mukherjee J. An examination of the effect of cytochrome P450 drug interactions of hydroxymethylglutaryl-coenzyme A reductase... 

Figure 8.13 Interaction between cytochrome P450 (E), substrate (S), and NADPH cytochrome P450 reductase (NPR). (Modified from Shimada, Mernaugh, and Guengerich, Arch. Biochem. Biophys 435 307-216, 2005.)...

Shimada, T., Mernaugh, R. L., Sc Guengerich, F. P. (2005). Interactions of mammalian cytochrome P450, NADPH-cytochrome P450 reductase, and cytochrome b5 enzymes. Archives of Biochemistry and Biophysics, 435, 207—216. 

Shimizu, T., T. Tateishi, M. Hatano, and Y. Fujiikuriyama (1991). Probing the role of lysines and arginines in the catalytic function of cytochrome-P450d by site-directed mutagenesis— interaction with NADPH-cytochrome-P450 reductase.,/ Sto/. Chem. 266, 3372-3375. 

Shen, S. and H.W. Strobel (1993). Role of lysine and arginine residues of cytochrome P450 in the interaction between cytochrome P4502B1 and NADPH-cytochrome P450 reductase. Arch. Biochem. Biophys. 304, 257-265. 

Kaminsky, L.S. and E.P. Guengerich (1985). Cytochrome P450 isozyme/isozyme functional interactions and NADPH-cytochrome P450 reductase concentrations as factors in microsomal metabolism of warfarin. Eur. J. Biochem. 149, 479-489. 

Backes, W.L., C.J Batie, and G.F. Cawley (1998). Interactions among P450 enzymes when combined in reconstituted systems Formation of a 2B4-1A2 complex with a high affinity for NADPH cytochrome P450 reductase. Biochemistry 37, 12852-12859. 

CYP oxidation reactions involve a complex series of steps that have been well defined Rose and Hodgson, 2004). The initial step involves the binding of substrate to oxidized CYP, followed by a one-electron reduction catalyzed hy NADPH cytochrome P450 reductase to form a reduced cytochrome-substrate complex. The next several steps involve interaction with molecular oxygen, the acceptance of a second electron from NADPH cytochrome P450 reductase or NADH cytochrome b reductase, followed by the subsequent release of water and the oxygenated product of the reaction. This complicated reaction sequence results in the transfer of one atom of molecular oxygen to the substrate while the other atom is reduced to water. 

Jenldns CM, Waterman MR (1999) Flavodoxin as a model for the P450-interacting domain of NADPH cytochrome P450 reductase. Drug Metab Rev 31 195-203... 

Nikfarjam L, Izumi S, Yamazaki T, Kominami S (2006) The interaction of cytochrome P450 17alpha with NADPH-cytochrome P450 reductase, investigated using chemical modification and MALDl-TOF mass spectrometry. Biochim Biophys Acta 1764 1126-1131... 

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