Flexibility of human cytochrome P450 enzymes: Molecular dynamics and spectroscopy reveal important function-related variations

Membrane Position of Ibuprofen Agrees with Suggested Access Path Entrance to Cytochrome P450 2C9 Active Site

“…Interestingly, the F/G loop, which is flexible in some CYPs, is rather rigid. 6 Also, the central part of the protein close to the catalytic site is relatively rigid. The simulation of CYP2C9 in water shows highly enhanced flexibility of the N-terminal part (FR1) and of the F/G-loop (FR6) in comparison with simulation of CYP2C9 anchored to the membrane.…”

“…The profiles of RMSF calculated from all simulations have similar trends, which also agree well with published data. 6−8 .…”

Effects of sulforaphane and its S- and R-enantiomers on the expression and activities of human drug-metabolizing cytochromes P450

“…5) that sulforaphane interacts with the heme moiety of cytochromes P450, with relatively modest specificity (KS = 6.76 ± 0.93 µM for racemic sulforaphane), it may well bind also to the heme of the respective NO synthase as both these proteins are known to exhibit similar properties of the heme (Renaud, Boucher, Vadon, Delaforge, & Mansuy, 1993). Interestingly, the inhibition of CYP enzymes in human microsomes occurred with the forms with better accessibility of the heme group: CYP3A4 and CYP2D6 (Hendrychova et al, 2011); on the other hand, in hepatocytes, all the CYP forms studied were inhibited which may indicate better access of the sulforaphane to the CYP active sites in their natural neighborhood (endoplasmic reticulum) than in artificially formed vesicles of microsomes. An alternative explanation of the inhibition of CYP activities in hepatocytes may stem from the fact that sulforaphane has been shown to accumulate in the cells; and, hence, the sulforaphane level inside the cell may reach toxic levels being at least one order of magnitude higher than in the surrounding medium (Ye et al, 2002;Zhang, 2000).…”

Comprehensive assessment of Cytochrome P450 reactions: A multiplex approach using real-time ESI-MS

“…K M values for the CYP3A4 testosterone 6-hydroxylation are between 50-100 µM and this is about 100 times higher than for the CYP2A6 coumarin 7-hydroxylation (K M 0.5-2 µM) [48]. Prior studies described variable structural properties and binding features of different CYPs [11,49]. CYP3A4 contributes to the metabolism of approximately 30 % of all xenobiotics [9][10][11].…”