Chemistry Reference
In-Depth Information
Phe-181
Phe-181
Tyr-437
Tyr-437
hr-268
hr-268
Position of
metabolism
Heme
Heme
Position of
metabolic
attack
fIgure 2.6
The procarcinogen benzo[
a
]pyrene oriented in the CYP1A1 active site (stereo
view) via π- π stacking between aromatic rings on the substrate and those of the complemen-
tary amino acid side chains, such that 7,8-epoxidation can occur. The substrate is shown with
pale lines in the upper structures. The position of metabolism is indicated by an arrow in the
lower structure (after Lewis 1996).
inhibited by, planar molecules (e.g., planar PAHs and coplanar PCBs). This can be
explained in terms of the deduced structure of the active site of these CYP1A enzymes
(Figure 2.6; Lewis 1996, and Lewis and Lake 1996). This takes the form of a rect-
angular slot, composed of several aromatic side chains, including the coplanar rings
of phenylalanine 181 and tyrosine 437, which restrict the size of the cavity such that
only planar structures of a certain rectangular dimension will be able to take up the
binding position. Small differences in structure between the active sites of CYP1A1
and CYP1A2 may explain their differences in substrate preference (Table 2.3), for
example, phenylalanine 259 (CYP1A1) versus anserine 259 (1A2). CYP1A1 metabo-
lizes especially heterocyclic molecules, whereas CYP1A1 is more concerned with
PAHs. By contrast, the active sites of families CYP2 and 3 have more open structures
and are capable of binding a wide variety of different compounds, some planar but
many of more globular shape. CYP2 is a particularly diverse family, whose rapid evo-
lution coincides with the movement of animals from water to land (for discussion, see
Chapter 1). Very many lipophilic xenobiotics are metabolized by enzymes belonging
to this family. Of particular interest from an ecotoxicological point of view, CYP2B
is involved in the metabolism of organochlorine insecticides such as aldrin and endrin
and some OP insecticides including parathion, CYP2C with warfarin metabolism,
and CYP2E with solvents of low-molecular weight, including acetone and ethanol.
CYP3 is noteworthy for the great diversity of substrates that it can metabolize, both
Search WWH ::
Custom Search