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EUR.J.BIOCHEMISTRY 200 599-611 (1991).
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Metazoan Cytochrome P450 evolution.
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AND DEISENHOFER, J.
Crystal structure of hemoprotein domain of P450BM-3, a prototype for
SCIENCE 261 731-736 (1993).
P450 enzymes constitute a superfamily of haem-thiolate proteins ,
widely distributed in bacteria, fungi, plants and animals. The enzymes
are involved in metabolism of a plethora of both exogenous and endogenous
compounds . Usually, they act as terminal oxidases in multi-component
electron transfer chains, called P450-containing monooxygenase systems.
Current P450 nomenclature, based on divergent evolution of the P450
superfamily, was proposed and developed by Nebert et al. . On the basis
of sequence similarity, all P450s can be categorised into 2 main classes,
the so-called B- and E-classes: P450 proteins of prokaryotic 3-component
systems and fungal P450nor (CYP55) belong to the B-class; all other known
P450s from distinct systems are of the E-class . E-class P450S may be
further divided into 5 subclasses (groups) according to protein sequence
On the basis of sequence similarity, Nelson introduced the concept of a
higher order classification of P450 families into clans , which is
similar to the previous grouping into B- and E-classes; both classifications
are still used. According to Nelson's system, clans 3 and 4 correspond to
the E-class group II proteins .
Group II P450s are distributed widely in life, i.e., in eubacteria (family
CYP102), cyanobacteria (CYP110), fungi (CYP52, CYP53 and CYP56), insects
(CYP4 and CYP6) and mammals (CYP3, CYP4 and CYP5). Many group II P450s
catalyse hydroxylation of linear chains such as alkanes (CYP52), alcohols
and fatty acids (CYP4, CYP5, CYP102); Aspergillus niger CYP53 carries out
para-hydroxylation of benzoate; yeast CYP56 is possibly involved in
oxidation of tyrosine residues; insect CYP6 metabolises a wide range of
toxic compounds; and members of the CYP3 family are omnivorous . The
existence of two prokaryotic P450s in group II strongly suggests that the
divergence of the P450 superfamily into B- and E-classes, and further
divergence into stable P450 groups within the E-class, must be very ancient
and had occured before the appearance of eukaryotes .
The 3D structure of the P450 domain of P450BM-3 (CYP102) has been determined
 and is used as a model for microsomal P450s. The P450 molecule is an
alpha/beta protein, shaped like a triangular prism: the overall structure
can be roughly divided into alpha-rich (`right side') and beta-rich (`left
side') domains. However, this division appears to be artificial since the
alpha- and beta-rich domains comprise discontinuous assemblies of secondary
structure elements, and do not constitute independent folding units.
EP450II is a 3-element fingerprint that provides a signature for group II
E-class P450s. The fingerprint was derived from an initial alignment of 21
sequences: the motifs were drawn from conserved regions spanning the
C-terminal half of the alignment, focusing on those sections that
characterise the group II E class proteins but distinguish them from the
rest of the P450 superfamily - motifs 1 and 2 denote helices C and E; motif
3 spans the beta-strand 8 and helix K' (according to the structure of the
P450BM-3 hemoprotein domain ). Four iterations on SPTR37_10f were
required to reach convergence, at which point a true set comprising 139
sequences was identified. Numerous partial matches were also found, most of
which are group II E-class P450s (those belonging to CYP4 and CYP52 were
missing motif 3), while others are group I E-class P450s.