| Literature References | 1. NOMENCLATURE COMMITTEE OF THE INTERNATIONAL UNION OF BIOCHEMISTRY (NC-IUB).
Nomenclature of electron-transfer proteins. Recommendations 1989.
EUR.J.BIOCHEMISTRY 200 599-611 (1991).
2. NEBERT, D.W. AND GONZALEZ, F.J.
P450 genes: structure, evolution, and regulation.
ANNU.REV.BIOCHEMISTRY 56 945-993 (1987).
3. NELSON, D.R., KAMATAKI, T., WAXMAN, D.J., GUENGERICH, F.P.,
ESTABROOK, R.W., FEYEREISEN, R., GONZALEZ, F.J., COON, M.J.,
GUNSALUS, I.C., GOTOH, O., OKUDA, K. AND NEBERT, D.W.
The P450 superfamily: update on new sequences, gene mapping, accession
numbers, early trivial names of enzymes, and nomenclature.
DNA CELL BIOL. 12 1-51 (1993).
4. GOTOH, O.
Evolution and differentiation of P-450 genes.
IN CYTOCHROME P-450, OMURA, T., ISHIMURA, Y. AND FUJII-KURIYAMA, Y., EDS.
2ND ED., PP.255-272 (1993). KODANSHA, TOKYO.
5. NELSON, D.R.
Metazoan Cytochrome P450 evolution.
COMPARATIVE BIOCHEMISTRY AND PHYSIOLOGY PART C 121 15-22 (1998).
6. NELSON, D.R.
Cytochrome P450 homepage.
http://drnelson.utmem.edu/CytochromeP450.html
7. RAVICHANDRAN, K.G., BODDUPALLI, S.S., HASEMANN, C.A., PETERSON, J.A.
AND DEISENHOFER, J.
Crystal structure of hemoprotein domain of P450BM-3, a prototype for
microsomal P450s.
SCIENCE 261 731-736 (1993).
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| Documentation | P450 enzymes constitute a superfamily of haem-thiolate proteins [1],
widely distributed in bacteria, fungi, plants and animals. The enzymes
are involved in metabolism of a plethora of both exogenous and endogenous
compounds [2]. 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. [3]. 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 [4]. E-class P450S may be
further divided into 5 subclasses (groups) according to protein sequence
similarities.
On the basis of sequence similarity, Nelson introduced the concept of a
higher order classification of P450 families into clans [6], 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 [5].
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 [4]. 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 [4].
The CYP52 family is only present in Candida species. Nelson suggests that
this begs the question whether a progenitor CYP52 P450 existed in the common
ancestor that was lost in S.cerevisiae and pombe, or whether alkane
hydroxylases evolved from a CYP51 ancestor? Conversely, did the common
ancestor to all eukaryotes bring with it an alkane or fatty acid hydroxylase
that gave rise to CYP51? [6].
CYP52 proteins belong to the eukaryote-like cluster of bacterial P450s,
which includes CYP102 and CYP110. In the original nomenclature, this would
be group II E-class proteins, while in Nelson's classification the cluster
adjoins CYP4 (clan 4), which includes fatty acid hydroxylases. It has been
suggested that if the distribution of CYP52 sequences is only among fungi
related to Candida, they might represent a novel development of Candida
yeasts [6].
The 3D structure of the P450 domain of P450BM-3 (CYP102) has been determined
[7] 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.
EP450IICYP52 is a 4-element fingerprint that provides a signature for CYP52
P450s. The fingerprint was derived from an initial alignment of 12 sequences:
the motifs were drawn from conserved regions spanning the central portion of
the alignment, focusing on those sections that characterise the CYP52
proteins but distinguish them from the rest of the P450 superfamily and
clan 4 P450s. Two iterations on SPTR_10f were required to reach convergence,
at which point a true set comprising 29 sequences was identified.
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