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PR01687

Identifier
EP450ICYP2E  [View Relations]  [View Alignment]  
Accession
PR01687
No. of Motifs
4
Creation Date
13-MAR-2002
Title
CYP2E P450 family signature
Database References
PRINTS; PR00385 P450; PR00463 EP450I
Literature References
1. NOMENCLATURE COMMITTEE OF THE INTERNATIONAL UNION OF BIOCHEMISTRY
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 BIOCHEMISTRY T., 2ND ED., ISHIMURA, Y. AND FUJII-KURIYAMA, Y., EDS., 
KODANSHA, TOKYO, 1993, PP.255-272.
 
5. NELSON, D.R.
Cytochrome P450 homepage.
http://drnelson.utmem.edu/CytochromeP450.html
 
6. NELSON, D.R.
Metazoan Cytochrome P450 evolution.
COMPARATIVE BIOCHEMISTRY AND PHYSIOLOGY PART C 121 15-22 (1998).
 
7. LEWIS, D.F.V.
P450 substrate specificity and metabolism.
IN CYTOCHROMES P450: STRUCTURE, FUNCTION AND MECHANISM, TAYLOR AND FRANCIS
LTD., LONDON, 1996, PP.115-167.
 
8. GRAHAM-LORENCE, S.E. AND PETERSON, J.A.
Structural alignments of P450s and extrapolations to the unknown.
METHODS ENZYMOL. 272 315-26 (1996).

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. The data suggest that 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. 
 
Due to the rapid increase in numbers of P450s, Nelson introduced the concept
of a higher order classification of P450 families into clans [3] based on
sequence similarity. This is similar to the previous grouping into B- and
E-classes; both classifications are still used. According to Nelson's
system, clan 2 contains the CYP2 plus CYP1, 17, 18, 21 and 71 families, and
corresponds to the E-class group I proteins [5,6]. Members of the first 4
families are of vertebrate origin, while those from CYP71 derive from plants.
CYP1 and CYP2 enzymes mainly metabolise exogenous substrates, whereas CYP17
and CYP21 are involved in metabolism of endogenous physiologically-active
compounds. 
 
The CYP2 family, comprising 15 subfamilies (A-H, J-N, P and Q), is the most
dominant in clan 2. Six of these subfamilies are non-mammalian: 2H derives
from chicken; 2K, 2M, 2N and 2P are from fish; 2L is from lobster; and 2Q
from Xenopus [5]. The first five (A-E) are present in mammalian liver, but
in differing amounts and with different inducibilities [7]. These five 
subfamilies show varied substrate specificities, with some degree of 
overlap. There is growing evidence for the involvement of 2E in the 
activation of carcinogens and other toxic chemicals, although isozymes
in this subfamily also exhibit detoxifying metabolic pathways. In addition
to oxygenations, 2E is able to carry out reductive dehalogenation reactions
under low oxygen conditions, and this usually gives rise to cytotoxic
species. The different 2E orthologues are highly similar across species,
resulting in the sole designation CYP2E1.
 
Although highly similar in terms of amino acid sequence, it is possible that
a number of key residue changes between mammalian 2E proteins may explain
some of the known species differences in substrate metabolism. Site-directed
mutagenesis of a threonine residue (Thr-301) in 2E1 has indicated that the
rate of metabolism of substrates can be altered by changing this residue,
and it is likely that the electronic properties of certain key atoms in the
substrate are also relevant to metabolism [7]. The CYP2E gene is located on
chromosome 10 in mouse and man [3].
 
EP450ICYP2E is a 4-element fingerprint that provides a signature for the
CYP2E P450 family. The fingerprint was derived from an initial alignment of
7 sequences: the motifs were drawn from conserved regions spanning the
N-terminal half of the alignment, focusing on those sections that
characterise the CYP2E proteins but distinguish them from the rest of the
CYP2 family - using the model of Graham-Lorence and Peterson [8], motifs 1
and 2 span the N-terminal membrane anchor domain; motif 3 encodes the 
N-terminus of the I helix; and motif 4 resides between the J and K helices. 
Two iterations on SPTR40_18f were required to reach convergence, at which
point a true set comprising 11 sequences was identified.
Summary Information
11 codes involving  4 elements
0 codes involving 3 elements
0 codes involving 2 elements
Composite Feature Index
411111111
30000
20000
1234
True Positives
CPE1_BOVIN    CPE1_HUMAN    CPE1_MESAU    CPE1_MOUSE    
CPE1_PIG CPE1_RABIT CPE1_RAT Q29508
Q9MZY0 Q9MZY1 Q9UK47
Sequence Titles
CPE1_BOVIN  Cytochrome P450 2E1 (EC 1.14.14.1) (CYPIIE1) - Bos taurus (Bovine). 
CPE1_HUMAN Cytochrome P450 2E1 (EC 1.14.14.1) (CYPIIE1) (P450-J) - Homo sapiens (Human).
CPE1_MESAU Cytochrome P450 2E1 (EC 1.14.14.1) (CYPIIE1) (P450-J) - Mesocricetus auratus (Golden hamster).
CPE1_MOUSE Cytochrome P450 2E1 (EC 1.14.14.1) (CYPIIE1) (P450-J) (P450-ALC) - Mus musculus (Mouse).
CPE1_PIG Cytochrome P450 2E1 (EC 1.14.14.1) (CYPIIE1) (P450-J) (P-450-J) - Sus scrofa (Pig).
CPE1_RABIT Cytochrome P450 2E1 (EC 1.14.14.1) (CYPIIE1) (Isozyme 3A) (P450-ALC) - Oryctolagus cuniculus (Rabbit).
CPE1_RAT Cytochrome P450 2E1 (EC 1.14.14.1) (CYPIIE1) (P450-J) (P450RLM6) - Rattus norvegicus (Rat).
Q29508 CYTOCHROME P450 (P450IIE2) (EC 1.14.14.1) - Oryctolagus cuniculus (Rabbit).
Q9MZY0 CYTOCHROME P450 2E1 - Canis familiaris (Dog).
Q9MZY1 CYTOCHROME P450 2E1-VAR.1 - Canis familiaris (Dog).
Q9UK47 CYTOCHROME P450-2E1 (EC 1.14.14.1) - Homo sapiens (Human).
Scan History
SPTR40_18f 2  125  NSINGLE    
Initial Motifs
Motif 1  width=11
Element Seqn Id St Int Rpt
GITVALLVWMA CPE1_BOVIN 5 5 -
GITVALLVWIA CPE1_MOUSE 5 5 -
GITVALLVWLV CPE1_PIG 5 5 -
GITIALLVWVA CPE1_RAT 5 5 -
GITVALLGWMV CPE1_RABIT 5 5 -
GVTIALLVWVA CPE1_MESAU 5 5 -
GVTVALLVWAA CPE1_HUMAN 5 5 -

Motif 2 width=14
Element Seqn Id St Int Rpt
LLFISIWKHIYSSW CPE1_BOVIN 17 1 -
LLLVSIWKQIYRSW CPE1_MOUSE 17 1 -
LLLISIWKHIHSSW CPE1_PIG 17 1 -
LLVISIWKQIYNSW CPE1_RAT 17 1 -
LLFISVWKQIHSSW CPE1_RABIT 17 1 -
LLIVSIWKQIYSSW CPE1_MESAU 17 1 -
LLLVSMWRQVHSSW CPE1_HUMAN 17 1 -

Motif 3 width=16
Element Seqn Id St Int Rpt
DPMYTLENIAVTVADL CPE1_BOVIN 281 250 -
EPMYTMENISVTLADL CPE1_MOUSE 281 250 -
EPIYTLDNIAVTVADM CPE1_PIG 281 250 -
EPMYTMENVSVTLADL CPE1_RAT 281 250 -
EPLYTLENIAVTVADM CPE1_RABIT 281 250 -
EPMYTMENISVTLADL CPE1_MESAU 281 250 -
ERLYTMDGITVTVADL CPE1_HUMAN 281 250 -

Motif 4 width=11
Element Seqn Id St Int Rpt
GPSRIPAVKDR CPE1_BOVIN 334 37 -
GPSRAPAVRDR CPE1_MOUSE 334 37 -
GPNRIPAIKDR CPE1_PIG 334 37 -
GPSRVPAVRDR CPE1_RAT 334 37 -
GPSRMPSVRDR CPE1_RABIT 334 37 -
GPSRVPVFKDR CPE1_MESAU 334 37 -
GPSRIPAIKDR CPE1_HUMAN 334 37 -
Final Motifs
Motif 1  width=11
Element Seqn Id St Int Rpt
GITVALLVWMA CPE1_BOVIN 5 5 -
GITVALLVWMA Q9MZY0 5 5 -
GITVALLVWMA Q9MZY1 5 5 -
GITVALLGWMA Q29508 5 5 -
GITVALLVWIA CPE1_MOUSE 5 5 -
GITVALLVWLV CPE1_PIG 5 5 -
GITIALLVWVA CPE1_RAT 5 5 -
GITVALLGWMV CPE1_RABIT 5 5 -
GVTIALLVWVA CPE1_MESAU 5 5 -
GVTVALLVWAA CPE1_HUMAN 5 5 -
GVTVALLVWAA Q9UK47 5 5 -

Motif 2 width=14
Element Seqn Id St Int Rpt
LMLISIWKQIYSRW Q9MZY0 17 1 -
LMLISIWKQIYSRW Q9MZY1 17 1 -
LLFISIWKHIYSSW CPE1_BOVIN 17 1 -
LLFISVWKQIHSSW Q29508 17 1 -
LLLVSIWKQIYRSW CPE1_MOUSE 17 1 -
LLLISIWKHIHSSW CPE1_PIG 17 1 -
LLVISIWKQIYNSW CPE1_RAT 17 1 -
LLFISVWKQIHSSW CPE1_RABIT 17 1 -
LLIVSIWKQIYSSW CPE1_MESAU 17 1 -
LLLVSMWRQVHSSW CPE1_HUMAN 17 1 -
LLLVSMWRQVHSSW Q9UK47 17 1 -

Motif 3 width=16
Element Seqn Id St Int Rpt
EPWYTLDNIAVTVADL Q9MZY0 281 250 -
EPWYTLDNIAVTVADL Q9MZY1 281 250 -
DPMYTLENIAVTVADL CPE1_BOVIN 281 250 -
EPLYTLENIAVTVADL Q29508 281 250 -
EPMYTMENISVTLADL CPE1_MOUSE 281 250 -
EPIYTLDNIAVTVADM CPE1_PIG 281 250 -
EPMYTMENVSVTLADL CPE1_RAT 281 250 -
EPLYTLENIAVTVADM CPE1_RABIT 281 250 -
EPMYTMENISVTLADL CPE1_MESAU 281 250 -
ERLYTMDGITVTVADL CPE1_HUMAN 281 250 -
ERLYTMDGITVTVADL Q9UK47 281 250 -

Motif 4 width=11
Element Seqn Id St Int Rpt
GPSRVPAIKDR Q9MZY0 334 37 -
GPSRVPAIKDR Q9MZY1 334 37 -
GPSRIPAVKDR CPE1_BOVIN 334 37 -
GPSRMPSVRDR Q29508 334 37 -
GPSRAPAVRDR CPE1_MOUSE 334 37 -
GPNRIPAIKDR CPE1_PIG 334 37 -
GPSRVPAVRDR CPE1_RAT 334 37 -
GPSRMPSVRDR CPE1_RABIT 334 37 -
GPSRVPVFKDR CPE1_MESAU 334 37 -
GPSRIPAIKDR CPE1_HUMAN 334 37 -
GPSRIPAIKDR Q9UK47 334 37 -