108
Cytochrome P450
yet been made. However, because drug-
metabolizing P450s have a broad substrate
specifcity, it is clear that,
in vitro
,the
se
P450s can metabolize various endogenous
compounds. Thus, it will not be surpris-
ing to see the distinction between these
two classes oF P450 become less sharp in
the Future.
3
How Many P450s Are There?
The P450 superFamily is very large, hav-
ing members in most iF not all liFe-Forms.
In 1996, only 400 CYPs were known and
now the P450 superFamily contains more
than 2400 enzymes. The majority oF these
have been identifed in genomic sequences
and For the vast majority, the Function is
unknown. Classifcation oF members oF
the superFamily based on Function has not
been possible, originally because enzymes
From the same superFamily in diFFerent
species have diFFerent activities and now
because we have Far too many genes with
unknown activities. Rather, a systematic
classifcation For P450s has been devel-
oped on the basis oF amino acid sequence
P450.html). BeFore development oF this
classifcation by Dan Nebert and David
Nelson, the feld was in disarray because
individual investigators selected names For
the diFFerent P450s, and in cases in which
discovery occurred in two laboratories at
about the same time, there were two names
For the same CYP. The nomenclature in-
volves a number that identifes the gene
Family, a letter that identifes the subFam-
ily, and another number that identifes the
member oF the subFamily. CYP2C23 indi-
cates gene Family 2, subFamily C oF gene
Family 2, and member 23 oF subFamily C
oF gene Family 2. The subFamily member
designation is sequential based on order
oF discovery. CYP2C23 and CYP2C24 are
rat P450s, while CYP2C25 is From the Syr-
ian hamster. Gene Family members have
about 40% amino acid sequence identity
or greater, while subFamilies have about
55% amino acid identity or greater. Cer-
tain gene Families that have very restricted
enzymatic activity and are Found to have
thesameFunc
t
ionind
iF
Feren
torgan
isms
do not have subFamilies. CYP51 (sterol
14
α
-demethylase) is an example because
it is involved in sterol biosynthesis in
many organisms in which it removes the
14
α
-methyl group From the cyclized sterol
ring. Another such example is CYP17
(17
α
-hydroxylase/17,20-lyase) Found in the
gonads oF animals, birds, and fsh serving
an identical role in androgen biosynthesis.
However, the P450s in the CYP2C sub-
Family generally have diFFerent substrate
specifcities From those in the CYP2B sub-
Family. It would not even be surprising to
learn that CYP2C23 and CYP2C24 have
diFFerent
substrate
specifcities. Some-
times, a single amino acid change can
proFoundly change the specifcity oF a
P450. In the mouse, the Cyp2A subFam-
ily (Phe209
Leu) changes the specifcity
oF mouse coumarin hydroxylase (Cyp2A5)
to steroid 15
α
-hydroxylase (Cyp2a4). ±or
mouse P450s Cyp is used, while For P450s
in all other species the designation CYP
is used.
CYP51 is expressed in all kingdoms
oF liFe, and the approximately 50 known
CYP51 sequences contain 40 conserved
amino
acids.
Obviously,
sterol
14
α
-
demethylation is a highly conserved enzy-
matic activity. Another highly conserved
enzymatic activity is
ω
-hydroxylation oF
Fatty acids. However, in this case diF-
Ferent
gene
Families
are
involved
in
diFFerent phyla. There is not enough
amino acid conservation between diFFerent
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