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Superfamily name: Cytochrome P450

The cytochrome P450 superfamily is a highly diversified set of heme containing proteins.

These proteins were discovered in 1958 by their unusual reduced carbon monoxide

difference spectrum that has an absorbance at 450 nm, thus Pigment at 450 nm or P450.

This odd spectrum is caused by a thiolate anion acting as the 5th ligand to the the heme.

The most common reaction catalyzed is hydroxylation, often of a lipophilic substrate.

Consequently, the proteins are frequently called hydroxylases, but P450 proteins can

perform a wide spectrum of reactions including N-oxidation, sulfoxidation, epoxidation,

N-, S-, and O-dealkylation, peroxidation, deamination, desulfuration and dehalogenation

(1).  In bacteria these proteins are soluble and approximately 400 amino acids long.  The

eukaryotic P450s are larger, being about 500 amino acids.  In eukaryotes the proteins are

ususally membrane bound through an N-terminal hydrophobic peptide and other less well

understood contacts.  The two locations of these proteins in eukaryotes are the endoplasmic

reticulum membrane and the mitochondrial inner membrane.  There are a few examples

known of soluble eukaryotic P450s, but these seem to be bacterial P450s that have been

acquired by some fungi by a lateral transfer across kingdoms.

Cytochrome P450s are sometimes called mixed function oxidases or monooxygenases.

This refers to the way molecular oxygen is incorporated into product.  In the usual

hydroxylation, one atom of oxygen is added to the substrate and the other contributes to

forming a water molecule.  This process is complex and requires the donation of two

electrons sequentially from an electron donor.  The donor is different depending on the

location of the P450 in the cell or whether it is a bacterial protein or a eukaryotic protein.

At the ER membrane, NADPH cytochrome P450 reductase is the usual electron donor,

though cytochrome b5 can also participate.  In the mitochondria, ferredoxin (adrenodoxin)

and ferredoxin reductase (adrenodoxin reductase) form a short electron transfer chain to

supply the electrons.  The bacterial donors are of both types.  The Bacillus megaterium

P450 CYP102 actually has the NADPH cytochrome P450 reductase fused to the P450 in a

single gene.

There are more than 1500 known P450 sequences.  To aid in communication, a

standardized curated nomenclature has been established (2).  This nomenclature is based on

evolution of the protein sequences, with similar sequences being clustered into families and

subfamilies.  The root for cytochrome P450 names is CYP.  By convention this is Cyp in

the mouse and Drosophila.  Families are designated by a number and subfamilies by a

letter.  Individual members in a subfamily are numbered consecutively as they are reported

to the nomenclature committee.  The first P450 named was CYP1A1.  When this system

was established, blocks of family names were reserved for different taxonomic groups.

Families 1-49 were for animals, 51-69 were for lower eukaryotes, 71-99 were for plants

and 101 and higher were for bacteria.  This original allocation was too small and the

numbers have had to migrate into three digit numbers to continue naming new families.

CYP301-CYP499 are for animals, CYP501-699 are for lower eukaryotes, CYP701-999

are for plants and bacteria remain in the 101-299 range.  The exact count of P450s is a

moving target and precise numbers have not been tallied except in plants where this was

done recently.  As of April 2000, there were 513 plant P450 sequences known.  There are

probably a larger number of animal P450 sequences.  Bacteria and lower eukaryotes are

close to 100 named P450s each, but this will surely grow as the genome projects continue

to sequence whole genomes.  Individual species are of some interest since the complete

genomes of yeast, C. elegans and Drosophila are known.  Yeast have ony three P450s, and

the nearly complete Schizosaccharomyces pombe seems to have only two.  C. elegans has

80 P450 genes, with about 6 of these being pseudogenes.  Drosophila has 90 P450s with 4

pseudogenes.  Humans have 56, not counting pseudogenes, but the human genome is only

94% sequenced mostly in draft form and this number may rise by one or two.  Arabidopsis

is the undisputed record holder with 274 named P450 genes with 100% of the genome

completed.  For detailed information on P450 nomenclature and other information see the

cytochrome P450 homepage at http://drnelson.uthsc.edu/CytochromeP450.html.


The functions of P450s are very broad.  In mammals they are critical for drug metabolism,

blood hemostasis, cholesterol biosynthesis and steroidogenesis.  They are responsible for a

number of human diseases.  In plants they are involved in plant hormone synthesis,

phytoalexin synthesis, flower petal pigment biosynthesis and perhaps hundreds of

unknown functions.  In fungi they make ergosterol and they are involved in pathogenesis,

by detoxifying host plant defenses.  CYP51, the lanosterol 14-alpha demethylase is the

primary target of antifungal triazole drugs.  Bacterial P450s are key players in antibiotic



Because the eukaryotic P450s are membrane bound, it has not been possible until very

recently to obtain a crystal structure of a representative enzyme.  This has finally been

done, but the result is still unpublished.  There are six soluble bacterial P450s that have

crystal structures CYP101, CYP102, CYP105A3, CYP55A1, CYP107A1, CYP108.

CYP55A1 is a pirated bacterial P450 found in a fungus.  These have been reviewed by

Graham and Peterson (3).  The general structure is globular, almost triangular, with the C-

terminal half being helix rich and the N-terminal half being more beta sheet rich.  The C-

terminal half is more highly conserved.  The P450 siganture motif includes the heme ligand

cys and is ususally represented as FXXGXXXCXG, though there are exceptions at all

three non-cys positions.  This heme binding region is about 50 amino acids from the C-

terminal of the protein.  The helix rich half of the protein starts with the I-helix.  This long

helix contributes a conserved motif A(A,G)X(E,D)T where the thr residue is part of the

oxygen binding site.  The K helix has an invariant EXXR sequence which tolerates no

substitutions.  The E, the R and the C at the heme binding site are the only completely

conserved amino acids in P450s.  For more