The Evolution and Genomics of Cytochrome P450

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The Evolution and Genomics of Cytochrome P450

David R. Nelson University of Tennessee
Health Science Center
Memphis
UTSA Dept. of Chemistry April 20, 2007
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Mammalian CYP2C5 from rabbit
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Heme binding signature sequence showing the
conserved Cys
S
G
H
H
L
G
C
F
FGHGSHLCLG
4
.
7000
6766 April 11
6000
5000
07
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The AmpliChip CYP450 array from Roche The first
pharmacogenomics diagnostic chip
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8
(5)
1016
(287)
754
(179)
2345
(101)
2417
(94)
226
(54)
6766
(720)
JGI Tree of Life
April 11, 2007
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CYP Families are 40 identical or more at the
protein sequence level.
CYP Subfamilies are 55 identical or more at the
protein sequence level.
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Synteny of cytochrome P450s in vertebrates

frog
fish
chick
human
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Human Chr 1 vs. mouse and chicken Phylogeneticall
y Inferred Groups synteny viewer
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32
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Human Chr 7 vs. zebrafish Phylogenetically
Inferred Groups synteny viewer
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Human Chr 5 vs. Ciona Phylogenetically Inferred
Groups synteny viewer
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Human CYP2AC1P
Xenopus CYP2AC gene cluster
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Human CYP2J2 and HOOK1
chicken CYP2J cluster and HOOK1
zebrafish CYP2P, CYP2V, CYP2AD and CYP2N gene
cluster
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Human CYP2ABFGST gene cluster
Xenopus CYP2Q gene cluster
Fugu CYP2Y1 and CYP2Y2
Zebrafish CYP2Y3
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human CYP19 and gliomedin
zebrafish CYP19 and gliomedin ortholog
Ciona CYP20 and best BLAST hit to zebrafish
gliomedin ortholog
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CYP51
UPGMA tree of Amphioxus CYPs (not mito clan)
CYP7/39 Clan
CYP20
CYP26 Clan
CYP4 Clan
CYP3 Clan
CYP19
CYP2 Clan
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3 Clan
UPGMA tree of
4 Clan
Hydra P450s
2 Clan
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Ecdysone metabolic pathway in insects
From Niwa et al. J Biol Chem. Aug. 20 279,
35942-9 2004
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71 moss P450s with 48 additional plant sequences
Physcomitrella
patens
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Possible precursor to CYP3/CYP4 clan in animals
jasmonate pathway
gibberellins
brassinosteroids
sterol C-22 desaturase
sterol 14a demethylase
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Brassinosteroid pathway
CYP90D
CYP90D
CYP90C
ROT3
CYP85A2
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From Thom Volks Fungus of the Month Webpage With
permission
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• Some fungal toxins (that require P450s for
  synthesis)
• Polyketide synthase mycotoxins/pigments (from
  acetate)
• Sesquiterpene toxins (from farnesyl PP)
• Diterpene toxins (from geranylgeranyl PP)

sterigmatocystin/aflatoxin (6 P450s 58B1,
59A1, 60A2, 60B1, 62A1, 64A1)
fusarin C (at least one P450, CYP627A)
fumonisin (2 P450s CYP65 and CYP617 families)
ochratoxin A (2 P450s)
Lovastatin/compactin (2 P450s, lovA CYP68R,
504A)
zearalenone
note there are at least 14 PKS genes in Nectria,
9 are near P450 genes
trichothecenes (4 P450s Tri1 68C1, Tri4 58A1)
Tri11 65A1, Tri13 526A1)
fungal gibberellin (4 P450s, 68A1, 68B1, 69A1,
503A1)
fusicoccins (1 P450)
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Polyketide synthase 46 to conidial yellow
pigment PKS wA of Emericella nidulans
Methyltransferase
oxidoreductase, zinc-binding
dehydrogenase family
65W1
Fungal specific transcription factor With Zn2Cys6
binuclear cluster, 49 to G. zeae
Maleylacetate reductase 2
Polyketide synthase pksN perithecial red pigment
PKS
Chromosome 2 P450 pigment gene cluster
(1219207-1261946)
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578A2
Homogentisate 1,2 diooxygenase
5040A1
532J1
Fumarylacetoacetate hydrolase
504B4
3,4-dihydroxyphenylacetate 6-hydroxylase
Chromosome 12 P450 gene cluster b
(249111-271400)
This is part of the phenylacetate catabolic
pathway that includes 504B4, 504A6, Homogentisate
1,2 diooxygenase and Fumarylacetoacetate
hydrolase. The 504A6 gene is 60kb downstream of
504B4 (see next slide)
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504A6
Phenylacetate 2-hydroxylase
5078A1
5060A1
Chromosome 12 P450 gene cluster c
(330000-351000)
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Heme binding signature sequence showing the
conserved Cys
S
G
H
H
L
G
C
F
FGHGSHLCLG
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(No Transcript)
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Mammalian CYP2C5 from rabbit
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J. Craig Venters Sorcerer II Global Ocean
Sampling expedition
6.1 million new protein sequences, 3305 new P450s
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Ernst Haeckels Tree of life circa 1891
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all biology is evolutionary biology. This is
the future, he said, of biological and
biomedical science. Douglas Futuyma quoted by
David Quammen in The Reluctant Mr. Darwin
2006 p. 234
David Quammen Douglas Futuyma