Transcript A Powerpoint for my talk given at UTSA San Antonio, TX

The Evolution and Genomics of Cytochrome P450
David R. Nelson
University of Tennessee Health Science Center
Memphis
UTSA Dept. of Chemistry April 20, 2007
Mammalian CYP2C5 from rabbit
Heme binding signature sequence showing the conserved Cys
S
G
H
H
L
G
C
FGHGSHLCLG
F
7000
.
6766 April 11
6000
5000
07
The AmpliChip CYP450 array from Roche
The first pharmacogenomics diagnostic chip
(5)
(287)
(179)
(101)
(94)
(54)
(720)
JGI Tree of Life
April 11, 2007
CYP Families are 40% identical or more at the protein
sequence level.
CYP Subfamilies are 55% identical or more at the protein
sequence level.
Synteny of cytochrome P450s in vertebrates
fish
frog
chick
human
Human Chr 1
vs. mouse and
chicken
Phylogenetically
Inferred Groups
synteny viewer
32
37
Human Chr 7
vs. zebrafish
Phylogenetically
Inferred Groups
synteny viewer
Human Chr 5
vs. Ciona
Phylogenetically
Inferred Groups
synteny viewer
Human CYP2AC1P
Xenopus CYP2AC gene cluster
Human CYP2J2 and HOOK1
chicken CYP2J cluster and HOOK1
zebrafish CYP2P, CYP2V, CYP2AD and CYP2N gene cluster
Human CYP2ABFGST gene cluster
Xenopus CYP2Q gene cluster
Fugu CYP2Y1 and CYP2Y2
Zebrafish CYP2Y3
human CYP19 and gliomedin
zebrafish CYP19 and gliomedin ortholog
Ciona CYP20 and best BLAST hit to zebrafish gliomedin ortholog
CYP51
UPGMA tree of
Amphioxus CYPs
(not mito clan)
CYP7/39 Clan
CYP20
CYP26 Clan
CYP4 Clan
CYP3 Clan
CYP19
CYP2 Clan
3 Clan
UPGMA tree of
Hydra P450s
4 Clan
2 Clan
Ecdysone metabolic pathway in insects
From Niwa et al. J Biol Chem. Aug. 20 279, 35942-9 2004
71 moss P450s with 48 additional plant sequences
Physcomitrella
patens
Possible precursor to CYP3/CYP4 clan in animals
jasmonate pathway
gibberellins
brassinosteroids
sterol C-22 desaturase
sterol 14a demethylase
Brassinosteroid
pathway
CYP90D
CYP90D
CYP90C
ROT3
CYP85A2
From Thom Volk’s
Fungus of the Month
Webpage
With permission
Some fungal toxins (that require P450s for synthesis)
A. Polyketide synthase mycotoxins/pigments (from acetate)
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
B. Sesquiterpene toxins (from farnesyl PP)
trichothecenes (4 P450s Tri1 = 68C1, Tri4 = 58A1)
Tri11 = 65A1, Tri13 = 526A1)
C. Diterpene toxins (from geranylgeranyl PP)
fungal gibberellin (4 P450s, 68A1, 68B1, 69A1, 503A1)
fusicoccins (1 P450)
Polyketide synthase 46% to conidial yellow pigment
PKS wA of Emericella nidulans
Methyltransferase
65W1
oxidoreductase, zinc-binding
dehydrogenase family
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)
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)
504A6
Phenylacetate 2-hydroxylase
5078A1
5060A1
Chromosome 12 P450 gene cluster c
(330000-351000)
Heme binding signature sequence showing the conserved Cys
S
G
H
H
L
G
C
FGHGSHLCLG
F
Mammalian CYP2C5 from rabbit
J. Craig Venter’s Sorcerer II Global Ocean Sampling expedition
6.1 million new protein sequences, 3305 new P450s
Ernst Haeckel’s
Tree of life
circa 1891
…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