1. The Evolution and Genomics of Cytochrome P450 David R. Nelson University of Tennessee Health Science Center Memphis UTSA Dept. of Chemistry April 20, 2007

2. Mammalian CYP2C5 from rabbit

3. Heme binding signature sequence showing the conserved Cys FGHGSHLCLG C F L H S G H G

4. 5000 6000 7000 07. 6766 April 11

5. The AmpliChip CYP450 array from Roche The first pharmacogenomics diagnostic chip

6. JGI Tree of LifeApril 11, 2007 (5) (287) (101) (94) (54) (179) (720)

7. CYP Families are 40% identical or more at the protein sequence level. CYP Subfamilies are 55% identical or more at the protein sequence level.

8. fish frog chick Synteny of cytochrome P450s in vertebrates human

9. Human Chr 1 vs. mouse and chicken Phylogenetically Inferred Groups synteny viewer 3732

10. Human Chr 7 vs. zebrafish Phylogenetically Inferred Groups synteny viewer

11. Human Chr 5 vs. Ciona Phylogenetically Inferred Groups synteny viewer

12. Human CYP2AC1P Xenopus CYP2AC gene cluster

13. Human CYP2J2 and HOOK1 zebrafish CYP2P, CYP2V, CYP2AD and CYP2N gene cluster chicken CYP2J cluster and HOOK1

14. Human CYP2ABFGST gene cluster Xenopus CYP2Q gene cluster Fugu CYP2Y1 and CYP2Y2Zebrafish CYP2Y3

16. zebrafish CYP19 and gliomedin ortholog human CYP19 and gliomedin Ciona CYP20 and best BLAST hit to zebrafish gliomedin ortholog

18. UPGMA tree of Amphioxus CYPs (not mito clan) CYP51 CYP7/39 Clan CYP20 CYP26 Clan CYP4 Clan CYP3 Clan CYP19 CYP2 Clan

20. UPGMA tree of Hydra P450s 2 Clan 3 Clan 4 Clan

21. Ecdysone metabolic pathway in insects From Niwa et al. J Biol Chem. Aug. 20 279, 35942-9 2004

25. 71 moss P450s with 48 additional plant sequences Physcomitrella patens

26. Possible precursor to CYP3/CYP4 clan in animals jasmonate pathway gibberellins brassinosteroids sterol C-22 desaturase sterol 14  demethylase

27. Brassinosteroid pathway CYP90D CYP90C CYP85A2 ROT3

29. From Thom Volk’s Fungus of the Month Webpage With permission

30. Some fungal toxins (that require P450s for synthesis) A.Polyketide synthase mycotoxins/pigments (from acetate) B.Sesquiterpene toxins (from farnesyl PP) C.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 trichothecenes (4 P450s Tri1 = 68C1, Tri4 = 58A1) fungal gibberellin (4 P450s, 68A1, 68B1, 69A1, 503A1) fusicoccins (1 P450) note: there are at least 14 PKS genes in Nectria, 9 are near P450 genes Tri11 = 65A1, Tri13 = 526A1)

31. Chromosome 2 P450 pigment gene cluster (1219207-1261946) Polyketide synthase 46% to conidial yellow pigment PKS wA of Emericella nidulans 65W1 Maleylacetate reductase 2 Methyltransferase Fungal specific transcription factor With Zn2Cys6 binuclear cluster, 49% to G. zeae Polyketide synthase pksN perithecial red pigment PKS oxidoreductase, zinc-binding dehydrogenase family

32. Chromosome 12 P450 gene cluster b (249111-271400) 578A2 5040A1 532J1 504B4 Homogentisate 1,2 diooxygenase Fumarylacetoacetate hydrolase 3,4-dihydroxyphenylacetate 6-hydroxylase 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)

33. Chromosome 12 P450 gene cluster c (330000-351000) 504A6 5078A1 5060A1 Phenylacetate 2-hydroxylase

34. Heme binding signature sequence showing the conserved Cys FGHGSHLCLG C F L H S G H G

37. Mammalian CYP2C5 from rabbit

38. J. Craig Venter’s Sorcerer II Global Ocean Sampling expedition 6.1 million new protein sequences, 3305 new P450s

39. Ernst Haeckel’s Tree of life circa 1891

41. …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