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The Evolution and Genomics of Cytochrome P450 David R. Nelson University of Tennessee Hea

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.

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The Evolution and Genomics of Cytochrome P450 David R. Nelson University of Tennessee Hea

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  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 S G H H L G C F FGHGSHLCLG

  4. . 7000 6766 April 11 6000 5000 07

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

  6. 8 (5) 1016 (287) 754 (179) 2345 (101) 2417 (94) 226 (54) 6766 (720) JGI Tree of Life April 11, 2007

  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. Synteny of cytochrome P450s in vertebrates frog fish chick human

  9. Human Chr 1 vs. mouse and chicken Phylogenetically Inferred Groups synteny viewer 32 37

  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 chicken CYP2J cluster and HOOK1 zebrafish CYP2P, CYP2V, CYP2AD and CYP2N gene cluster

  14. Human CYP2ABFGST gene cluster Xenopus CYP2Q gene cluster Fugu CYP2Y1 and CYP2Y2 Zebrafish CYP2Y3

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

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

  17. 3 Clan UPGMA tree of 4 Clan Hydra P450s 2 Clan

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

  19. 71 moss P450s with 48 additional plant sequences Physcomitrella patens

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

  21. Brassinosteroid pathway CYP90D CYP90D CYP90C ROT3 CYP85A2

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

  23. 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 P450s58B1, 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)

  24. 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)

  25. 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)

  26. 504A6 Phenylacetate 2-hydroxylase 5078A1 5060A1 Chromosome 12 P450 gene cluster c (330000-351000)

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

  28. Mammalian CYP2C5 from rabbit

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

  30. Ernst Haeckel’s Tree of life circa 1891

  31. …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

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