Nelson David R.

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Nelson
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David R.
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  • Article
    Cytochrome P450 diversity and induction by gorgonian allelochemicals in the marine gastropod Cyphoma gibbosum
    (BioMed Central, 2010-12-01) Whalen, Kristen E. ; Starczak, Victoria R. ; Nelson, David R. ; Goldstone, Jared V. ; Hahn, Mark E.
    Intense consumer pressure strongly affects the structural organization and function of marine ecosystems, while also having a profound effect on the phenotype of both predator and prey. Allelochemicals produced by prey often render their tissues unpalatable or toxic to a majority of potential consumers, yet some marine consumers have evolved resistance to host chemical defenses. A key challenge facing marine ecologists seeking to explain the vast differences in consumer tolerance of dietary allelochemicals is understanding the biochemical and molecular mechanisms underlying diet choice. The ability of marine consumers to tolerate toxin-laden prey may involve the cooperative action of biotransformation enzymes, including the inducible cytochrome P450s (CYPs), which have received little attention in marine invertebrates despite the importance of allelochemicals in their evolution. Here, we investigated the diversity, transcriptional response, and enzymatic activity of CYPs possibly involved in allelochemical detoxification in the generalist gastropod Cyphoma gibbosum, which feeds exclusively on chemically defended gorgonians. Twelve new genes in CYP family 4 were identified from the digestive gland of C. gibbosum. Laboratory-based feeding studies demonstrated a 2.7- to 5.1-fold induction of Cyphoma CYP4BK and CYP4BL transcripts following dietary exposure to the gorgonian Plexaura homomalla, which contains high concentrations of anti-predatory prostaglandins. Phylogenetic analysis revealed that C. gibbosum CYP4BK and CYP4BL were most closely related to vertebrate CYP4A and CYP4F, which metabolize pathophysiologically important fatty acids, including prostaglandins. Experiments involving heterologous expression of selected allelochemically-responsive C. gibbosum CYP4s indicated a possible role of one or more CYP4BL forms in eicosanoid metabolism. Sequence analysis further demonstrated that Cyphoma CYP4BK/4BL and vertebrate CYP4A/4F forms share identical amino acid residues at key positions within fatty acid substrate recognition sites. These results demonstrate differential regulation of CYP transcripts in a marine consumer feeding on an allelochemical-rich diet, and significantly advance our understanding of both the adaptive molecular mechanisms that marine consumers use to cope with environmental chemical pressures and the evolutionary history of allelochemical-metabolizing enzymes in the CYP superfamily.
  • Article
    Identification and developmental expression of the full complement of Cytochrome P450 genes in Zebrafish
    (BioMed Central, 2010-11-18) Goldstone, Jared V. ; McArthur, Andrew G. ; Kubota, Akira ; Zanette, Juliano ; Parente, Thiago ; Jonsson, Maria E. ; Nelson, David R. ; Stegeman, John J.
    Increasing use of zebrafish in drug discovery and mechanistic toxicology demands knowledge of cytochrome P450 (CYP) gene regulation and function. CYP enzymes catalyze oxidative transformation leading to activation or inactivation of many endogenous and exogenous chemicals, with consequences for normal physiology and disease processes. Many CYPs potentially have roles in developmental specification, and many chemicals that cause developmental abnormalities are substrates for CYPs. Here we identify and annotate the full suite of CYP genes in zebrafish, compare these to the human CYP gene complement, and determine the expression of CYP genes during normal development. Zebrafish have a total of 94 CYP genes, distributed among 18 gene families found also in mammals. There are 32 genes in CYP families 5 to 51, most of which are direct orthologs of human CYPs that are involved in endogenous functions including synthesis or inactivation of regulatory molecules. The high degree of sequence similarity suggests conservation of enzyme activities for these CYPs, confirmed in reports for some steroidogenic enzymes (e.g. CYP19, aromatase; CYP11A, P450scc; CYP17, steroid 17a-hydroxylase), and the CYP26 retinoic acid hydroxylases. Complexity is much greater in gene families 1, 2, and 3, which include CYPs prominent in metabolism of drugs and pollutants, as well as of endogenous substrates. There are orthologous relationships for some CYP1 s and some CYP3 s between zebrafish and human. In contrast, zebrafish have 47 CYP2 genes, compared to 16 in human, with only two (CYP2R1 and CYP2U1) recognized as orthologous based on sequence. Analysis of shared synteny identified CYP2 gene clusters evolutionarily related to mammalian CYP2 s, as well as unique clusters. Transcript profiling by microarray and quantitative PCR revealed that the majority of zebrafish CYP genes are expressed in embryos, with waves of expression of different sets of genes over the course of development. Transcripts of some CYP occur also in oocytes. The results provide a foundation for the use of zebrafish as a model in toxicological, pharmacological and chemical disease research.
  • Article
    On the occurrence of cytochrome P450 in viruses
    (National Academy of Sciences, 2019-06-05) Lamb, David C. ; Follmer, Alec H. ; Goldstone, Jared V. ; Nelson, David R. ; Warrilow, Andrew G. ; Price, Claire L. ; True, Marie Y. ; Kelly, Steven L. ; Poulos, Thomas L. ; Stegeman, John J.
    Genes encoding cytochrome P450 (CYP; P450) enzymes occur widely in the Archaea, Bacteria, and Eukarya, where they play important roles in metabolism of endogenous regulatory molecules and exogenous chemicals. We now report that genes for multiple and unique P450s occur commonly in giant viruses in the Mimiviridae, Pandoraviridae, and other families in the proposed order Megavirales. P450 genes were also identified in a herpesvirus (Ranid herpesvirus 3) and a phage (Mycobacterium phage Adler). The Adler phage P450 was classified as CYP102L1, and the crystal structure of the open form was solved at 2.5 Å. Genes encoding known redox partners for P450s (cytochrome P450 reductase, ferredoxin and ferredoxin reductase, and flavodoxin and flavodoxin reductase) were not found in any viral genome so far described, implying that host redox partners may drive viral P450 activities. Giant virus P450 proteins share no more than 25% identity with the P450 gene products we identified in Acanthamoeba castellanii, an amoeba host for many giant viruses. Thus, the origin of the unique P450 genes in giant viruses remains unknown. If giant virus P450 genes were acquired from a host, we suggest it could have been from an as yet unknown and possibly ancient host. These studies expand the horizon in the evolution and diversity of the enormously important P450 superfamily. Determining the origin and function of P450s in giant viruses may help to discern the origin of the giant viruses themselves.
  • Article
    The cytochrome P450 (CYP) superfamily in cnidarians
    (Nature Research, 2021-05-10) Pankov, Kirill V. ; McArthur, Andrew G. ; Gold, David A. ; Nelson, David R. ; Goldstone, Jared V. ; Wilson, Joanne
    The cytochrome P450 (CYP) superfamily is a diverse and important enzyme family, playing a central role in chemical defense and in synthesis and metabolism of major biological signaling molecules. The CYPomes of four cnidarian genomes (Hydra vulgaris, Acropora digitifera, Aurelia aurita, Nematostella vectensis) were annotated; phylogenetic analyses determined the evolutionary relationships amongst the sequences and with existing metazoan CYPs. 155 functional CYPs were identified and 90 fragments. Genes were from 24 new CYP families and several new subfamilies; genes were in 9 of the 12 established metazoan CYP clans. All species had large expansions of clan 2 diversity, with H. vulgaris having reduced diversity for both clan 3 and mitochondrial clan. We identified potential candidates for xenobiotic metabolism and steroidogenesis. That each genome contained multiple, novel CYP families may reflect the large evolutionary distance within the cnidarians, unique physiology in the cnidarian classes, and/or different ecology of the individual species.
  • Article
    The African coelacanth genome provides insights into tetrapod evolution
    (Nature Publishing Group, 2013-04-17) Amemiya, Chris T. ; Alfoldi, Jessica ; Lee, Alison P. ; Fan, Shaohua ; Philippe, Herve ; MacCallum, Iain ; Braasch, Ingo ; Manousaki, Tereza ; Schneider, Igor ; Rohner, Nicolas ; Organ, Chris ; Chalopin, Domitille ; Smith, Jeramiah J. ; Robinson, Mark ; Dorrington, Rosemary A. ; Gerdol, Marco ; Aken, Bronwen ; Assunta Biscotti, Maria ; Barucca, Marco ; Baurain, Denis ; Berlin, Aaron M. ; Blatch, Gregory L. ; Buonocore, Francesco ; Burmester, Thorsten ; Campbell, Michael S. ; Canapa, Adriana ; Cannon, John P. ; Christoffels, Alan ; De Moro, Gianluca ; Edkins, Adrienne L. ; Fan, Lin ; Fausto, Anna Maria ; Feiner, Nathalie ; Forconi, Mariko ; Gamieldien, Junaid ; Gnerre, Sante ; Gnirke, Andreas ; Goldstone, Jared V. ; Haerty, Wilfried ; Hahn, Mark E. ; Hesse, Uljana ; Hoffmann, Steve ; Johnson, Jeremy ; Karchner, Sibel I. ; Kuraku, Shigehiro ; Lara, Marcia ; Levin, Joshua Z. ; Litman, Gary W. ; Mauceli, Evan ; Miyake, Tsutomu ; Mueller, M. Gail ; Nelson, David R. ; Nitsche, Anne ; Olmo, Ettore ; Ota, Tatsuya ; Pallavicini, Alberto ; Panji, Sumir ; Picone, Barbara ; Ponting, Chris P. ; Prohaska, Sonja J. ; Przybylski, Dariusz ; Ratan Saha, Nil ; Ravi, Vydianathan ; Ribeiro, Filipe J. ; Sauka-Spengler, Tatjana ; Scapigliati, Giuseppe ; Searle, Stephen M. J. ; Sharpe, Ted ; Simakov, Oleg ; Stadler, Peter F. ; Stegeman, John J. ; Sumiyama, Kenta ; Tabbaa, Diana ; Tafer, Hakim ; Turner-Maier, Jason ; van Heusden, Peter ; White, Simon ; Williams, Louise ; Yandell, Mark ; Brinkmann, Henner ; Volff, Jean-Nicolas ; Tabin, Clifford J. ; Shubin, Neil ; Schartl, Manfred ; Jaffe, David B. ; Postlethwait, John H. ; Venkatesh, Byrappa ; Di Palma, Federica ; Lander, Eric S. ; Meyer, Axel ; Lindblad-Toh, Kerstin
    The discovery of a living coelacanth specimen in 1938 was remarkable, as this lineage of lobe-finned fish was thought to have become extinct 70 million years ago. The modern coelacanth looks remarkably similar to many of its ancient relatives, and its evolutionary proximity to our own fish ancestors provides a glimpse of the fish that first walked on land. Here we report the genome sequence of the African coelacanth, Latimeria chalumnae. Through a phylogenomic analysis, we conclude that the lungfish, and not the coelacanth, is the closest living relative of tetrapods. Coelacanth protein-coding genes are significantly more slowly evolving than those of tetrapods, unlike other genomic features. Analyses of changes in genes and regulatory elements during the vertebrate adaptation to land highlight genes involved in immunity, nitrogen excretion and the development of fins, tail, ear, eye, brain and olfaction. Functional assays of enhancers involved in the fin-to-limb transition and in the emergence of extra-embryonic tissues show the importance of the coelacanth genome as a blueprint for understanding tetrapod evolution.