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  • 1
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    Concerning P450 evolution: Structural Analyses Support Bacterial Origin of Sterol 14α-Demethylases (2020)
    Oxford University Press
    Details
    Publication Date: 2020-10-08
    Description: Sterol biosynthesis, primarily associated with eukaryotic kingdoms of life, occurs as an abbreviated pathway in the bacterium Methylococcus capsulatus. Sterol 14α-demethylation is an essential step in this pathway and is catalyzed by cytochrome P450 51 (CYP51). In M. capsulatus the enzyme consists of the P450 domain naturally fused to a ferredoxin domain at the C-terminus (CYP51fx). The structure of M. capsulatus CYP51fx was solved to 2.7 Å resolution and is the first structure of a bacterial sterol biosynthetic enzyme. The structure contained one P450 molecule per asymmetric unit with no electron density seen for ferredoxin. We connect this with the requirement of P450 substrate binding in order to activate productive ferredoxin binding. Further, the structure of the P450 domain with bound detergent (which replaced the substrate upon crystallization) was solved to 2.4 Å resolution. Comparison of these two structures to the CYP51s from human, fungi and protozoa reveals strict conservation of the overall protein architecture. However, the structure of an “orphan” P450 from non-sterol producing Mycobacterium tuberculosis that also has CYP51 activity reveals marked differences, suggesting that loss of function in vivo might have led to alterations in the structural constraints. Our results are consistent with the idea that eukaryotic and bacterial CYP51s evolved from a common cenancestor and that early eukaryotes may have recruited CYP51 from a bacterial source. The idea is supported by bioinformatic analysis, revealing the presence of CYP51 genes in 〉 1000 bacteria from 9 different phyla, more than 50 of them being natural CYP51fx fusion proteins.
    Print ISSN: 0737-4038
    Electronic ISSN: 1537-1719
    Topics: Biology
    Published by Oxford University Press
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  • 2
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    The chemical defensome of five model teleost fish (2021)
    Nature Research
    Details
    Publication Date: 2022-05-27
    Description: © The Author(s), 2021. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Eide, M., Zhang, X., Karlsen, O. A., Goldstone, J., Stegeman, J., Jonassen, I., & Goksoyr, A. The chemical defensome of five model teleost fish. Scientific Reports, 11(1), (2021): 10546, https://doi.org/10.1038/s41598-021-89948-0.
    Description: How an organism copes with chemicals is largely determined by the genes and proteins that collectively function to defend against, detoxify and eliminate chemical stressors. This integrative network includes receptors and transcription factors, biotransformation enzymes, transporters, antioxidants, and metal- and heat-responsive genes, and is collectively known as the chemical defensome. Teleost fish is the largest group of vertebrate species and can provide valuable insights into the evolution and functional diversity of defensome genes. We have previously shown that the xenosensing pregnane x receptor (pxr, nr1i2) is lost in many teleost species, including Atlantic cod (Gadus morhua) and three-spined stickleback (Gasterosteus aculeatus), but it is not known if compensatory mechanisms or signaling pathways have evolved in its absence. In this study, we compared the genes comprising the chemical defensome of five fish species that span the teleosteii evolutionary branch often used as model species in toxicological studies and environmental monitoring programs: zebrafish (Danio rerio), medaka (Oryzias latipes), Atlantic killifish (Fundulus heteroclitus), Atlantic cod, and three-spined stickleback. Genome mining revealed evolved differences in the number and composition of defensome genes that can have implication for how these species sense and respond to environmental pollutants, but we did not observe any candidates of compensatory mechanisms or pathways in cod and stickleback in the absence of pxr. The results indicate that knowledge regarding the diversity and function of the defensome will be important for toxicological testing and risk assessment studies.
    Description: The work was supported by the Norwegian Research Council as part of the iCOD and iCOD 2.0 projects (Grant Nos. 192441/I30 and 244654/E40), and the dCod 1.0 project (Grant No. 248840) which is part of Centre for Digital Life Norway. The American collaborators were funded by the National Institute of Health (USA) NIH P42ES007381 (Boston University Superfund Center to JJS and JVG), NIH R21HD073805 (JVG) and NHI R01ES029917 (JVG) grants. The Ocean Outlook exchange program funded the trans-Atlantic collaboration.
    Repository Name: Woods Hole Open Access Server
    Type: Article
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  • 3
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    Developmental exposure to non-dioxin-like polychlorinated biphenyls promotes sensory deficits and disrupts dopaminergic and GABAergic signaling in zebrafish (2021)
    Nature Research
    Details
    Publication Date: 2022-05-27
    Description: © The Author(s), 2021. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Brun, N. R., Panlilio, J. M., Zhang, K., Zhao, Y., Ivashkin, E., Stegeman, J. J., & Goldstone, J. Developmental exposure to non-dioxin-like polychlorinated biphenyls promotes sensory deficits and disrupts dopaminergic and GABAergic signaling in zebrafish. Communications Biology, 4(1), (2021): 1129, https://doi.org/10.1038/s42003-021-02626-9.
    Description: The most abundant polychlorinated biphenyl (PCB) congeners found in the environment and in humans are neurotoxic. This is of particular concern for early life stages because the exposure of the more vulnerable developing nervous system to neurotoxic chemicals can result in neurobehavioral disorders. In this study, we uncover currently unknown links between PCB target mechanisms and neurobehavioral deficits using zebrafish as a vertebrate model. We investigated the effects of the abundant non-dioxin-like (NDL) congener PCB153 on neuronal morphology and synaptic transmission linked to the proper execution of a sensorimotor response. Zebrafish that were exposed during development to concentrations similar to those found in human cord blood and PCB contaminated sites showed a delay in startle response. Morphological and biochemical data demonstrate that even though PCB153-induced swelling of afferent sensory neurons, the disruption of dopaminergic and GABAergic signaling appears to contribute to PCB-induced motor deficits. A similar delay was observed for other NDL congeners but not for the potent dioxin-like congener PCB126. The effects on important and broadly conserved signaling mechanisms in vertebrates suggest that NDL PCBs may contribute to neurodevelopmental abnormalities in humans and increased selection pressures in vertebrate wildlife.
    Description: This work was supported by the Swiss National Science Foundation P2EZP2_165200 (NRB), the Boston University Superfund Research Program NIH 5P42ES007381 (J.J.S. and J.V.G.), the Woods Hole Center for Oceans and Human Health (NIH: P01ES021923 and P01ES028938; NSF: OCE-1314642 and OCE-1840381) (N.R.B., J.M.P., and J.J.S.), and the National Natural Science Foundation of China 22006099 (K.Z. and Y.Z.) and the Shanghai Pujiang Program 19PJ1404900 (K.Z. and Y.Z.).
    Repository Name: Woods Hole Open Access Server
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  • 4
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    Orphan cytochrome P450 20a1 CRISPR/Cas9 mutants and neurobehavioral phenotypes in zebrafish (2022)
    Nature Research
    Details
    Publication Date: 2022-05-27
    Description: © The Author(s), 2021. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Brun, N. R., Salanga, M. C., Mora-Zamorano, F. X., Lamb, D. C., Goldstone, J. V., & Stegeman, J. J. Orphan cytochrome P450 20a1 CRISPR/Cas9 mutants and neurobehavioral phenotypes in zebrafish. Scientific Reports, 11(1), (2021): 23892, https://doi.org/10.1038/s41598-021-03068-3.
    Description: Orphan cytochrome P450 (CYP) enzymes are those for which biological substrates and function(s) are unknown. Cytochrome P450 20A1 (CYP20A1) is the last human orphan P450 enzyme, and orthologs occur as single genes in every vertebrate genome sequenced to date. The occurrence of high levels of CYP20A1 transcripts in human substantia nigra and hippocampus and abundant maternal transcripts in zebrafish eggs strongly suggest roles both in the brain and during early embryonic development. Patients with chromosome 2 microdeletions including CYP20A1 show hyperactivity and bouts of anxiety, among other conditions. Here, we created zebrafish cyp20a1 mutants using CRISPR/Cas9, providing vertebrate models with which to study the role of CYP20A1 in behavior and other neurodevelopmental functions. The homozygous cyp20a1 null mutants exhibited significant behavioral differences from wild-type zebrafish, both in larval and adult animals. Larval cyp20a1-/- mutants exhibited a strong increase in light-simulated movement (i.e., light–dark assay), which was interpreted as hyperactivity. Further, the larvae exhibited mild hypoactivity during the adaptation period of the optomotor assays. Adult cyp20a1 null fish showed a pronounced delay in adapting to new environments, which is consistent with an anxiety paradigm. Taken together with our earlier morpholino cyp20a1 knockdown results, the results described herein suggest that the orphan CYP20A1 has a neurophysiological role.
    Description: These studies were supported in part by the Boston University Superfund Research Program NIH 5P42ES007381 (MCS, NRB, FXM, JVG, JJS), the Woods Hole Center for Oceans and Human Health (NIH: P01ES021923 and P01ES028938; NSF: OCE-1314642 and OCE-1840381; NRB and JJS), and EBI/EMBL Medakatox NIEHS R01ES029917 (JVG). DCL was funded by a UK-US Fulbright Scholarship.
    Repository Name: Woods Hole Open Access Server
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  • 5
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    Concerning P450 evolution: structural analyses support bacterial origin of sterol 14α-demethylases (2020)
    Oxford University Press
    Details
    Publication Date: 2022-05-26
    Description: © The Author(s), 2020. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Lamb, D. C., Hargrove, T. Y., Zhao, B., Wawrzak, Z., Goldstone, J. V., Nes, W. D., Kelly, S. L., Waterman, M. R., Stegeman, J. J., & Lepesheva, G. I. Concerning P450 evolution: structural analyses support bacterial origin of sterol 14α-demethylases. Molecular Biology and Evolution, (2020): msaa260, doi:10.1093/molbev/msaa260.
    Description: Sterol biosynthesis, primarily associated with eukaryotic kingdoms of life, occurs as an abbreviated pathway in the bacterium Methylococcus capsulatus. Sterol 14α-demethylation is an essential step in this pathway and is catalyzed by cytochrome P450 51 (CYP51). In M. capsulatus, the enzyme consists of the P450 domain naturally fused to a ferredoxin domain at the C-terminus (CYP51fx). The structure of M. capsulatus CYP51fx was solved to 2.7 Å resolution and is the first structure of a bacterial sterol biosynthetic enzyme. The structure contained one P450 molecule per asymmetric unit with no electron density seen for ferredoxin. We connect this with the requirement of P450 substrate binding in order to activate productive ferredoxin binding. Further, the structure of the P450 domain with bound detergent (which replaced the substrate upon crystallization) was solved to 2.4 Å resolution. Comparison of these two structures to the CYP51s from human, fungi, and protozoa reveals strict conservation of the overall protein architecture. However, the structure of an “orphan” P450 from nonsterol-producing Mycobacterium tuberculosis that also has CYP51 activity reveals marked differences, suggesting that loss of function in vivo might have led to alterations in the structural constraints. Our results are consistent with the idea that eukaryotic and bacterial CYP51s evolved from a common cenancestor and that early eukaryotes may have recruited CYP51 from a bacterial source. The idea is supported by bioinformatic analysis, revealing the presence of CYP51 genes in 〉1,000 bacteria from nine different phyla, 〉50 of them being natural CYP51fx fusion proteins.
    Description: The study was supported by National Institutes of Health (Grant No. R01 GM067871 to G.I.L.) and by a UK-USA Fulbright Scholarship and the Royal Society (to D.C.L.).
    Keywords: sterol biosynthesis ; evolution ; cytochrome P450 ; CYP51 redox partner ; crystallography
    Repository Name: Woods Hole Open Access Server
    Type: Article
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