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Unique Structural Features Relate to Evolutionary Adaptation of Cytochrome P450 in the Abyssal Zone

Tatiana Y. Hargrove, David Lamb Orcid Logo, Zdzislaw Wawrzak, George Minasov, Jared V. Goldstone, Steven Kelly, John J. Stegeman, Galina I. Lepesheva Orcid Logo

International Journal of Molecular Sciences, Volume: 26, Issue: 12, Start page: 5689

Swansea University Authors: David Lamb Orcid Logo, Steven Kelly

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DOI (Published version): 10.3390/ijms26125689

Abstract

Cytochromes P450 (CYPs) form one of the largest enzyme superfamilies, with similar structural folds yet biological functions varying from synthesis of physiologically essential compounds to metabolism of myriad xenobiotics. Sterol 14α-demethylases (CYP51s) represent a very special P450 family, regar...

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Published in: International Journal of Molecular Sciences
ISSN: 1422-0067
Published: MDPI AG 2025
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URI: https://cronfa.swan.ac.uk/Record/cronfa69797
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Sterol 14&#x3B1;-demethylases (CYP51s) represent a very special P450 family, regarded as a possible evolutionary progenitor for all currently existing P450s. In metazoans CYP51 is critical for the biosynthesis of sterols including cholesterol. Here we determined the crystal structures of ligand-free CYP51s from the abyssal fish Coryphaenoides armatus and human-. Comparative sequence&#x2013;structure&#x2013;function analysis revealed specific structural elements that imply elevated conformational flexibility, uncovering a molecular basis for faster catalytic rates, lower substrate selectivity, and intrinsic resistance to inhibition. In addition, the C. armatus structure displayed a large-scale repositioning of structural segments that, in vivo, are immersed in the endoplasmic reticulum membrane and border the substrate entrance (the FG arm, &gt;20 &#xC5;, and the &#x3B2;4 hairpin, &gt;15 &#xC5;). The structural distinction of C. armatus CYP51, which is the first structurally characterized deep sea P450, suggests stronger involvement of the membrane environment in regulation of the enzyme function. 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spelling 2025-06-23T15:28:59.5813557 v2 69797 2025-06-23 Unique Structural Features Relate to Evolutionary Adaptation of Cytochrome P450 in the Abyssal Zone 1dc64e55c2c28d107ef7c3db984cccd2 0000-0001-5446-2997 David Lamb David Lamb true false b17cebaf09b4d737b9378a3581e3de93 Steven Kelly Steven Kelly true false 2025-06-23 MEDS Cytochromes P450 (CYPs) form one of the largest enzyme superfamilies, with similar structural folds yet biological functions varying from synthesis of physiologically essential compounds to metabolism of myriad xenobiotics. Sterol 14α-demethylases (CYP51s) represent a very special P450 family, regarded as a possible evolutionary progenitor for all currently existing P450s. In metazoans CYP51 is critical for the biosynthesis of sterols including cholesterol. Here we determined the crystal structures of ligand-free CYP51s from the abyssal fish Coryphaenoides armatus and human-. Comparative sequence–structure–function analysis revealed specific structural elements that imply elevated conformational flexibility, uncovering a molecular basis for faster catalytic rates, lower substrate selectivity, and intrinsic resistance to inhibition. In addition, the C. armatus structure displayed a large-scale repositioning of structural segments that, in vivo, are immersed in the endoplasmic reticulum membrane and border the substrate entrance (the FG arm, >20 Å, and the β4 hairpin, >15 Å). The structural distinction of C. armatus CYP51, which is the first structurally characterized deep sea P450, suggests stronger involvement of the membrane environment in regulation of the enzyme function. We interpret this as a co-adaptation of the membrane protein structure with membrane lipid composition during evolutionary incursion to life in the deep sea. Journal Article International Journal of Molecular Sciences 26 12 5689 MDPI AG 1422-0067 cytochrome P450; sterol 14α-demethylase (CYP51); crystal structure; structure–function; conformational flexibility; biological membranes; evolutionary adaptation 13 6 2025 2025-06-13 10.3390/ijms26125689 COLLEGE NANME Medical School COLLEGE CODE MEDS Swansea University Another institution paid the OA fee This research was funded by the National Institutes of Health Grant R35 GM151876 (G.I.L.). Vanderbilt University is a member institution of the Life Sciences Collaborative Access Team at Sector 21 of the Advanced Photon Source (Argonne, IL, USA). Use of the Advanced Photon Source at Argonne National Laboratory was supported by the United States Department of Energy, Office of Science, Office of Basic Energy Sciences, under contract DE-AC02-06CH11357. 2025-06-23T15:28:59.5813557 2025-06-23T15:20:21.5303070 Faculty of Medicine, Health and Life Sciences Swansea University Medical School - Biomedical Science Tatiana Y. Hargrove 1 David Lamb 0000-0001-5446-2997 2 Zdzislaw Wawrzak 3 George Minasov 4 Jared V. Goldstone 5 Steven Kelly 6 John J. Stegeman 7 Galina I. Lepesheva 0000-0002-6975-1131 8 69797__34548__e569d146803d493d899c3873218351a8.pdf 69797.VOR.pdf 2025-06-23T15:24:18.3681896 Output 3367584 application/pdf Version of Record true © 2025 by the authors. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license. true eng https://creativecommons.org/licenses/by/4.0/
title Unique Structural Features Relate to Evolutionary Adaptation of Cytochrome P450 in the Abyssal Zone
spellingShingle Unique Structural Features Relate to Evolutionary Adaptation of Cytochrome P450 in the Abyssal Zone
David Lamb
Steven Kelly
title_short Unique Structural Features Relate to Evolutionary Adaptation of Cytochrome P450 in the Abyssal Zone
title_full Unique Structural Features Relate to Evolutionary Adaptation of Cytochrome P450 in the Abyssal Zone
title_fullStr Unique Structural Features Relate to Evolutionary Adaptation of Cytochrome P450 in the Abyssal Zone
title_full_unstemmed Unique Structural Features Relate to Evolutionary Adaptation of Cytochrome P450 in the Abyssal Zone
title_sort Unique Structural Features Relate to Evolutionary Adaptation of Cytochrome P450 in the Abyssal Zone
author_id_str_mv 1dc64e55c2c28d107ef7c3db984cccd2
b17cebaf09b4d737b9378a3581e3de93
author_id_fullname_str_mv 1dc64e55c2c28d107ef7c3db984cccd2_***_David Lamb
b17cebaf09b4d737b9378a3581e3de93_***_Steven Kelly
author David Lamb
Steven Kelly
author2 Tatiana Y. Hargrove
David Lamb
Zdzislaw Wawrzak
George Minasov
Jared V. Goldstone
Steven Kelly
John J. Stegeman
Galina I. Lepesheva
format Journal article
container_title International Journal of Molecular Sciences
container_volume 26
container_issue 12
container_start_page 5689
publishDate 2025
institution Swansea University
issn 1422-0067
doi_str_mv 10.3390/ijms26125689
publisher MDPI AG
college_str Faculty of Medicine, Health and Life Sciences
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hierarchy_top_id facultyofmedicinehealthandlifesciences
hierarchy_top_title Faculty of Medicine, Health and Life Sciences
hierarchy_parent_id facultyofmedicinehealthandlifesciences
hierarchy_parent_title Faculty of Medicine, Health and Life Sciences
department_str Swansea University Medical School - Biomedical Science{{{_:::_}}}Faculty of Medicine, Health and Life Sciences{{{_:::_}}}Swansea University Medical School - Biomedical Science
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description Cytochromes P450 (CYPs) form one of the largest enzyme superfamilies, with similar structural folds yet biological functions varying from synthesis of physiologically essential compounds to metabolism of myriad xenobiotics. Sterol 14α-demethylases (CYP51s) represent a very special P450 family, regarded as a possible evolutionary progenitor for all currently existing P450s. In metazoans CYP51 is critical for the biosynthesis of sterols including cholesterol. Here we determined the crystal structures of ligand-free CYP51s from the abyssal fish Coryphaenoides armatus and human-. Comparative sequence–structure–function analysis revealed specific structural elements that imply elevated conformational flexibility, uncovering a molecular basis for faster catalytic rates, lower substrate selectivity, and intrinsic resistance to inhibition. In addition, the C. armatus structure displayed a large-scale repositioning of structural segments that, in vivo, are immersed in the endoplasmic reticulum membrane and border the substrate entrance (the FG arm, >20 Å, and the β4 hairpin, >15 Å). The structural distinction of C. armatus CYP51, which is the first structurally characterized deep sea P450, suggests stronger involvement of the membrane environment in regulation of the enzyme function. We interpret this as a co-adaptation of the membrane protein structure with membrane lipid composition during evolutionary incursion to life in the deep sea.
published_date 2025-06-13T05:29:07Z
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