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Unravelling the role of transient redox partner complexes in P450 electron transfer mechanics

Tatiana Y. Hargrove, David Lamb Orcid Logo, Jarrod A. Smith, Zdzislaw Wawrzak, Steven Kelly, Galina I. Lepesheva

Scientific Reports, Volume: 12, Issue: 1

Swansea University Authors: David Lamb Orcid Logo, Steven Kelly

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DOI (Published version): 10.1038/s41598-022-20671-0

Abstract

The molecular evolution of cytochromes P450 and associated redox-driven oxidative catalysis remains a mystery in biology. It is widely believed that sterol 14α-demethylase (CYP51), an essential enzyme of sterol biosynthesis, is the ancestor of the whole P450 superfamily given its conservation across...

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Published in: Scientific Reports
ISSN: 2045-2322
Published: Springer Science and Business Media LLC 2022
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URI: https://cronfa.swan.ac.uk/Record/cronfa61474
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It is widely believed that sterol 14α-demethylase (CYP51), an essential enzyme of sterol biosynthesis, is the ancestor of the whole P450 superfamily given its conservation across species in different biological kingdoms. Herein we have utilized X-ray crystallography, molecular dynamics simulations, phylogenetics and electron transfer measurements to interrogate the nature of P450-redox partner binding using the naturally occurring fusion protein, CYP51-ferredoxin found in the sterol-producing bacterium Methylococcus capsulatus. Our data advocates that the electron transfer mechanics in the M. capsulatus CYP51-ferredoxin fusion protein involves an ensemble of ferredoxin molecules in various orientations and the interactions are transient. Close proximity of ferredoxin, however, is required to complete the substrate-induced large-scale structural switch in the P450 domain that enables proton-coupled electron transfer and subsequent oxygen scission and catalysis. These results have fundamental implications regarding the early evolution of electron transfer proteins and for the redox reactions in the early steps of sterol biosynthesis. They also shed new light on redox protein mechanics and the subsequent diversification of the P450 electron transfer machinery in nature.</abstract><type>Journal Article</type><journal>Scientific Reports</journal><volume>12</volume><journalNumber>1</journalNumber><paginationStart/><paginationEnd/><publisher>Springer Science and Business Media LLC</publisher><placeOfPublication/><isbnPrint/><isbnElectronic/><issnPrint/><issnElectronic>2045-2322</issnElectronic><keywords/><publishedDay>28</publishedDay><publishedMonth>9</publishedMonth><publishedYear>2022</publishedYear><publishedDate>2022-09-28</publishedDate><doi>10.1038/s41598-022-20671-0</doi><url/><notes>Data availability:Te atomic coordinates and structure factors have been deposited in the Protein Data Bank (http://wwwpdb.org) under the accession number 7SNM. Te ferredoxin model and the pdb fles obtained upon molecular dynamics simulations are available at request. All other data included in this article or its online Supplementary Material.</notes><college>COLLEGE NANME</college><department>Medical School</department><CollegeCode>COLLEGE CODE</CollegeCode><DepartmentCode>MEDS</DepartmentCode><institution>Swansea University</institution><apcterm/><funders>The study was supported by National Institutes of Health grants R01 GM067871 (G.I.L.) and by The Royal Society (to D.C.L.). Funding at Swansea University supported by the European Regional Development Fund/ Welsh European Funding Ofce via the BEACON project (SLK).</funders><projectreference/><lastEdited>2024-07-15T12:08:01.1826254</lastEdited><Created>2022-10-07T11:43:00.3562127</Created><path><level id="1">Faculty of Medicine, Health and Life Sciences</level><level id="2">Swansea University Medical School - Medicine</level></path><authors><author><firstname>Tatiana Y.</firstname><surname>Hargrove</surname><order>1</order></author><author><firstname>David</firstname><surname>Lamb</surname><orcid>0000-0001-5446-2997</orcid><order>2</order></author><author><firstname>Jarrod A.</firstname><surname>Smith</surname><order>3</order></author><author><firstname>Zdzislaw</firstname><surname>Wawrzak</surname><order>4</order></author><author><firstname>Steven</firstname><surname>Kelly</surname><order>5</order></author><author><firstname>Galina I.</firstname><surname>Lepesheva</surname><order>6</order></author></authors><documents><document><filename>61474__25542__eba59eb010e24684b9e5cc5919a64a8e.pdf</filename><originalFilename>61474_VoR.pdf</originalFilename><uploaded>2022-10-21T10:50:20.2204768</uploaded><type>Output</type><contentLength>3863348</contentLength><contentType>application/pdf</contentType><version>Version of Record</version><cronfaStatus>true</cronfaStatus><documentNotes>© The Author(s) 2022. 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spelling v2 61474 2022-10-07 Unravelling the role of transient redox partner complexes in P450 electron transfer mechanics 1dc64e55c2c28d107ef7c3db984cccd2 0000-0001-5446-2997 David Lamb David Lamb true false b17cebaf09b4d737b9378a3581e3de93 Steven Kelly Steven Kelly true false 2022-10-07 MEDS The molecular evolution of cytochromes P450 and associated redox-driven oxidative catalysis remains a mystery in biology. It is widely believed that sterol 14α-demethylase (CYP51), an essential enzyme of sterol biosynthesis, is the ancestor of the whole P450 superfamily given its conservation across species in different biological kingdoms. Herein we have utilized X-ray crystallography, molecular dynamics simulations, phylogenetics and electron transfer measurements to interrogate the nature of P450-redox partner binding using the naturally occurring fusion protein, CYP51-ferredoxin found in the sterol-producing bacterium Methylococcus capsulatus. Our data advocates that the electron transfer mechanics in the M. capsulatus CYP51-ferredoxin fusion protein involves an ensemble of ferredoxin molecules in various orientations and the interactions are transient. Close proximity of ferredoxin, however, is required to complete the substrate-induced large-scale structural switch in the P450 domain that enables proton-coupled electron transfer and subsequent oxygen scission and catalysis. These results have fundamental implications regarding the early evolution of electron transfer proteins and for the redox reactions in the early steps of sterol biosynthesis. They also shed new light on redox protein mechanics and the subsequent diversification of the P450 electron transfer machinery in nature. Journal Article Scientific Reports 12 1 Springer Science and Business Media LLC 2045-2322 28 9 2022 2022-09-28 10.1038/s41598-022-20671-0 Data availability:Te atomic coordinates and structure factors have been deposited in the Protein Data Bank (http://wwwpdb.org) under the accession number 7SNM. Te ferredoxin model and the pdb fles obtained upon molecular dynamics simulations are available at request. All other data included in this article or its online Supplementary Material. COLLEGE NANME Medical School COLLEGE CODE MEDS Swansea University The study was supported by National Institutes of Health grants R01 GM067871 (G.I.L.) and by The Royal Society (to D.C.L.). Funding at Swansea University supported by the European Regional Development Fund/ Welsh European Funding Ofce via the BEACON project (SLK). 2024-07-15T12:08:01.1826254 2022-10-07T11:43:00.3562127 Faculty of Medicine, Health and Life Sciences Swansea University Medical School - Medicine Tatiana Y. Hargrove 1 David Lamb 0000-0001-5446-2997 2 Jarrod A. Smith 3 Zdzislaw Wawrzak 4 Steven Kelly 5 Galina I. Lepesheva 6 61474__25542__eba59eb010e24684b9e5cc5919a64a8e.pdf 61474_VoR.pdf 2022-10-21T10:50:20.2204768 Output 3863348 application/pdf Version of Record true © The Author(s) 2022. This article is licensed under a Creative Commons Attribution 4.0 International License true eng http://creativecommons.org/licenses/by/4.0/
title Unravelling the role of transient redox partner complexes in P450 electron transfer mechanics
spellingShingle Unravelling the role of transient redox partner complexes in P450 electron transfer mechanics
David Lamb
Steven Kelly
title_short Unravelling the role of transient redox partner complexes in P450 electron transfer mechanics
title_full Unravelling the role of transient redox partner complexes in P450 electron transfer mechanics
title_fullStr Unravelling the role of transient redox partner complexes in P450 electron transfer mechanics
title_full_unstemmed Unravelling the role of transient redox partner complexes in P450 electron transfer mechanics
title_sort Unravelling the role of transient redox partner complexes in P450 electron transfer mechanics
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
Jarrod A. Smith
Zdzislaw Wawrzak
Steven Kelly
Galina I. Lepesheva
format Journal article
container_title Scientific Reports
container_volume 12
container_issue 1
publishDate 2022
institution Swansea University
issn 2045-2322
doi_str_mv 10.1038/s41598-022-20671-0
publisher Springer Science and Business Media LLC
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 - Medicine{{{_:::_}}}Faculty of Medicine, Health and Life Sciences{{{_:::_}}}Swansea University Medical School - Medicine
document_store_str 1
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description The molecular evolution of cytochromes P450 and associated redox-driven oxidative catalysis remains a mystery in biology. It is widely believed that sterol 14α-demethylase (CYP51), an essential enzyme of sterol biosynthesis, is the ancestor of the whole P450 superfamily given its conservation across species in different biological kingdoms. Herein we have utilized X-ray crystallography, molecular dynamics simulations, phylogenetics and electron transfer measurements to interrogate the nature of P450-redox partner binding using the naturally occurring fusion protein, CYP51-ferredoxin found in the sterol-producing bacterium Methylococcus capsulatus. Our data advocates that the electron transfer mechanics in the M. capsulatus CYP51-ferredoxin fusion protein involves an ensemble of ferredoxin molecules in various orientations and the interactions are transient. Close proximity of ferredoxin, however, is required to complete the substrate-induced large-scale structural switch in the P450 domain that enables proton-coupled electron transfer and subsequent oxygen scission and catalysis. These results have fundamental implications regarding the early evolution of electron transfer proteins and for the redox reactions in the early steps of sterol biosynthesis. They also shed new light on redox protein mechanics and the subsequent diversification of the P450 electron transfer machinery in nature.
published_date 2022-09-28T12:08:00Z
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