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Structure–Function Analysis of the Biotechnologically Important Cytochrome P450 107 (CYP107) Enzyme Family

Tiara Padayachee Orcid Logo, David Lamb Orcid Logo, David R. Nelson Orcid Logo, Khajamohiddin Syed Orcid Logo

Biomolecules, Volume: 13, Issue: 12, Start page: 1733

Swansea University Author: David Lamb Orcid Logo

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DOI (Published version): 10.3390/biom13121733

Abstract

Cytochrome P450 monooxygenases (CYPs) are a superfamily of heme-containing enzymes that are recognized for their vast substrate range and oxidative multifunctionality. CYP107 family members perform hydroxylation and epoxidation processes, producing a variety of biotechnologically useful secondary me...

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Published in: Biomolecules
ISSN: 2218-273X
Published: MDPI AG 2023
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URI: https://cronfa.swan.ac.uk/Record/cronfa66029
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Despite their biotechnological importance, a thorough examination of CYP107 protein structures regarding active site cavity dynamics and key amino acids interacting with bound ligands has yet to be undertaken. To address this research knowledge gap, 44 CYP107 crystal structures were investigated in this study. We demonstrate that the CYP107 active site cavity is very flexible, with ligand binding reducing the volume of the active site in some situations and increasing volume size in other instances. Polar interactions between the substrate and active site residues result in crucial salt bridges and the formation of proton shuttling pathways. Hydrophobic interactions, however, anchor the substrate within the active site. The amino acid residues within the binding pocket influence substrate orientation and anchoring, determining the position of the hydroxylation site and hence direct CYP107's catalytic activity. 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spelling v2 66029 2024-04-10 Structure–Function Analysis of the Biotechnologically Important Cytochrome P450 107 (CYP107) Enzyme Family 1dc64e55c2c28d107ef7c3db984cccd2 0000-0001-5446-2997 David Lamb David Lamb true false 2024-04-10 MEDS Cytochrome P450 monooxygenases (CYPs) are a superfamily of heme-containing enzymes that are recognized for their vast substrate range and oxidative multifunctionality. CYP107 family members perform hydroxylation and epoxidation processes, producing a variety of biotechnologically useful secondary metabolites. Despite their biotechnological importance, a thorough examination of CYP107 protein structures regarding active site cavity dynamics and key amino acids interacting with bound ligands has yet to be undertaken. To address this research knowledge gap, 44 CYP107 crystal structures were investigated in this study. We demonstrate that the CYP107 active site cavity is very flexible, with ligand binding reducing the volume of the active site in some situations and increasing volume size in other instances. Polar interactions between the substrate and active site residues result in crucial salt bridges and the formation of proton shuttling pathways. Hydrophobic interactions, however, anchor the substrate within the active site. The amino acid residues within the binding pocket influence substrate orientation and anchoring, determining the position of the hydroxylation site and hence direct CYP107's catalytic activity. Additionally, the amino acid dynamics within and around the binding pocket determine CYP107's multifunctionality. This study serves as a reference for understanding the structure-function analysis of CYP107 family members precisely and the structure-function analysis of P450 enzymes in general. Finally, this work will aid in the genetic engineering of CYP107 enzymes to produce novel molecules of biotechnological interest. Journal Article Biomolecules 13 12 1733 MDPI AG 2218-273X CYP107; P450; active site; amino acid dynamics; crystal structure; enzymatic reaction; polar and hydrophobic interactions; secondary metabolites; substrate. 1 12 2023 2023-12-01 10.3390/biom13121733 COLLEGE NANME Medical School COLLEGE CODE MEDS Swansea University Another institution paid the OA fee Khajamohiddin Syed expresses sincere gratitude to the University of Zululand (Grant number P419), and Tiara Padayachee thanks the National Research Foundation (NRF), South Africa, for postgraduate scholarships (grant number MND210504599108). 2024-05-22T14:46:49.2571091 2024-04-10T10:00:53.6572222 Faculty of Medicine, Health and Life Sciences Swansea University Medical School - Biomedical Science Tiara Padayachee 0000-0001-6667-9982 1 David Lamb 0000-0001-5446-2997 2 David R. Nelson 0000-0003-0583-5421 3 Khajamohiddin Syed 0000-0002-1497-3570 4 66029__30434__289aabf0bca8478ab8946d59f1a1f634.pdf 66029.VoR.pdf 2024-05-22T14:44:45.6490327 Output 16598966 application/pdf Version of Record true © 2023 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 Structure–Function Analysis of the Biotechnologically Important Cytochrome P450 107 (CYP107) Enzyme Family
spellingShingle Structure–Function Analysis of the Biotechnologically Important Cytochrome P450 107 (CYP107) Enzyme Family
David Lamb
title_short Structure–Function Analysis of the Biotechnologically Important Cytochrome P450 107 (CYP107) Enzyme Family
title_full Structure–Function Analysis of the Biotechnologically Important Cytochrome P450 107 (CYP107) Enzyme Family
title_fullStr Structure–Function Analysis of the Biotechnologically Important Cytochrome P450 107 (CYP107) Enzyme Family
title_full_unstemmed Structure–Function Analysis of the Biotechnologically Important Cytochrome P450 107 (CYP107) Enzyme Family
title_sort Structure–Function Analysis of the Biotechnologically Important Cytochrome P450 107 (CYP107) Enzyme Family
author_id_str_mv 1dc64e55c2c28d107ef7c3db984cccd2
author_id_fullname_str_mv 1dc64e55c2c28d107ef7c3db984cccd2_***_David Lamb
author David Lamb
author2 Tiara Padayachee
David Lamb
David R. Nelson
Khajamohiddin Syed
format Journal article
container_title Biomolecules
container_volume 13
container_issue 12
container_start_page 1733
publishDate 2023
institution Swansea University
issn 2218-273X
doi_str_mv 10.3390/biom13121733
publisher MDPI AG
college_str Faculty of Medicine, Health and Life Sciences
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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 Cytochrome P450 monooxygenases (CYPs) are a superfamily of heme-containing enzymes that are recognized for their vast substrate range and oxidative multifunctionality. CYP107 family members perform hydroxylation and epoxidation processes, producing a variety of biotechnologically useful secondary metabolites. Despite their biotechnological importance, a thorough examination of CYP107 protein structures regarding active site cavity dynamics and key amino acids interacting with bound ligands has yet to be undertaken. To address this research knowledge gap, 44 CYP107 crystal structures were investigated in this study. We demonstrate that the CYP107 active site cavity is very flexible, with ligand binding reducing the volume of the active site in some situations and increasing volume size in other instances. Polar interactions between the substrate and active site residues result in crucial salt bridges and the formation of proton shuttling pathways. Hydrophobic interactions, however, anchor the substrate within the active site. The amino acid residues within the binding pocket influence substrate orientation and anchoring, determining the position of the hydroxylation site and hence direct CYP107's catalytic activity. Additionally, the amino acid dynamics within and around the binding pocket determine CYP107's multifunctionality. This study serves as a reference for understanding the structure-function analysis of CYP107 family members precisely and the structure-function analysis of P450 enzymes in general. Finally, this work will aid in the genetic engineering of CYP107 enzymes to produce novel molecules of biotechnological interest.
published_date 2023-12-01T14:46:47Z
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