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Structure–Function Analysis of the Self-Sufficient CYP102 Family Provides New Insights into Their Biochemistry

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

International Journal of Molecular Sciences, Volume: 26, Issue: 5, Start page: 2161

Swansea University Author: David Lamb Orcid Logo

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DOI (Published version): 10.3390/ijms26052161

Abstract

Cytochromes P450 are a superfamily of heme-containing monooxygenases involved in a variety of oxidative metabolic reactions, primarily catalyzing the insertion of an oxygen atom into a C-H bond. CYP102 represents the first example of a bacterial P450 that can be classified as a type II (eukaryotic-l...

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Published in: International Journal of Molecular Sciences
ISSN: 1422-0067
Published: MDPI 2025
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URI: https://cronfa.swan.ac.uk/Record/cronfa69085
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These unique features have made CYP102 an attractive system for studying P450 structure and function. However, an overall picture of the specific amino acid residues that are crucial to the functioning of CYP102 and the effect of mutations on the P450 structure and catalysis is yet to be reported. Such an approach will aid protein engineering approaches used to improve this enzyme. To address this research knowledge gap, we have investigated 105 CYP102 crystal structures in this study. We demonstrate that the CYP102 active site is highly dynamic and flexible. Amino acid residues that play critical roles in substrate binding, orientation, and anchoring were identified. Mutational studies highlighted the roles of amino acids and provided possible bioengineering improvement strategies for CYP102. Decoy molecules are a promising agent for deceiving CYP102 and permitting non-native substrates into the active site. 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spelling 2025-03-12T13:36:48.5824857 v2 69085 2025-03-12 Structure–Function Analysis of the Self-Sufficient CYP102 Family Provides New Insights into Their Biochemistry 1dc64e55c2c28d107ef7c3db984cccd2 0000-0001-5446-2997 David Lamb David Lamb true false 2025-03-12 MEDS Cytochromes P450 are a superfamily of heme-containing monooxygenases involved in a variety of oxidative metabolic reactions, primarily catalyzing the insertion of an oxygen atom into a C-H bond. CYP102 represents the first example of a bacterial P450 that can be classified as a type II (eukaryotic-like) P450 and functions as a catalytically self-sufficient enzyme. These unique features have made CYP102 an attractive system for studying P450 structure and function. However, an overall picture of the specific amino acid residues that are crucial to the functioning of CYP102 and the effect of mutations on the P450 structure and catalysis is yet to be reported. Such an approach will aid protein engineering approaches used to improve this enzyme. To address this research knowledge gap, we have investigated 105 CYP102 crystal structures in this study. We demonstrate that the CYP102 active site is highly dynamic and flexible. Amino acid residues that play critical roles in substrate binding, orientation, and anchoring were identified. Mutational studies highlighted the roles of amino acids and provided possible bioengineering improvement strategies for CYP102. Decoy molecules are a promising agent for deceiving CYP102 and permitting non-native substrates into the active site. Ru(II)-diimine photosensitizers and zinc/cobalt (III) sepulchrate (Co(III)Sep) could be used as alternative electron sources. The present study serves as a reference for understanding the structure–functional analysis of CYP102 family members precisely and of P450 enzymes in general. Significantly, this work contributes to the effort to develop an improved CYP102 enzyme, thereby advancing the field of P450 research and potentially leading to new industrial applications. Journal Article International Journal of Molecular Sciences 26 5 2161 MDPI 1422-0067 cytochrome P450; CYP102; heme domain; redox partner; fatty acid; active site; mutant; hydrogen bond 28 2 2025 2025-02-28 10.3390/ijms26052161 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). 2025-03-12T13:36:48.5824857 2025-03-12T13:30:23.8711889 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 69085__33798__b35b50e95942490284414ff06c2d4d7d.pdf ijms-26-02161.pdf 2025-03-12T13:30:23.8595439 Output 23834475 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 Structure–Function Analysis of the Self-Sufficient CYP102 Family Provides New Insights into Their Biochemistry
spellingShingle Structure–Function Analysis of the Self-Sufficient CYP102 Family Provides New Insights into Their Biochemistry
David Lamb
title_short Structure–Function Analysis of the Self-Sufficient CYP102 Family Provides New Insights into Their Biochemistry
title_full Structure–Function Analysis of the Self-Sufficient CYP102 Family Provides New Insights into Their Biochemistry
title_fullStr Structure–Function Analysis of the Self-Sufficient CYP102 Family Provides New Insights into Their Biochemistry
title_full_unstemmed Structure–Function Analysis of the Self-Sufficient CYP102 Family Provides New Insights into Their Biochemistry
title_sort Structure–Function Analysis of the Self-Sufficient CYP102 Family Provides New Insights into Their Biochemistry
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 International Journal of Molecular Sciences
container_volume 26
container_issue 5
container_start_page 2161
publishDate 2025
institution Swansea University
issn 1422-0067
doi_str_mv 10.3390/ijms26052161
publisher MDPI
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 are a superfamily of heme-containing monooxygenases involved in a variety of oxidative metabolic reactions, primarily catalyzing the insertion of an oxygen atom into a C-H bond. CYP102 represents the first example of a bacterial P450 that can be classified as a type II (eukaryotic-like) P450 and functions as a catalytically self-sufficient enzyme. These unique features have made CYP102 an attractive system for studying P450 structure and function. However, an overall picture of the specific amino acid residues that are crucial to the functioning of CYP102 and the effect of mutations on the P450 structure and catalysis is yet to be reported. Such an approach will aid protein engineering approaches used to improve this enzyme. To address this research knowledge gap, we have investigated 105 CYP102 crystal structures in this study. We demonstrate that the CYP102 active site is highly dynamic and flexible. Amino acid residues that play critical roles in substrate binding, orientation, and anchoring were identified. Mutational studies highlighted the roles of amino acids and provided possible bioengineering improvement strategies for CYP102. Decoy molecules are a promising agent for deceiving CYP102 and permitting non-native substrates into the active site. Ru(II)-diimine photosensitizers and zinc/cobalt (III) sepulchrate (Co(III)Sep) could be used as alternative electron sources. The present study serves as a reference for understanding the structure–functional analysis of CYP102 family members precisely and of P450 enzymes in general. Significantly, this work contributes to the effort to develop an improved CYP102 enzyme, thereby advancing the field of P450 research and potentially leading to new industrial applications.
published_date 2025-02-28T08:19:02Z
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