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Selective steroidogenic cytochrome P450 haem iron ligation by steroid-derived isonitriles
Alkyl isonitriles, R—NC, have previously been shown to ligate the heme (haem) iron of cytochromes P450 in both accessible oxidation states (ferrous, Fe(2+), and ferric, Fe(3+)). Herein, the preparation of four steroid-derived isonitriles and their interactions with several P450s, including the stero...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Nature Publishing Group UK
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10475101/ https://www.ncbi.nlm.nih.gov/pubmed/37660137 http://dx.doi.org/10.1038/s42004-023-00994-3 |
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author | Richard, Alaina M. Wong, Nathan R. Harris, Kurt Sundar, Reethy Scott, Emily E. Pochapsky, Thomas C. |
author_facet | Richard, Alaina M. Wong, Nathan R. Harris, Kurt Sundar, Reethy Scott, Emily E. Pochapsky, Thomas C. |
author_sort | Richard, Alaina M. |
collection | PubMed |
description | Alkyl isonitriles, R—NC, have previously been shown to ligate the heme (haem) iron of cytochromes P450 in both accessible oxidation states (ferrous, Fe(2+), and ferric, Fe(3+)). Herein, the preparation of four steroid-derived isonitriles and their interactions with several P450s, including the steroidogenic CYP17A1 and CYP106A2, as well as the more promiscuous drug metabolizers CYP3A4 and CYP2D6, is described. It was found that successful ligation of the heme iron by the isonitrile functionality for a given P450 depends on both the position and stereochemistry of the isonitrile on the steroid skeleton. Spectral studies indicate that isonitrile ligation of the ferric heme is stable upon reduction to the ferrous form, with reoxidation resulting in the original complex. A crystallographic structure of CYP17A1 with an isonitrile derived from pregnanalone further confirmed the interaction and identified the absolute stereochemistry of the bound species. |
format | Online Article Text |
id | pubmed-10475101 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-104751012023-09-04 Selective steroidogenic cytochrome P450 haem iron ligation by steroid-derived isonitriles Richard, Alaina M. Wong, Nathan R. Harris, Kurt Sundar, Reethy Scott, Emily E. Pochapsky, Thomas C. Commun Chem Article Alkyl isonitriles, R—NC, have previously been shown to ligate the heme (haem) iron of cytochromes P450 in both accessible oxidation states (ferrous, Fe(2+), and ferric, Fe(3+)). Herein, the preparation of four steroid-derived isonitriles and their interactions with several P450s, including the steroidogenic CYP17A1 and CYP106A2, as well as the more promiscuous drug metabolizers CYP3A4 and CYP2D6, is described. It was found that successful ligation of the heme iron by the isonitrile functionality for a given P450 depends on both the position and stereochemistry of the isonitrile on the steroid skeleton. Spectral studies indicate that isonitrile ligation of the ferric heme is stable upon reduction to the ferrous form, with reoxidation resulting in the original complex. A crystallographic structure of CYP17A1 with an isonitrile derived from pregnanalone further confirmed the interaction and identified the absolute stereochemistry of the bound species. Nature Publishing Group UK 2023-09-02 /pmc/articles/PMC10475101/ /pubmed/37660137 http://dx.doi.org/10.1038/s42004-023-00994-3 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Richard, Alaina M. Wong, Nathan R. Harris, Kurt Sundar, Reethy Scott, Emily E. Pochapsky, Thomas C. Selective steroidogenic cytochrome P450 haem iron ligation by steroid-derived isonitriles |
title | Selective steroidogenic cytochrome P450 haem iron ligation by steroid-derived isonitriles |
title_full | Selective steroidogenic cytochrome P450 haem iron ligation by steroid-derived isonitriles |
title_fullStr | Selective steroidogenic cytochrome P450 haem iron ligation by steroid-derived isonitriles |
title_full_unstemmed | Selective steroidogenic cytochrome P450 haem iron ligation by steroid-derived isonitriles |
title_short | Selective steroidogenic cytochrome P450 haem iron ligation by steroid-derived isonitriles |
title_sort | selective steroidogenic cytochrome p450 haem iron ligation by steroid-derived isonitriles |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10475101/ https://www.ncbi.nlm.nih.gov/pubmed/37660137 http://dx.doi.org/10.1038/s42004-023-00994-3 |
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