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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...

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Autores principales: Richard, Alaina M., Wong, Nathan R., Harris, Kurt, Sundar, Reethy, Scott, Emily E., Pochapsky, Thomas C.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2023
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.
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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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