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.

doi:10.1038/s42004-023-00994-3

Title: Selective steroidogenic cytochrome P450 haem iron ligation by steroid-derived isonitriles

Journal Article · 02 September 2023 · Communications Chemistry

DOI: https://doi.org/10.1038/s42004-023-00994-3 · OSTI ID:2423926

Richard, Alaina M. ^[1]; Wong, Nathan R. ^[2]; Harris, Kurt ^[1]; Sundar, Reethy ^[2]; Scott, Emily E. ^[1];

^[2]

Univ. of Michigan, Ann Arbor, MI (United States)
Brandeis Univ., Waltham, MA (United States)

Alkyl isonitriles, R—NC, have previously been shown to ligate the heme (haem) iron of cytochromes P450 in both accessible oxidation states (ferrous, Fe²⁺, and ferric, Fe³⁺). 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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Research Organization:: SLAC National Accelerator Laboratory, Menlo Park, CA (United States). Stanford Synchrotron Radiation Lightsource (SSRL)

Sponsoring Organization:: National Institute of General Medical Sciences (NIGMS); National Institutes of Health (NIH); USDOE Office of Science (SC), Basic Energy Sciences (BES); USDOE Office of Science (SC), Biological and Environmental Research (BER)

Grant/Contract Number:: AC02-76SF00515

OSTI ID:: 2423926

Journal Information:: Communications Chemistry, Journal Name: Communications Chemistry Journal Issue: 1 Vol. 6; ISSN 2399-3669

Publisher:: Springer NatureCopyright Statement

Country of Publication:: United States

Language:: English

References (32)

Isonitrile Syntheses Ugi, I.; Fetzer, U.; Eholzer, U. Angewandte Chemie International Edition in English, Vol. 4, Issue 6 https://doi.org/10.1002/anie.196504721	journal	June 1965
A New Cytochrome in Liver Microsomes Omura, Tsuneo; Sato, Ryo Journal of Biological Chemistry, Vol. 237, Issue 4 https://doi.org/10.1016/S0021-9258(18)60338-2	journal	April 1962
Human cytochrome P450 17A1 structures with metabolites of prostate cancer drug abiraterone reveal substrate-binding plasticity and a second binding site Petrunak, Elyse M.; Bart, Aaron G.; Peng, Hwei-Ming Journal of Biological Chemistry, Vol. 299, Issue 3 https://doi.org/10.1016/j.jbc.2023.102999	journal	March 2023
Conformational heterogeneity suggests multiple substrate binding modes in CYP106A2 Wong, Nathan R.; Sundar, Reethy; Kazanis, Sophia Journal of Inorganic Biochemistry, Vol. 241 https://doi.org/10.1016/j.jinorgbio.2023.112129	journal	April 2023
Structural insights into the function of steroidogenic cytochrome P450 17A1 Yadav, Rahul; Petrunak, Elyse M.; Estrada, D. Fernando Molecular and Cellular Endocrinology, Vol. 441 https://doi.org/10.1016/j.mce.2016.08.035	journal	February 2017
Cytochrome P450 enzymes in drug metabolism: Regulation of gene expression, enzyme activities, and impact of genetic variation Zanger, Ulrich M.; Schwab, Matthias Pharmacology & Therapeutics, Vol. 138, Issue 1 https://doi.org/10.1016/j.pharmthera.2012.12.007	journal	April 2013
What Your Crystal Structure Will Not Tell You about Enzyme Function Pochapsky, Thomas C.; Pochapsky, Susan Sondej Accounts of Chemical Research, Vol. 52, Issue 5 https://doi.org/10.1021/acs.accounts.9b00066	journal	April 2019
Medicinal Chemistry of Isocyanides Massarotti, Alberto; Brunelli, Francesca; Aprile, Silvio Chemical Reviews, Vol. 121, Issue 17 https://doi.org/10.1021/acs.chemrev.1c00143	journal	July 2021
Leuckart–Wallach Route Toward Isocyanides and Some Applications Neochoritis, Constantinos G.; Zarganes-Tzitzikas, Tryfon; Stotani, Silvia ACS Combinatorial Science, Vol. 17, Issue 9 https://doi.org/10.1021/acscombsci.5b00066	journal	August 2015
Structural Characterization of n -Butyl-isocyanide Complexes of Cytochromes P450nor and P450cam Lee, Dong-Sun; Park, Sam-Yong; Yamane, Kazuhide Biochemistry, Vol. 40, Issue 9 https://doi.org/10.1021/bi002225s	journal	February 2001
The Structural Basis for Homotropic and Heterotropic Cooperativity of Midazolam Metabolism by Human Cytochrome P450 3A4 Roberts, Arthur G.; Yang, Jing; Halpert, James R. Biochemistry, Vol. 50, Issue 50 https://doi.org/10.1021/bi200924t	journal	November 2011
Dissecting Cytochrome P450 3A4–Ligand Interactions Using Ritonavir Analogues Sevrioukova, Irina F.; Poulos, Thomas L. Biochemistry, Vol. 52, Issue 26 https://doi.org/10.1021/bi4005396	journal	June 2013
Notes. A Novel Preparation of Isonitriles Hertler, W.; Corey, E. The Journal of Organic Chemistry, Vol. 23, Issue 8 https://doi.org/10.1021/jo01102a612	journal	August 1958
Structures of cytochrome P450 17A1 with prostate cancer drugs abiraterone and TOK-001 DeVore, Natasha M.; Scott, Emily E. Nature, Vol. 482, Issue 7383 https://doi.org/10.1038/nature10743	journal	January 2012
CYP17 inhibitors—abiraterone, C17,20-lyase inhibitors and multi-targeting agents Yin, Lina; Hu, Qingzhong Nature Reviews Urology, Vol. 11, Issue 1 https://doi.org/10.1038/nrurol.2013.274	journal	November 2013
Engineering precision nanoparticles for drug delivery Mitchell, Michael J.; Billingsley, Margaret M.; Haley, Rebecca M. Nature Reviews Drug Discovery, Vol. 20, Issue 2 https://doi.org/10.1038/s41573-020-0090-8	journal	December 2020
Targeted drug delivery strategies for precision medicines Manzari, Mandana T.; Shamay, Yosi; Kiguchi, Hiroto Nature Reviews Materials, Vol. 6, Issue 4 https://doi.org/10.1038/s41578-020-00269-6	journal	February 2021
Binding modes of CYP106A2 redox partners determine differences in progesterone hydroxylation product patterns Sagadin, Tanja; Riehm, Jan L.; Milhim, Mohammed Communications Biology, Vol. 1, Issue 1 https://doi.org/10.1038/s42003-018-0104-9	journal	July 2018
Synthesis and biological evaluation of imidazolylmethylacridones as cytochrome P-450 enzymes inhibitors Abadi, Ashraf H.; Abou-Seri, Sahar M.; Hu, Qingzhong MedChemComm, Vol. 3, Issue 6 https://doi.org/10.1039/c2md20072d	journal	January 2012
Human Cytochrome P450 17A1 Conformational Selection: MODULATION BY LIGAND AND CYTOCHROME b Estrada, D. Fernando; Skinner, Andria L.; Laurence, Jennifer S. Journal of Biological Chemistry, Vol. 289, Issue 20 https://doi.org/10.1074/jbc.M114.560144	journal	March 2014
Crystal Structure of Human Cytochrome P450 2D6 Rowland, Paul; Blaney, Frank E.; Smyth, Martin G. Journal of Biological Chemistry, Vol. 281, Issue 11 https://doi.org/10.1074/jbc.M511232200	journal	March 2006
Structural and functional effects of cytochrome b5 interactions with human cytochrome P450 enzymes Bart, Aaron G.; Scott, Emily E. Journal of Biological Chemistry, Vol. 292, Issue 51 https://doi.org/10.1074/jbc.RA117.000220	journal	December 2017
Phaser crystallographic software McCoy, Airlie J.; Grosse-Kunstleve, Ralf W.; Adams, Paul D. Journal of Applied Crystallography, Vol. 40, Issue 4 https://doi.org/10.1107/S0021889807021206	journal	July 2007
Scaling and assessment of data quality Evans, Philip Acta Crystallographica Section D Biological Crystallography, Vol. 62, Issue 1, p. 72-82 https://doi.org/10.1107/S0907444905036693	journal	December 2005
XDS Kabsch, Wolfgang Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 2 https://doi.org/10.1107/S0907444909047337	journal	January 2010
PHENIX: a comprehensive Python-based system for macromolecular structure solution Adams, Paul D.; Afonine, Pavel V.; Bunkóczi, Gábor Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 2, p. 213-221 https://doi.org/10.1107/S0907444909052925	journal	January 2010
Features and development of Coot Emsley, P.; Lohkamp, B.; Scott, W. G. Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 4 https://doi.org/10.1107/S0907444910007493	journal	March 2010
Key Residues Controlling Binding of Diverse Ligands to Human Cytochrome P450 2A Enzymes DeVore, N. M.; Smith, B. D.; Wang, J. L. Drug Metabolism and Disposition, Vol. 37, Issue 6 https://doi.org/10.1124/dmd.109.026765	journal	February 2009
Structural and Functional Evaluation of Clinically Relevant Inhibitors of Steroidogenic Cytochrome P450 17A1 Petrunak, Elyse M.; Rogers, Steven A.; Aubé, Jeffrey Drug Metabolism and Disposition, Vol. 45, Issue 6 https://doi.org/10.1124/dmd.117.075317	journal	April 2017
Comparison of Antifungal Azole Interactions with Adult Cytochrome P450 3A4 versus Neonatal Cytochrome P450 3A7 Godamudunage, Malika P.; Grech, Anne M.; Scott, Emily E. Drug Metabolism and Disposition, Vol. 46, Issue 9 https://doi.org/10.1124/dmd.118.082032	journal	July 2018
Characterization of Ritonavir-Mediated Inactivation of Cytochrome P450 3A4 Rock, Brooke M.; Hengel, Shawna M.; Rock, Dan A. Molecular Pharmacology, Vol. 86, Issue 6 https://doi.org/10.1124/mol.114.094862	journal	October 2014
Effect of Antifungal Drugs on Cytochrome P450 (CYP) 2C9, CYP2C19, and CYP3A4 Activities in Human Liver Microsomes Niwa, Toshiro; Shiraga, Toshifumi; Takagi, Akira Biological and Pharmaceutical Bulletin, Vol. 28, Issue 9 https://doi.org/10.1248/bpb.28.1805	journal	January 2005

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