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Ophiobolin A Covalently Targets Complex IV Leading to Mitochondrial Metabolic Collapse in Cancer Cells

Ophiobolin A (OPA) is a sesterterpenoid fungal natural product with broad anti-cancer activity. While OPA possesses multiple electrophilic moieties that can covalently react with nucleophilic amino acids on proteins, the proteome-wide targets and mechanism of OPA remain poorly understood in many con...

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Autores principales: Gowans, Flor A., Thach, Danny Q., Wang, Yangzhi, Altamirano Poblano, Belen E., Dovala, Dustin, Tallarico, John A., McKenna, Jeffrey M., Schirle, Markus, Maimone, Thomas J., Nomura, Daniel K.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cold Spring Harbor Laboratory 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10029012/
https://www.ncbi.nlm.nih.gov/pubmed/36945520
http://dx.doi.org/10.1101/2023.03.09.531918
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author Gowans, Flor A.
Thach, Danny Q.
Wang, Yangzhi
Altamirano Poblano, Belen E.
Dovala, Dustin
Tallarico, John A.
McKenna, Jeffrey M.
Schirle, Markus
Maimone, Thomas J.
Nomura, Daniel K.
author_facet Gowans, Flor A.
Thach, Danny Q.
Wang, Yangzhi
Altamirano Poblano, Belen E.
Dovala, Dustin
Tallarico, John A.
McKenna, Jeffrey M.
Schirle, Markus
Maimone, Thomas J.
Nomura, Daniel K.
author_sort Gowans, Flor A.
collection PubMed
description Ophiobolin A (OPA) is a sesterterpenoid fungal natural product with broad anti-cancer activity. While OPA possesses multiple electrophilic moieties that can covalently react with nucleophilic amino acids on proteins, the proteome-wide targets and mechanism of OPA remain poorly understood in many contexts. In this study, we used covalent chemoproteomic platforms to map the proteome-wide reactivity of OPA in a highly sensitive lung cancer cell line. Among several proteins that OPA engaged, we focused on two targets—cysteine C53 of HIG2DA and lysine K72 of COX5A—that are part of complex IV of the electron transport chain and contributed significantly to the anti-proliferative activity. OPA activated mitochondrial respiration in a HIG2DA and COX5A-dependent manner, led to an initial spike in mitochondrial ATP, but then compromised mitochondrial membrane potential leading to ATP depletion. We have used chemoproteomic strategies to discover a unique anti-cancer mechanism of OPA through activation of complex IV leading to compromised mitochondrial energetics and rapid cell death.
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spelling pubmed-100290122023-03-22 Ophiobolin A Covalently Targets Complex IV Leading to Mitochondrial Metabolic Collapse in Cancer Cells Gowans, Flor A. Thach, Danny Q. Wang, Yangzhi Altamirano Poblano, Belen E. Dovala, Dustin Tallarico, John A. McKenna, Jeffrey M. Schirle, Markus Maimone, Thomas J. Nomura, Daniel K. bioRxiv Article Ophiobolin A (OPA) is a sesterterpenoid fungal natural product with broad anti-cancer activity. While OPA possesses multiple electrophilic moieties that can covalently react with nucleophilic amino acids on proteins, the proteome-wide targets and mechanism of OPA remain poorly understood in many contexts. In this study, we used covalent chemoproteomic platforms to map the proteome-wide reactivity of OPA in a highly sensitive lung cancer cell line. Among several proteins that OPA engaged, we focused on two targets—cysteine C53 of HIG2DA and lysine K72 of COX5A—that are part of complex IV of the electron transport chain and contributed significantly to the anti-proliferative activity. OPA activated mitochondrial respiration in a HIG2DA and COX5A-dependent manner, led to an initial spike in mitochondrial ATP, but then compromised mitochondrial membrane potential leading to ATP depletion. We have used chemoproteomic strategies to discover a unique anti-cancer mechanism of OPA through activation of complex IV leading to compromised mitochondrial energetics and rapid cell death. Cold Spring Harbor Laboratory 2023-03-09 /pmc/articles/PMC10029012/ /pubmed/36945520 http://dx.doi.org/10.1101/2023.03.09.531918 Text en https://creativecommons.org/licenses/by-nc-nd/4.0/This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (https://creativecommons.org/licenses/by-nc-nd/4.0/) , which allows reusers to copy and distribute the material in any medium or format in unadapted form only, for noncommercial purposes only, and only so long as attribution is given to the creator.
spellingShingle Article
Gowans, Flor A.
Thach, Danny Q.
Wang, Yangzhi
Altamirano Poblano, Belen E.
Dovala, Dustin
Tallarico, John A.
McKenna, Jeffrey M.
Schirle, Markus
Maimone, Thomas J.
Nomura, Daniel K.
Ophiobolin A Covalently Targets Complex IV Leading to Mitochondrial Metabolic Collapse in Cancer Cells
title Ophiobolin A Covalently Targets Complex IV Leading to Mitochondrial Metabolic Collapse in Cancer Cells
title_full Ophiobolin A Covalently Targets Complex IV Leading to Mitochondrial Metabolic Collapse in Cancer Cells
title_fullStr Ophiobolin A Covalently Targets Complex IV Leading to Mitochondrial Metabolic Collapse in Cancer Cells
title_full_unstemmed Ophiobolin A Covalently Targets Complex IV Leading to Mitochondrial Metabolic Collapse in Cancer Cells
title_short Ophiobolin A Covalently Targets Complex IV Leading to Mitochondrial Metabolic Collapse in Cancer Cells
title_sort ophiobolin a covalently targets complex iv leading to mitochondrial metabolic collapse in cancer cells
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10029012/
https://www.ncbi.nlm.nih.gov/pubmed/36945520
http://dx.doi.org/10.1101/2023.03.09.531918
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