Post-translational regulation of metabolism in fumarate hydratase deficient cancer cells
Autor(a) principal: | |
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Data de Publicação: | 2018 |
Outros Autores: | , , , , , , |
Tipo de documento: | Artigo |
Idioma: | eng |
Título da fonte: | Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
Texto Completo: | http://hdl.handle.net/1822/50466 |
Resumo: | Deregulated signal transduction and energy metabolism are hallmarks of cancer and both play a fundamental role in tumorigenesis. While it is increasingly recognised that signalling and metabolism are highly interconnected, the underpinning mechanisms of their co-regulation are still largely unknown. Here we designed and acquired proteomics, phosphoproteomics, and metabolomics experiments in fumarate hydratase (FH) deficient cells and developed a computational modelling approach to identify putative regulatory phosphorylation-sites of metabolic enzymes. We identified previously reported functionally relevant phosphosites and potentially novel regulatory residues in enzymes of the central carbon metabolism. In particular, we showed that pyruvate dehydrogenase (PDHA1) enzymatic activity is inhibited by increased phosphorylation in FH-deficient cells, restricting carbon entry from glucose to the tricarboxylic acid cycle. Moreover, we confirmed PDHA1 phosphorylation in human FH-deficient tumours. Our work provides a novel approach to investigate how post-translational modifications of enzymes regulate metabolism and could have important implications for understanding the metabolic transformation of FH-deficient cancers with potential clinical applications. |
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Post-translational regulation of metabolism in fumarate hydratase deficient cancer cellsMetabolismCancerPhosphoproteomicsModellingScience & TechnologyDeregulated signal transduction and energy metabolism are hallmarks of cancer and both play a fundamental role in tumorigenesis. While it is increasingly recognised that signalling and metabolism are highly interconnected, the underpinning mechanisms of their co-regulation are still largely unknown. Here we designed and acquired proteomics, phosphoproteomics, and metabolomics experiments in fumarate hydratase (FH) deficient cells and developed a computational modelling approach to identify putative regulatory phosphorylation-sites of metabolic enzymes. We identified previously reported functionally relevant phosphosites and potentially novel regulatory residues in enzymes of the central carbon metabolism. In particular, we showed that pyruvate dehydrogenase (PDHA1) enzymatic activity is inhibited by increased phosphorylation in FH-deficient cells, restricting carbon entry from glucose to the tricarboxylic acid cycle. Moreover, we confirmed PDHA1 phosphorylation in human FH-deficient tumours. Our work provides a novel approach to investigate how post-translational modifications of enzymes regulate metabolism and could have important implications for understanding the metabolic transformation of FH-deficient cancers with potential clinical applications.info:eu-repo/semantics/publishedVersionElsevierUniversidade do MinhoGonçalves, EmanuelSciacovelli, MarcoCosta, Ana S. H.Tran, Maxine Gia BinhJohnson, Timothy IsaacMachado, DanielFrezza, ChristianSaez-Rodriguez, Julio20182018-01-01T00:00:00Zinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleapplication/pdfhttp://hdl.handle.net/1822/50466engGonçalves, Emanuel; Sciacovelli, Marco; Costa, Ana S. H.; Tran, Maxine Gia Binh; Johnson, Timothy Isaac; Machado, Daniel; Frezza, Christian; Saez-Rodriguez, Julio, Post-translational regulation of metabolism in fumarate hydratase deficient cancer cells. Metabolic Engineering, 45, 149-157, 20181096-71761096-718410.1016/j.ymben.2017.11.01129191787info:eu-repo/semantics/openAccessreponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãoinstacron:RCAAP2023-07-21T12:42:19Zoai:repositorium.sdum.uminho.pt:1822/50466Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-19T19:39:32.015342Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãofalse |
dc.title.none.fl_str_mv |
Post-translational regulation of metabolism in fumarate hydratase deficient cancer cells |
title |
Post-translational regulation of metabolism in fumarate hydratase deficient cancer cells |
spellingShingle |
Post-translational regulation of metabolism in fumarate hydratase deficient cancer cells Gonçalves, Emanuel Metabolism Cancer Phosphoproteomics Modelling Science & Technology |
title_short |
Post-translational regulation of metabolism in fumarate hydratase deficient cancer cells |
title_full |
Post-translational regulation of metabolism in fumarate hydratase deficient cancer cells |
title_fullStr |
Post-translational regulation of metabolism in fumarate hydratase deficient cancer cells |
title_full_unstemmed |
Post-translational regulation of metabolism in fumarate hydratase deficient cancer cells |
title_sort |
Post-translational regulation of metabolism in fumarate hydratase deficient cancer cells |
author |
Gonçalves, Emanuel |
author_facet |
Gonçalves, Emanuel Sciacovelli, Marco Costa, Ana S. H. Tran, Maxine Gia Binh Johnson, Timothy Isaac Machado, Daniel Frezza, Christian Saez-Rodriguez, Julio |
author_role |
author |
author2 |
Sciacovelli, Marco Costa, Ana S. H. Tran, Maxine Gia Binh Johnson, Timothy Isaac Machado, Daniel Frezza, Christian Saez-Rodriguez, Julio |
author2_role |
author author author author author author author |
dc.contributor.none.fl_str_mv |
Universidade do Minho |
dc.contributor.author.fl_str_mv |
Gonçalves, Emanuel Sciacovelli, Marco Costa, Ana S. H. Tran, Maxine Gia Binh Johnson, Timothy Isaac Machado, Daniel Frezza, Christian Saez-Rodriguez, Julio |
dc.subject.por.fl_str_mv |
Metabolism Cancer Phosphoproteomics Modelling Science & Technology |
topic |
Metabolism Cancer Phosphoproteomics Modelling Science & Technology |
description |
Deregulated signal transduction and energy metabolism are hallmarks of cancer and both play a fundamental role in tumorigenesis. While it is increasingly recognised that signalling and metabolism are highly interconnected, the underpinning mechanisms of their co-regulation are still largely unknown. Here we designed and acquired proteomics, phosphoproteomics, and metabolomics experiments in fumarate hydratase (FH) deficient cells and developed a computational modelling approach to identify putative regulatory phosphorylation-sites of metabolic enzymes. We identified previously reported functionally relevant phosphosites and potentially novel regulatory residues in enzymes of the central carbon metabolism. In particular, we showed that pyruvate dehydrogenase (PDHA1) enzymatic activity is inhibited by increased phosphorylation in FH-deficient cells, restricting carbon entry from glucose to the tricarboxylic acid cycle. Moreover, we confirmed PDHA1 phosphorylation in human FH-deficient tumours. Our work provides a novel approach to investigate how post-translational modifications of enzymes regulate metabolism and could have important implications for understanding the metabolic transformation of FH-deficient cancers with potential clinical applications. |
publishDate |
2018 |
dc.date.none.fl_str_mv |
2018 2018-01-01T00:00:00Z |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/article |
format |
article |
status_str |
publishedVersion |
dc.identifier.uri.fl_str_mv |
http://hdl.handle.net/1822/50466 |
url |
http://hdl.handle.net/1822/50466 |
dc.language.iso.fl_str_mv |
eng |
language |
eng |
dc.relation.none.fl_str_mv |
Gonçalves, Emanuel; Sciacovelli, Marco; Costa, Ana S. H.; Tran, Maxine Gia Binh; Johnson, Timothy Isaac; Machado, Daniel; Frezza, Christian; Saez-Rodriguez, Julio, Post-translational regulation of metabolism in fumarate hydratase deficient cancer cells. Metabolic Engineering, 45, 149-157, 2018 1096-7176 1096-7184 10.1016/j.ymben.2017.11.011 29191787 |
dc.rights.driver.fl_str_mv |
info:eu-repo/semantics/openAccess |
eu_rights_str_mv |
openAccess |
dc.format.none.fl_str_mv |
application/pdf |
dc.publisher.none.fl_str_mv |
Elsevier |
publisher.none.fl_str_mv |
Elsevier |
dc.source.none.fl_str_mv |
reponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação instacron:RCAAP |
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Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
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RCAAP |
institution |
RCAAP |
reponame_str |
Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
collection |
Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
repository.name.fl_str_mv |
Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
repository.mail.fl_str_mv |
|
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1799132936939765760 |