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Aryl urea substituted fatty acids: a new class of protonophoric mitochondrial uncoupler that utilises a synthetic anion transporter

Respiring mitochondria establish a proton gradient across the mitochondrial inner membrane (MIM) that is used to generate ATP. Protein-independent mitochondrial uncouplers collapse the proton gradient and disrupt ATP production by shuttling protons back across the MIM in a protonophoric cycle. Conti...

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Autores principales: Rawling, Tristan, MacDermott-Opeskin, Hugo, Roseblade, Ariane, Pazderka, Curtis, Clarke, Callum, Bourget, Kirsi, Wu, Xin, Lewis, William, Noble, Benjamin, Gale, Philip A., O'Mara, Megan L., Cranfield, Charles, Murray, Michael
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Royal Society of Chemistry 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8163295/
https://www.ncbi.nlm.nih.gov/pubmed/34094462
http://dx.doi.org/10.1039/d0sc02777d
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author Rawling, Tristan
MacDermott-Opeskin, Hugo
Roseblade, Ariane
Pazderka, Curtis
Clarke, Callum
Bourget, Kirsi
Wu, Xin
Lewis, William
Noble, Benjamin
Gale, Philip A.
O'Mara, Megan L.
Cranfield, Charles
Murray, Michael
author_facet Rawling, Tristan
MacDermott-Opeskin, Hugo
Roseblade, Ariane
Pazderka, Curtis
Clarke, Callum
Bourget, Kirsi
Wu, Xin
Lewis, William
Noble, Benjamin
Gale, Philip A.
O'Mara, Megan L.
Cranfield, Charles
Murray, Michael
author_sort Rawling, Tristan
collection PubMed
description Respiring mitochondria establish a proton gradient across the mitochondrial inner membrane (MIM) that is used to generate ATP. Protein-independent mitochondrial uncouplers collapse the proton gradient and disrupt ATP production by shuttling protons back across the MIM in a protonophoric cycle. Continued cycling relies on the formation of MIM-permeable anionic species that can return to the intermembrane space after deprotonation in the mitochondrial matrix. Previously described protonophores contain acidic groups that are part of delocalised π-systems that provide large surfaces for charge delocalisation and facilitate anion permeation across the MIM. Here we present a new class of protonophoric uncoupler based on aryl-urea substituted fatty acids in which an acidic group and a π-system are separated by a long alkyl chain. The aryl-urea group in these molecules acts as a synthetic anion receptor that forms intermolecular hydrogen bonds with the fatty acid carboxylate after deprotonation. Dispersal of the negative charge across the aryl-urea system produces lipophilic dimeric complexes that can permeate the MIM and facilitate repeated cycling. Substitution of the aryl-urea group with lipophilic electron withdrawing groups is critical to complex lipophilicity and uncoupling activity. The aryl-urea substituted fatty acids represent the first biological example of mitochondrial uncoupling mediated by the interaction of a fatty acid and an anion receptor moiety, via self-assembly.
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spelling pubmed-81632952021-06-04 Aryl urea substituted fatty acids: a new class of protonophoric mitochondrial uncoupler that utilises a synthetic anion transporter Rawling, Tristan MacDermott-Opeskin, Hugo Roseblade, Ariane Pazderka, Curtis Clarke, Callum Bourget, Kirsi Wu, Xin Lewis, William Noble, Benjamin Gale, Philip A. O'Mara, Megan L. Cranfield, Charles Murray, Michael Chem Sci Chemistry Respiring mitochondria establish a proton gradient across the mitochondrial inner membrane (MIM) that is used to generate ATP. Protein-independent mitochondrial uncouplers collapse the proton gradient and disrupt ATP production by shuttling protons back across the MIM in a protonophoric cycle. Continued cycling relies on the formation of MIM-permeable anionic species that can return to the intermembrane space after deprotonation in the mitochondrial matrix. Previously described protonophores contain acidic groups that are part of delocalised π-systems that provide large surfaces for charge delocalisation and facilitate anion permeation across the MIM. Here we present a new class of protonophoric uncoupler based on aryl-urea substituted fatty acids in which an acidic group and a π-system are separated by a long alkyl chain. The aryl-urea group in these molecules acts as a synthetic anion receptor that forms intermolecular hydrogen bonds with the fatty acid carboxylate after deprotonation. Dispersal of the negative charge across the aryl-urea system produces lipophilic dimeric complexes that can permeate the MIM and facilitate repeated cycling. Substitution of the aryl-urea group with lipophilic electron withdrawing groups is critical to complex lipophilicity and uncoupling activity. The aryl-urea substituted fatty acids represent the first biological example of mitochondrial uncoupling mediated by the interaction of a fatty acid and an anion receptor moiety, via self-assembly. The Royal Society of Chemistry 2020-08-19 /pmc/articles/PMC8163295/ /pubmed/34094462 http://dx.doi.org/10.1039/d0sc02777d Text en This journal is © The Royal Society of Chemistry https://creativecommons.org/licenses/by-nc/3.0/
spellingShingle Chemistry
Rawling, Tristan
MacDermott-Opeskin, Hugo
Roseblade, Ariane
Pazderka, Curtis
Clarke, Callum
Bourget, Kirsi
Wu, Xin
Lewis, William
Noble, Benjamin
Gale, Philip A.
O'Mara, Megan L.
Cranfield, Charles
Murray, Michael
Aryl urea substituted fatty acids: a new class of protonophoric mitochondrial uncoupler that utilises a synthetic anion transporter
title Aryl urea substituted fatty acids: a new class of protonophoric mitochondrial uncoupler that utilises a synthetic anion transporter
title_full Aryl urea substituted fatty acids: a new class of protonophoric mitochondrial uncoupler that utilises a synthetic anion transporter
title_fullStr Aryl urea substituted fatty acids: a new class of protonophoric mitochondrial uncoupler that utilises a synthetic anion transporter
title_full_unstemmed Aryl urea substituted fatty acids: a new class of protonophoric mitochondrial uncoupler that utilises a synthetic anion transporter
title_short Aryl urea substituted fatty acids: a new class of protonophoric mitochondrial uncoupler that utilises a synthetic anion transporter
title_sort aryl urea substituted fatty acids: a new class of protonophoric mitochondrial uncoupler that utilises a synthetic anion transporter
topic Chemistry
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8163295/
https://www.ncbi.nlm.nih.gov/pubmed/34094462
http://dx.doi.org/10.1039/d0sc02777d
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