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Aryl urea substituted fatty acids: a new class of protonophoric mitochondrial uncoupler that utilises a synthetic anion transporter
- Source :
- Chemical Science
- Publication Year :
- 2021
-
Abstract
- 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.<br />A new mitochondrial uncoupler that forms membrane permeable dimers through interactions of remote acidic and anion receptor groups.
- Subjects :
- chemistry.chemical_classification
0304 Medicinal and Biomolecular Chemistry
010405 organic chemistry
Stereochemistry
Fatty acid
General Chemistry
Mitochondrion
010402 general chemistry
01 natural sciences
0104 chemical sciences
3. Good health
Chemistry
Deprotonation
chemistry
Mitochondrial matrix
Moiety
Intermembrane space
Electrochemical gradient
Inner mitochondrial membrane
03 Chemical Sciences
Subjects
Details
- ISSN :
- 20416520
- Volume :
- 11
- Issue :
- 47
- Database :
- OpenAIRE
- Journal :
- Chemical science
- Accession number :
- edsair.doi.dedup.....9afc9b71402064df562109933ddbd66a