Unknown

Dataset Information

0

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


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.

SUBMITTER: Rawling T 

PROVIDER: S-EPMC8163295 | biostudies-literature |

REPOSITORIES: biostudies-literature

Similar Datasets

| S-EPMC3258527 | biostudies-literature
| S-EPMC10480478 | biostudies-literature
| S-EPMC5362113 | biostudies-literature
| S-EPMC5406605 | biostudies-literature
| S-EPMC127453 | biostudies-literature
| S-EPMC2664301 | biostudies-literature
| S-EPMC1847411 | biostudies-literature
| S-EPMC9303638 | biostudies-literature
| S-EPMC7467678 | biostudies-literature
| S-EPMC10779255 | biostudies-literature