{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Seim GL"],"funding":["U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences","U.S. Department of Health & Human Services | NIH | National Institute of Allergy and Infectious Diseases","NIAID NIH HHS","NIGMS NIH HHS"],"pagination":["265-274"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC9974485"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["19(3)"],"pubmed_abstract":["Pyruvate dehydrogenase complex (PDHC) and oxoglutarate dehydrogenase complex (OGDC), which belong to the mitochondrial α-ketoacid dehydrogenase family, play crucial roles in cellular metabolism. These multi-subunit enzyme complexes use lipoic arms covalently attached to their E2 subunits to transfer an acyl group to coenzyme A (CoA). Here, we report a novel mechanism capable of substantially inhibiting PDHC and OGDC: reactive nitrogen species (RNS) can covalently modify the thiols on their lipoic arms, generating a series of adducts that block catalytic activity. S-Nitroso-CoA, a product between RNS and the E2 subunit's natural substrate, CoA, can efficiently deliver these modifications onto the lipoic arm. We found RNS-mediated inhibition of PDHC and OGDC occurs during classical macrophage activation, driving significant rewiring of cellular metabolism over time. This work provides a new mechanistic link between RNS and mitochondrial metabolism with potential relevance for numerous physiological and pathological conditions in which RNS accumulate."],"journal":["Nature chemical biology"],"pubmed_title":["Nitric oxide-driven modifications of lipoic arm inhibit α-ketoacid dehydrogenases."],"pmcid":["PMC9974485"],"funding_grant_id":["F31 AI152280","T32 GM140935","R35 GM131795","R56 AI158958"],"pubmed_authors":["Pagliarini DJ","Fang Z","Fan J","Seim GL","John SV","Arp NL"],"additional_accession":[]},"is_claimable":false,"name":"Nitric oxide-driven modifications of lipoic arm inhibit α-ketoacid dehydrogenases.","description":"Pyruvate dehydrogenase complex (PDHC) and oxoglutarate dehydrogenase complex (OGDC), which belong to the mitochondrial α-ketoacid dehydrogenase family, play crucial roles in cellular metabolism. These multi-subunit enzyme complexes use lipoic arms covalently attached to their E2 subunits to transfer an acyl group to coenzyme A (CoA). Here, we report a novel mechanism capable of substantially inhibiting PDHC and OGDC: reactive nitrogen species (RNS) can covalently modify the thiols on their lipoic arms, generating a series of adducts that block catalytic activity. S-Nitroso-CoA, a product between RNS and the E2 subunit's natural substrate, CoA, can efficiently deliver these modifications onto the lipoic arm. We found RNS-mediated inhibition of PDHC and OGDC occurs during classical macrophage activation, driving significant rewiring of cellular metabolism over time. This work provides a new mechanistic link between RNS and mitochondrial metabolism with potential relevance for numerous physiological and pathological conditions in which RNS accumulate.","dates":{"release":"2023-01-01T00:00:00Z","publication":"2023 Mar","modification":"2025-04-05T14:21:16.421Z","creation":"2025-04-05T14:21:16.421Z"},"accession":"S-EPMC9974485","cross_references":{"pubmed":["36266351"],"doi":["10.1038/s41589-022-01153-w"]}}