Spontaneous hydrolysis and spurious metabolic properties of α-ketoglutarate esters.
Amino Acids
/ metabolism
Animals
Cell Line, Tumor
Cytosol
/ metabolism
Energy Metabolism
Esters
/ chemistry
Glycolysis
HEK293 Cells
Humans
Hydrolysis
Hydrophobic and Hydrophilic Interactions
Ketoglutaric Acids
/ chemistry
Mice
Mitochondria
/ metabolism
Oxygen Consumption
RAW 264.7 Cells
Succinic Acid
/ metabolism
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
12 08 2021
12 08 2021
Historique:
received:
09
10
2020
accepted:
27
07
2021
entrez:
13
8
2021
pubmed:
14
8
2021
medline:
31
8
2021
Statut:
epublish
Résumé
α-ketoglutarate (KG), also referred to as 2-oxoglutarate, is a key intermediate of cellular metabolism with pleiotropic functions. Cell-permeable esterified analogs are widely used to study how KG fuels bioenergetic and amino acid metabolism and DNA, RNA, and protein hydroxylation reactions, as cellular membranes are thought to be impermeable to KG. Here we show that esterified KG analogs rapidly hydrolyze in aqueous media, yielding KG that, in contrast to prevailing assumptions, imports into many cell lines. Esterified KG analogs exhibit spurious KG-independent effects on cellular metabolism, including extracellular acidification, arising from rapid hydrolysis and de-protonation of α-ketoesters, and significant analog-specific inhibitory effects on glycolysis or mitochondrial respiration. We observe that imported KG decarboxylates to succinate in the cytosol and contributes minimally to mitochondrial metabolism in many cell lines cultured in normal conditions. These findings demonstrate that nuclear and cytosolic KG-dependent reactions may derive KG from functionally distinct subcellular pools and sources.
Identifiants
pubmed: 34385458
doi: 10.1038/s41467-021-25228-9
pii: 10.1038/s41467-021-25228-9
pmc: PMC8361106
doi:
Substances chimiques
Amino Acids
0
Esters
0
Ketoglutaric Acids
0
Succinic Acid
AB6MNQ6J6L
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
4905Subventions
Organisme : NCI NIH HHS
ID : P30 CA016087
Pays : United States
Organisme : NCI NIH HHS
ID : R35 CA232124
Pays : United States
Organisme : NCI NIH HHS
ID : P01 CA117969
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA157490
Pays : United States
Organisme : NIGMS NIH HHS
ID : R01 GM095567
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA188048
Pays : United States
Informations de copyright
© 2021. The Author(s).
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