TY - JOUR
T1 - Reactivity-based metabolomics reveal cysteine has glyoxalase 1-like and glyoxalase 2-like activities
AU - Daniel Opfermann, Marc
AU - Bøgelund Søndergård, Maria
AU - Vase Bech, Louise
AU - Nielsen, Camilla B.
AU - Mahía, Alejandro
AU - Brinck Holt, Charlotte
AU - Wang, Tingting
AU - Bisgaard Olesen, Sarah
AU - Frisch, Kim
AU - Appel Østergaard, Jakob
AU - Britz, Dieter
AU - Lykke Nielsen, Kirstine
AU - Galligan, James J.
AU - Poulsen, Thomas B.
AU - Hansen, Jakob
AU - Johannsen, Mogens
N1 - Publisher Copyright:
© The Author(s), under exclusive licence to Springer Nature America, Inc. 2025.
PY - 2025
Y1 - 2025
N2 - Methylglyoxal (MG) is a reactive metabolite involved in diabetes and aging through the formation of protein adducts. Less is known about the extent that MG and its metabolic product S-d-lactoylglutathione (LGSH) form adducts with cell metabolites. Using a ‘symmetric’ isotope-labeled and reactivity-based metabolomics approach in living cells, we found over 200 adducts and, surprisingly, discovered that 10 of the most abundant are lactoylated amino acids mainly derived from LGSH. The most abundant adduct d-Lac-Cys is formed rapidly between LGSH and cysteine, whereas the diastereoisomer l-Lac-Cys is formed directly from MG and cysteine, assigning cysteine with both glyoxalase 1-like and glyoxalase 2-like activity. Cellular cysteine and MG dynamically regulate d-Lac-Cys and l-Lac-Cys levels and the adducts are increased in diabetes, suggesting their use as novel biomarkers. Lastly, cysteine amides, as proxies for protein cysteines, also undergo lactoylation by MG and LGSH, suggesting the existence of two additional pathways for nonenzymatic lactoylation of proteins. (Figure presented.)
AB - Methylglyoxal (MG) is a reactive metabolite involved in diabetes and aging through the formation of protein adducts. Less is known about the extent that MG and its metabolic product S-d-lactoylglutathione (LGSH) form adducts with cell metabolites. Using a ‘symmetric’ isotope-labeled and reactivity-based metabolomics approach in living cells, we found over 200 adducts and, surprisingly, discovered that 10 of the most abundant are lactoylated amino acids mainly derived from LGSH. The most abundant adduct d-Lac-Cys is formed rapidly between LGSH and cysteine, whereas the diastereoisomer l-Lac-Cys is formed directly from MG and cysteine, assigning cysteine with both glyoxalase 1-like and glyoxalase 2-like activity. Cellular cysteine and MG dynamically regulate d-Lac-Cys and l-Lac-Cys levels and the adducts are increased in diabetes, suggesting their use as novel biomarkers. Lastly, cysteine amides, as proxies for protein cysteines, also undergo lactoylation by MG and LGSH, suggesting the existence of two additional pathways for nonenzymatic lactoylation of proteins. (Figure presented.)
UR - http://www.scopus.com/inward/record.url?scp=105006920741&partnerID=8YFLogxK
U2 - 10.1038/s41589-025-01909-0
DO - 10.1038/s41589-025-01909-0
M3 - Journal article
C2 - 40437135
AN - SCOPUS:105006920741
SN - 1552-4450
JO - Nature Chemical Biology
JF - Nature Chemical Biology
M1 - 2004
ER -