Reactivity-based metabolomics reveal cysteine has glyoxalase 1-like and glyoxalase 2-like activities

Marc Daniel Opfermann, Maria Bøgelund Søndergård, Louise Vase Bech, Camilla B. Nielsen, Alejandro Mahía, Charlotte Brinck Holt, Tingting Wang, Sarah Bisgaard Olesen, Kim Frisch, Jakob Appel Østergaard, Dieter Britz, Kirstine Lykke Nielsen, James J. Galligan, Thomas B. Poulsen, Jakob Hansen, Mogens Johannsen*

*Corresponding author af dette arbejde

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Abstract

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.)

OriginalsprogEngelsk
Artikelnummer2004
TidsskriftNature Chemical Biology
ISSN1552-4450
DOI
StatusE-pub / Early view - 2025

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