Reactive oxygen species can oxidatively modify enzymes to reroute metabolism according to tumor needs, rendering identification of oxidized proteins important for understanding neoplastic survival mechanisms. Thiol groups are most susceptible to oxidative modifications but challenging to analyze in clinical settings. We here describe the protein and small-molecular thiol oxidation landscape of 70 human lung tumors (and their paired healthy counter parts) and demonstrate that cancer adapts metabolism to increase glutathione synthesis to counteract oxidative stress. Glyoxalases, the key enzymes in the detoxification of methylglyoxal, a byproduct of glycolysis and precursor of advanced glycation end-products, are compromised by oxidation and downregulation. Despite decreased methylglyoxal detoxification capacity, cancers do not accumulate advanced glycation end-products. Since in vitro downregulation or inhibition of GAPDH upregulates glyoxalases, we propose that tumors reduce methyl

Alpha-synuclein (α-Syn) misfolding and aggregation are key drivers of Parkinson’s disease (PD) pathology. Mutations and certain post-translational modifications impact its aggregation propensity and p...

Industrial processing and storage of milk products can strongly increase protein glycation level. Previously, we have reported that ingestion of highl…

Tipness unveils Ageless Mobi, a studio program designed to enhance mobility and combat glycation, launching on October 1st across Japan.

Glucose is a vital metabolic component in the functioning of organisms, but it can also bind to biom

The Global Advanced Glycation End Products (AGEs) market was valued at USD 1.70 Billion in 2024 and is expected to reach USD 2.96 Billion by 2032, growing at a CAGR of 7.2% (2025-2032). Get insights o...

Study reveals glycation-lowering compounds curb hunger, boost insulin sensitivity, extend lifespan in mice, published in Cell Reports.

Argpyrimidine (APY) is a methylglyoxal-derived advanced glycation end-product (AGE) that has been associated with multiple diseases. As APY formation occurs without an enzyme, it remains exceptionally difficult to pinpoint where APY is likely to be found, both on individual proteins and in cells. In this study, we used a peptide model system and mass spectrometry analysis to investigate the chemical mechanism through which APY forms from methylglyoxal (MGO), a biologically relevant glycating agent. Consistent with other proposed APY formation mechanisms, our results show that that another AGE, tetrahydropyrimidine (THP) is a direct precursor to APY. However, our results rule out previously proposed reductone or oxidative decarboxylation mechanisms. Instead, we show that a formal oxidation step is not required, and that formate, not CO2 is released. We further show the potential for a nearby residue such as Tyr to assist in the APY formation mechanism by acting as a general base. These experiments revealed that phosphorylated Tyr or Ser residues could also promote equivalent levels of APY formation, despite introducing additional negative charges that we previously showed to impede glycation. Guided by these mechanistic insights and newly defined role for phosphorylated residues on glycation substrates, we performed quantitative bottom-up proteomics analysis for MGO-treated cells. Gene ontology analysis for AGE-modified proteins revealed significant enrichment of phosphorylation-related terms (e.g. kinase activity or protein phosphorylation) for APY, while other Arg post-translational modifications did not. Collectively, these data define a chemical mechanistic path to APY and suggest significant crosstalk between cellular phosphorylation and glycation events including APY formation.

Chemicals and enzymes

Cardiovascular disorder (CVD) is a common comorbidity in people living with HIV (PLWH). Although the underlying mechanisms are unknown, virotoxic HIV proteins, such as the trans-activator of transcrip...

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