@article{TEXTUAL,
      recid = {13513},
      author = {Coukos, John S. and Moellering, Raymond E.},
      title = {Methylglyoxal Forms Diverse Mercaptomethylimidazole  Crosslinks with Thiol and Guanidine Pairs in Endogenous  Metabolites and Proteins},
      journal = {ACS Chemical Biology},
      address = {2021-09-28},
      number = {TEXTUAL},
      abstract = {Methylglyoxal (MGO) is a reactive byproduct formed by  several metabolic precursors, the most notable being  triosephosphates in glycolysis. While many MGO-mediated  adducts have been described, the reactivity and specific  biomolecular targets of MGO remain incompletely mapped.  Based on our recent discovery that MGO can form stable  mercaptomethylimidazole crosslinks between cysteine and  arginine (MICA) in proteins, we hypothesized that MGO may  participate in myriad reactions with biologically relevant  guanidines and thiols in proteins, metabolites, and perhaps  other biomolecules. Herein, we performed steady-state and  kinetic analyses of MGO reactivity with several model  thiols, guanidines, and biguanide drugs to establish the  plausible and prevalent adducts formed by MGO in proteins,  peptides, and abundant cellular metabolites. We identified  several novel, stable MICA metabolites that form in vitro  and in cells, as well as a novel intermolecular  post-translational MICA modification of surface cysteines  in proteins. These data confirm that kinetic trapping of  free MGO by thiols occurs rapidly and can decrease  formation of more stable imidazolone (MG-H1) arginine  adducts. However, reversible hemithioacetal adducts can go  on to form stable MICA modifications in an inter- and  intramolecular fashion with abundant or proximal  guanidines, respectively. Finally, we discovered that  intracellular MICA-glutathione metabolites are recognized  and exported by the efflux pump MRP1, providing a parallel  and perhaps complementary pathway for MGO detoxification  working alongside the glyoxalase pathway. These data  provide new insights into the plausible reactions involving  MGO in cells and tissues, as well as several new molecular  species in proteins and metabolites for further study.},
      url = {http://knowledge.uchicago.edu/record/13513},
}