Methylglyoxal Forms Diverse Mercaptomethylimidazole Crosslinks with Thiol and Guanidine Pairs in Endogenous Metabolites and Proteins.
Methylglyoxal Forms Diverse Mercaptomethylimidazole Crosslinks with Thiol and Guanidine Pairs in Endogenous Metabolites and Proteins.
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DOI：
10.1021/acschembio.1c00553
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发表时间：
2021-11-19
影响因子：
4
通讯作者：
Moellering RE
中科院分区：
文献类型：
--
作者：
Coukos JS;Moellering RE
甲基乙二醛（MGO）是由几种代谢前体形成的反应性副产物，最值得注意的是糖酵解中的磷酸丙糖。虽然已经描述了许多MGO介导的加合物，但MGO的反应性和特异性生物分子靶标仍然不完全映射。基于我们最近发现MGO可以在蛋白质中的半胱氨酸和精氨酸（云母）之间形成稳定的巯基甲基咪唑交联，我们假设MGO可能参与与蛋白质、代谢物和可能其他生物分子中的生物相关的胍和硫醇的无数反应。在此，我们进行了稳态和动力学分析的MGO反应与几个模型硫醇，胍，双胍类药物，以建立合理的和普遍的加合物形成的MGO在蛋白质，肽，和丰富的细胞代谢产物。我们鉴定了几种在体外和细胞中形成的新型稳定的云母代谢物，以及蛋白质中表面半胱氨酸的新型分子间翻译后云母修饰。这些数据证实，巯基对游离MGO的动力学捕获迅速发生，并且可以减少更稳定的咪唑酮（MG-H1）精氨酸加合物的形成。然而，可逆的半硫缩醛加合物可以继续以分子间和分子内的方式分别与丰富的或邻近的胍形成稳定的云母修饰。最后，我们发现细胞内MICA-谷胱甘肽代谢物被外排泵MRP 1识别和输出，为与谷胱甘肽酶途径一起工作的MGO解毒提供了平行且可能是互补的途径。这些数据为涉及细胞和组织中MGO的合理反应以及蛋白质和代谢物中的几种新分子种类提供了新的见解，以供进一步研究。
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.
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DOI：
10.1042/bj20081386
发表时间：
2009-01-01
期刊：
The Biochemical journal
影响因子：
--
作者：
Murphy MP
通讯作者：
Murphy MP
影响因子：
2.9
作者：
PAPOULIS, A;ALABED, Y;BUCALA, R
通讯作者：
BUCALA, R
DOI：
10.1007/bf01192954
发表时间：
1994-07-01
期刊：
ZEITSCHRIFT FUR LEBENSMITTEL-UNTERSUCHUNG UND-FORSCHUNG
影响因子：
--
作者：
HENLE, T;WALTER, AW;KLOSTERMEYER, H
通讯作者：
KLOSTERMEYER, H
影响因子：
4.1
作者：
Ahmed, MU;Frye, EB;Baynes, JW
通讯作者：
Baynes, JW
DOI：
10.1196/annals.1333.006
发表时间：
2005-01-01
期刊：
MAILLARD REACTION: CHEMISTRY AT THE INTERFACE OF NUTRITION, AGING, AND DISEASE
影响因子：
--
作者：
Alt, N;Schieberle, P
通讯作者：
Schieberle, P