Rabbani Naila, Thornalley Paul J
*Clinical Sciences Research Laboratories, Warwick Medical School, University of Warwick, University Hospital, Coventry CV2 2DX, U.K.
Biochem Soc Trans. 2014 Apr;42(2):425-32. doi: 10.1042/BST20140018.
Methylglyoxal is a potent protein-glycating agent. It is an arginine-directed glycating agent and often modifies functionally important sites in proteins. Glycation forms mainly MG-H1 [Nδ-(5-hydro-5-methyl-4-imidazolon-2-yl)ornithine] residues. MG-H1 content of proteins is quantified by stable isotopic dilution analysis-MS/MS and also by immunoblotting with specific monoclonal antibodies. Methylglyoxal-modified proteins undergo cellular proteolysis and release MG-H1 free adduct for excretion. MG-H1 residues have been found in proteins of animals, plants, bacteria, fungi and protoctista. MG-H1 is often the major advanced glycation end-product in proteins of tissues and body fluids, increasing in diabetes and associated vascular complications, renal failure, cirrhosis, Alzheimer's disease, arthritis, Parkinson's disease and aging. Proteins susceptible to methylglyoxal modification with related functional impairment are called the DCP (dicarbonyl proteome). The DCP includes albumin, haemoglobin, transcription factors, mitochondrial proteins, extracellular matrix proteins, lens crystallins and others. DCP component proteins are linked to mitochondrial dysfunction in diabetes and aging, oxidative stress, dyslipidaemia, cell detachment and anoikis and apoptosis. Methylglyoxal also modifies DNA where deoxyguanosine residues are modified to imidazopurinone MGdG {3-(2'-deoxyribosyl)-6,7-dihydro-6,7-dihydroxy-6/7-methylimidazo-[2,3-b]purine-9(8)one} isomers. MGdG was the major quantitative adduct detected in vivo. It was linked to frequency of DNA strand breaks and increased markedly during apoptosis induced by a cell-permeant glyoxalase I inhibitor. Glyoxalase I metabolizes >99% methylglyoxal and thereby protects the proteome and genome. Gene deletion of GLO1 is embryonically lethal and GLO1 silencing increases methylglyoxal concentration, MG-H1 and MGdG, premature aging and disease. Studies of methylglyoxal glycation have importance for human health, longevity and treatment of disease.
甲基乙二醛是一种强效的蛋白质糖基化剂。它是一种精氨酸定向糖基化剂，经常修饰蛋白质中功能重要的位点。糖基化主要形成MG-H1 [Nδ-(5-羟基-5-甲基-4-咪唑啉-2-基)鸟氨酸]残基。蛋白质中MG-H1的含量通过稳定同位素稀释分析-质谱/质谱以及用特异性单克隆抗体进行免疫印迹来定量。甲基乙二醛修饰的蛋白质会经历细胞内蛋白水解，并释放出游离的MG-H1加合物以供排泄。在动物、植物、细菌、真菌和原生生物的蛋白质中都发现了MG-H1残基。MG-H1通常是组织和体液蛋白质中主要的晚期糖基化终产物，在糖尿病及相关血管并发症、肾衰竭、肝硬化、阿尔茨海默病、关节炎、帕金森病和衰老过程中会增加。易受甲基乙二醛修饰并伴有相关功能损害的蛋白质被称为二羰基蛋白质组（DCP）。DCP包括白蛋白、血红蛋白、转录因子、线粒体蛋白质、细胞外基质蛋白质、晶状体晶状体蛋白等。DCP组成蛋白与糖尿病和衰老中的线粒体功能障碍、氧化应激、血脂异常、细胞脱离和失巢凋亡以及细胞凋亡有关。甲基乙二醛还会修饰DNA，其中脱氧鸟苷残基会被修饰为咪唑并嘌呤酮MGdG {3-(2'-脱氧核糖基)-6,7-二氢-6,7-二羟基-6/7-甲基咪唑-[2,3-b]嘌呤-9(8)酮}异构体。MGdG是体内检测到的主要定量加合物。它与DNA链断裂的频率有关，并且在细胞渗透性乙二醛酶I抑制剂诱导的细胞凋亡过程中显著增加。乙二醛酶I代谢>99%的甲基乙二醛，从而保护蛋白质组和基因组。GLO1基因缺失在胚胎期是致死性的，GLO1沉默会增加甲基乙二醛浓度、MG-H1和MGdG，导致早衰和疾病。甲基乙二醛糖基化研究对人类健康、长寿和疾病治疗具有重要意义。
