Vander Jagt David L, Hunsaker Lucy A
Department of Biochemistry and Molecular Biology, University of New Mexico School of Medicine, Albuquerque, NM 87131, USA.
Chem Biol Interact. 2003 Feb 1;143-144:341-51. doi: 10.1016/s0009-2797(02)00212-0.
The 2-oxoaldehyde methylglyoxal (MeG) is the precursor to a number of the known advanced glycation endproducts (AGE) implicated in the development of diabetic complications. Other 2-oxoaldehydes that are important in AGE formation, such as glyoxal, glucosone, deoxyglucosone, xylosone and deoxyxylosone, are produced by nonenzymatic reactions. By contrast, MeG is produced by both enzymatic and nonenzymatic processes, most of which appear to be enhanced in diabetes. MeG may be a major precursor to formation of AGE, and rates of production of MeG depend upon physiological conditions such as hyperglycemia and ketoacidosis. MeG is also unique compared to the other 2-oxoaldehydes in its complex metabolism. At least four pathways contribute to detoxification of MeG: (1) aldose reductase, a member of the aldo-keto reductase superfamily, catalyzes the NADPH-dependent reduction of a wide range of aldehydes. MeG is the best of the known physiological aldehyde substrates of aldose reductase. The distribution of aldose reductase in human tissue is restricted; there is little expression in liver; (2) the ubiquitous and highly active glyoxalase system converts MeG into D-lactate. However, this system depends upon the availability of glutathione; activity is severely limited by conditions of oxidative stress that impact levels of glutathione; (3) betaine aldehyde dehydrogenase, also known as ALDH9, is able to catalyze the oxidation of MeG to pyruvate, although less efficiently than with its substrate betaine aldehyde; (4) the long-known but not widely studied 2-oxoaldehyde dehydrogenases (2-ODHs) catalyze the oxidation of MeG to pyruvate, primarily in liver. There are two NADP-dependent 2-ODHs in human liver. Both of these require an activating amine. The physiological activator is unknown.
2-氧代醛甲基乙二醛（MeG）是许多已知的晚期糖基化终产物（AGE）的前体，这些终产物与糖尿病并发症的发生有关。其他在AGE形成中起重要作用的2-氧代醛，如乙二醛、葡萄糖酮、脱氧葡萄糖酮、木糖酮和脱氧木糖酮，是通过非酶反应产生的。相比之下，MeG是通过酶促和非酶促过程产生的，其中大多数在糖尿病中似乎会增强。MeG可能是AGE形成的主要前体，MeG的产生速率取决于高血糖和酮症酸中毒等生理状况。与其他2-氧代醛相比，MeG在其复杂的代谢过程中也具有独特性。至少有四条途径有助于MeG的解毒：（1）醛糖还原酶是醛糖-酮糖还原酶超家族的成员，催化多种醛的NADPH依赖性还原。MeG是醛糖还原酶已知的最佳生理醛底物。醛糖还原酶在人体组织中的分布有限；在肝脏中几乎没有表达；（2）普遍存在且高度活跃的乙二醛酶系统将MeG转化为D-乳酸。然而，该系统取决于谷胱甘肽的可用性；氧化应激条件会影响谷胱甘肽水平，从而严重限制其活性；（3）甜菜碱醛脱氢酶，也称为ALDH9，能够催化MeG氧化为丙酮酸，尽管效率低于其底物甜菜碱醛；（4）长期已知但未广泛研究的2-氧代醛脱氢酶（2-ODHs）主要在肝脏中催化MeG氧化为丙酮酸。人体肝脏中有两种NADP依赖性2-ODHs。这两种酶都需要一种活化胺。其生理活化剂尚不清楚。
