Monnier Vincent M, Sell David R
Department of Pathology, Case Western Reserve University, Cleveland, Ohio 44106, USA.
Rejuvenation Res. 2006 Summer;9(2):264-73. doi: 10.1089/rej.2006.9.264.
The aging human extracellular matrix (ECM) and tissues rich in long-lived proteins undergo extensive changes with age that include increased stiffening, loss of elasticity, insolubilization, and decreased proteolytic digestibility. Most if not all these changes can be duplicated by the Maillard reaction in vitro, that is, the incubation of the proteins with reducing sugars and oxoaldehydes. These carbonyls eventually form advanced glycation end products (AGEs) and crosslinks that impair proteolytic digestibility and alter protein conformation. To date, close to 20 AGEs have been found in the human skin, of which ornithine is the single major result of damage to arginine residues, and glucosepane the single major crosslink. Although redox active metals and oxoaldehydes appear to play an important role in protein damage in experimental diabetes, their role in diabetic humans is still poorly understood. Evidence for the existence of deglycating enzymes has been found in vertebrates, bacteria, and fungi. However, only the vertebrate enzymes can deglycate larger, intracellular proteins via an ATP-dependent mechanism. Protein engineering will thus be needed to adapt Amadoriase enzymes toward deglycation of ECM proteins for purpose of probing the role of advanced glycation in animal models of diabetes and age-related diseases. The blocking of the reactivity of the glucosepane precursor using potent nucleophiles may be useful in preventing age-related changes in ECM proteins. However, there currently is no evidence in support of the proposed ability of so-called "AGE breakers" to cleave existing crosslinks of the Maillard reaction in vivo, and other mechanisms of action should be sought for this class of compounds.
衰老的人体细胞外基质（ECM）以及富含长寿蛋白的组织会随着年龄的增长发生广泛变化，包括硬度增加、弹性丧失、不溶性增加以及蛋白水解消化率降低。这些变化中的大多数（如果不是全部的话）都可以在体外通过美拉德反应重现，即蛋白质与还原糖和氧代醛一起孵育。这些羰基最终形成晚期糖基化终产物（AGEs）和交联键，从而损害蛋白水解消化率并改变蛋白质构象。迄今为止，在人类皮肤中已发现近20种AGEs，其中鸟氨酸是精氨酸残基损伤的单一主要产物，而葡糖基赖氨酸是单一主要交联键。尽管氧化还原活性金属和氧代醛似乎在实验性糖尿病中的蛋白质损伤中起重要作用，但它们在糖尿病患者中的作用仍知之甚少。在脊椎动物、细菌和真菌中已发现存在去糖化酶的证据。然而，只有脊椎动物的酶能够通过依赖ATP的机制使更大的细胞内蛋白质去糖化。因此，需要进行蛋白质工程，以使阿玛多里酶适应ECM蛋白质的去糖化，以便探究晚期糖基化在糖尿病和与年龄相关疾病的动物模型中的作用。使用强亲核试剂阻断葡糖基赖氨酸前体的反应性可能有助于预防ECM蛋白质的年龄相关变化。然而，目前尚无证据支持所谓的“AGE裂解剂”在体内裂解美拉德反应现有交联键的能力，因此应寻找这类化合物的其他作用机制。
