Institute of Biology, Medicinal Chemistry and Biotechnology, National Helenic Research Foundation, 48 Vas. Constantinou Ave., 116 35 Athens, Greece.
Laboratoire de Biologie Cellulaire du Vieillissement, UR4-UPMC, IFR 83, Université Pierre et Marie Curie-Paris 6, 4 Place Jussieu, 75005 Paris, France.
Mol Aspects Med. 2014 Feb;35:1-71. doi: 10.1016/j.mam.2012.09.001. Epub 2012 Oct 26.
Proteins are continuously affected by various intrinsic and extrinsic factors. Damaged proteins influence several intracellular pathways and result in different disorders and diseases. Aggregation of damaged proteins depends on the balance between their generation and their reversal or elimination by protein repair systems and degradation, respectively. With regard to protein repair, only few repair mechanisms have been evidenced including the reduction of methionine sulfoxide residues by the methionine sulfoxide reductases, the conversion of isoaspartyl residues to L-aspartate by L-isoaspartate methyl transferase and deglycation by phosphorylation of protein-bound fructosamine by fructosamine-3-kinase. Protein degradation is orchestrated by two major proteolytic systems, namely the lysosome and the proteasome. Alteration of the function for both systems has been involved in all aspects of cellular metabolic networks linked to either normal or pathological processes. Given the importance of protein repair and degradation, great effort has recently been made regarding the modulation of these systems in various physiological conditions such as aging, as well as in diseases. Genetic modulation has produced promising results in the area of protein repair enzymes but there are not yet any identified potent inhibitors, and, to our knowledge, only one activating compound has been reported so far. In contrast, different drugs as well as natural compounds that interfere with proteolysis have been identified and/or developed resulting in homeostatic maintenance and/or the delay of disease progression.
蛋白质不断受到各种内在和外在因素的影响。受损的蛋白质会影响多种细胞内途径，导致不同的紊乱和疾病。受损蛋白质的聚集取决于它们的产生与通过蛋白质修复系统的逆转或消除以及降解之间的平衡。关于蛋白质修复，只有少数修复机制得到了证实，包括通过蛋氨酸亚砜还原酶还原蛋氨酸亚砜残基、通过 L-异天冬氨酸甲基转移酶将异天冬氨酸残基转化为 L-天冬氨酸以及通过果糖胺-3-激酶磷酸化使蛋白结合的果糖胺去糖化。蛋白质降解由两个主要的蛋白酶体系统协调，即溶酶体和蛋白酶体。这两个系统的功能改变都与正常或病理过程相关的细胞代谢网络的各个方面有关。鉴于蛋白质修复和降解的重要性，最近在各种生理条件下（如衰老）以及在疾病中，对这些系统的调节进行了大量的研究。遗传调节在蛋白质修复酶方面取得了有希望的结果，但目前还没有发现有效的抑制剂，据我们所知，迄今为止仅报道了一种激活化合物。相比之下，已经鉴定和/或开发了不同的药物以及与蛋白水解作用有关的天然化合物，从而实现了体内平衡的维持和/或疾病进展的延缓。
