谷胱甘肽胞质降解酶ChaC1的生物学特征与功能

Biological Characteristics and Functions of ChaC1-Catalyzed Glutathione Degradation in the Cytoplasm

谷胱甘肽是一种神奇的小分子活性肽,在生物体内发挥着重要的抗氧化与解毒排毒功能。目前,对谷胱甘肽代谢的了解主要集中在合成代谢,对于其分解代谢的了解知之甚少。谷胱甘肽的分解代谢长期以来被认为不会发生在细胞质内。随着谷胱甘肽特异性γ-谷氨酰环转移酶ChaC1的发现和研究,谷胱甘肽在细胞质中分解代谢逐步揭开神秘面纱。ChaC1是γ-谷氨酰环转移酶家族的一员,可特异性将还原型谷胱甘肽(GSH)分解成半胱氨酰甘氨酸和5-氧脯氨酸,而不作用于氧化型谷胱甘肽(GSSG)。人源和鼠源ChaC1的氨基酸序列高度相似。人源ChaC1的第115位谷氨酸或鼠源ChaC1第116位谷氨酸突变会导致ChaC1丧失降解谷胱甘肽的活性。ChaC 1基因的敲除会导致小鼠和斑马鱼死亡,提示ChaC1在个体发育中发挥着极其重要的生理作用。另一方面,在不同的肿瘤类型中均发现ChaC 1基因高表达,并且与预后差成正相关。这提示ChaC1同样有着重要的病理生理作用。本文从结构特征、催化活性及表达调控等几个方面对近年来ChaC1的研究进展进行综述,同时概述了ChaC1在个体发育及疾病发生中的作用,为解析相关疾病的发病机制及寻找治疗策略提供了新思路。

Glutathione is a tri-peptide that plays key roles in antioxidation and detoxification.At present,research on glutathione metabolism mainly focuses on anabolism.And little is known about its catabolism in the cytoplasm.With the discovery of glutathione-specificγ-glutamylcyclotransferase ChaC1,the catabolism of glutathione in the cytoplasm has gradually been unveiled.ChaC1 is one member of theγ-glutamylcyclotransferase(GGCT)family,catalyzing the degradation of glutathione and production of Cys-Gly and 5-oxoproline.ChaC1 is highly conserved,with a~88%identity between human and mouse genes.Mutation of E115 in human ChaC1 or E116 in mouse ChaC1 abolishes its enzymatic activity.Notably,ChaC1 deficiency leads to embryonic lethality in the mouse and zebrafish,indicating ChaC1 is essential for embryo development.On the other side,ChaC1 is highly expressed in different types of cancer and correlates with a poor prognosis,suggesting that ChaC1 also has important pathophysiological function.In this paper,we review the research progress on the structure,enzymatic activity and expression pattern of ChaC1 in recent years,and summarize the role of ChaC1 in development and diseases,providing new insights on the mechanisms and therapeutic strategies.