Proline modulates the intracellular redox environment and protects mammalian cells against oxidative stress
Proline modulates the intracellular redox environment and protects mammalian cells against oxidative stress
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DOI：
10.1016/j.freeradbiomed.2007.10.054
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发表时间：
2008-02-15
影响因子：
7.4
通讯作者：
Becker, Donald F.
中科院分区：
文献类型：
--
作者：
Krishnan, Navasona;Dickman, Martin B.;Becker, Donald F.
脯氨酸抑制活性氧（ROS）和细胞凋亡的潜力在哺乳动物细胞中进行了测试，通过操纵细胞内脯氨酸水平外源性和内源性的脯氨酸代谢酶的过度表达。脯氨酸被观察到保护细胞免受H2 O2，叔丁基过氧化氢，和致癌的氧化应激诱导剂，但对超氧化物生成剂，如甲萘醌是无效的。脯氨酸的氧化应激保护需要吡咯烷环的仲胺，并涉及谷胱甘肽氧化还原环境的保护。脯氨酸脱氢酶（PRODH），一种线粒体黄素酶，氧化脯氨酸，过表达导致细胞内脯氨酸含量降低6倍，细胞存活率降低相对于对照细胞。过表达PRODH的细胞被哌可酯（一种模拟脯氨酸抗氧化特性的类似物）和四氢-2-糠酸（一种PRODH特异性抑制剂）拯救。相比之下，脯氨酸生物合成酶Δ（1）-吡咯啉-5-羧酸（P5 C）合成酶（P5 CS）和P5 C还原酶（P5 CR）的过表达导致相对于对照细胞2倍更高的脯氨酸含量、显著更低的ROS水平和增加的细胞存活。在不同的哺乳动物细胞系暴露于生理H2 O2水平，增加内源性P5 CS和P5 CR的表达进行了观察，表明脯氨酸生物合成的上调是一种氧化应激反应。(c)2007年爱思唯尔公司All rights reserved.
The potential of proline to suppress reactive oxygen species (ROS) and apoptosis in mammalian cells was tested by manipulating intracellular proline levels exogenously and endogenously by overexpression of proline metabolic enzymes. Proline was observed to protect cells against H2O2, tert-butyl hydroperoxide, and a carcinogenic oxidative stress inducer but was not effective against superoxide generators such as menadione. Oxidative stress protection by proline requires the secondary amine of the pyrrolidine ring and involves preservation of the glutatbione redox environment. Overexpression of proline dehydrogenase (PRODH), a mitochondrial flavoenzyme that oxidizes proline, resulted in 6-fold lower intracellular proline content and decreased cell survival relative to control cells. Cells overexpressing PRODH were rescued by pipecolate, an analog that mimics the antioxidant properties of proline, and by tetrahydro-2-furoic acid, a specific inhibitor of PRODH. In contrast, overexpression of the proline biosynthetic enzymes Delta(1)-pyrroline-5-carboxylate (P5C) synthetase (P5CS) and P5C reductase (P5CR) resulted in 2-fold higher proline content, significantly lower ROS levels, and increased cell survival relative to control cells. In different mammalian cell lines exposed to physiological H2O2 levels, increased endogenous P5CS and P5CR expression was observed, indicating that upregulation of proline biosynthesis is an oxidative stress response. (c) 2007 Elsevier Inc. All rights reserved.