GABA metabolism pathway genes, UGA1 and GAD1, regulate replicative lifespan in Saccharomyces cerevisiae
GABA metabolism pathway genes, UGA1 and GAD1, regulate replicative lifespan in Saccharomyces cerevisiae
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DOI：
10.1016/j.bbrc.2011.02.136
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发表时间：
2011-04-01
影响因子：
3.1
通讯作者：
Mukai, Yukio
中科院分区：
文献类型：
--
作者：
Kamei, Yuka;Tamura, Takayuki;Mukai, Yukio
从酵母菌到人类，许多与衰老有关的基因已经在生物体中被发现。我们之前的研究表明，缺失uga3基因（编码γ -氨基丁酸（GABA）依赖性诱导VGA1 （GABA转氨酶）、UGA2（琥珀酸半醛脱氢酶）和UGA4 （GABA渗透酶）基因所必需的锌指转录因子）可以延长出芽酵母酿酒酵母的复制寿命。在这里，我们发现VGA1的缺失延长了寿命，UGA3的缺失也是如此；相比之下，UGA2或UGA4缺失的菌株没有延长寿命。δ uga1菌株不能将GABA脱胺生成琥珀酸半醛。GAD1编码谷氨酸脱羧酶，将谷氨酸转化为GABA， GAD1的缺失也会延长寿命。因此，GABA代谢途径中的两个基因VGA1和GAD1被确定为衰老基因。出乎意料的是，突变细胞（Delta uga2细胞除外）的细胞内GABA水平与野生型细胞没有差异。在培养基中添加GABA可以诱导UGA结构基因的转录，但对野生型细胞的繁殖寿命没有影响。H-1核磁共振谱对全细胞代谢物水平的多变量分析表明，长寿菌株和正常菌株之间存在分离。鉴定代谢物的气相色谱-质谱分析表明，三羧酸循环中间体的水平与寿命延长呈正相关。这些结果强烈表明，gaba代谢酶活性的降低通过将碳代谢转向呼吸来延长寿命，就像限制卡路里一样。(C) 2011爱思唯尔公司版权所有。
Many of the genes involved in aging have been identified in organisms ranging from yeast to human. Our previous study showed that deletion of the UGA3-gene-which encodes a zinc-finger transcription factor necessary for gamma-aminobutyric acid (GABA)-dependent induction of the VGA1 (GABA aminotransferase), UGA2 (succinate semialdehyde dehydrogenase), and UGA4 (GABA permease) genes-extends replicative lifespan in the budding yeast Saccharomyces cerevisiae. Here, we found that deletion of VGA1 lengthened the lifespan, as did deletion of UGA3; in contrast, strains with UGA2 or UGA4 deletions exhibited no lifespan extension. The Delta uga1 strain cannot deaminate GABA to succinate semialdehyde. Deletion of GAD1, which encodes the glutamate decarboxylase that converts glutamate into GABA, also increased lifespan. Therefore, two genes in the GABA metabolism pathway, VGA1 and GAD1, were identified as aging genes. Unexpectedly, intracellular GABA levels in mutant cells (except for Delta uga2 cells) did not differ from those in wild-type cells. Addition of GABA to culture media, which induces transcription of the UGA structural genes, had no effect on replicative lifespan of wild-type cells. Multivariate analysis of H-1 nuclear magnetic resonance spectra for the whole-cell metabolite levels demonstrated a separation between long-lived and normal-lived strains. Gas chromatography-mass spectrometry analysis of identified metabolites showed that levels of tricarboxylic acid cycle intermediates positively correlated with lifespan extension. These results strongly suggest reduced activity of the GABA-metabolizing enzymes extends lifespan by shifting carbon metabolism toward respiration, as calorie restriction does. (C) 2011 Elsevier Inc. All rights reserved.