The Caenorhabditis elegans K10C2.4 gene encodes a member of the fumarylacetoacetate hydrolase family - A caenorhabditis elegans model of type i tyrosinemia
The Caenorhabditis elegans K10C2.4 gene encodes a member of the fumarylacetoacetate hydrolase family - A caenorhabditis elegans model of type i tyrosinemia
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DOI：
10.1074/jbc.m708341200
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发表时间：
2008-04-04
影响因子：
4.8
通讯作者：
Nash, Lindsey
中科院分区：
文献类型：
--
作者：
Fisher, Alfred L.;Page, Kathryn E.;Nash, Lindsey
在真核生物和许多细菌中，酪氨酸通过五步酪氨酸降解途径降解以产生能量。影响酪氨酸降解途径的突变也具有医学重要性，因为影响途径中酶的突变是I型、II型和III型酪氨酸血症的原因。其中最严重的是I型酪氨酸血症，其由影响途径中的最后一种酶延胡索酰乙酰乙酸水解酶（FAH）的突变引起。到目前为止，在线虫秀丽隐杆线虫酪氨酸降解尚未研究，然而，基因预测编码酶在这一途径已被确定在几个微阵列，蛋白质组学，RNA干扰（RNAi）的屏幕可能参与衰老和蛋白质折叠的控制。我们试图识别和表征蠕虫酪氨酸降解途径中的基因，作为理解这些发现的第一步。在这里，我们描述的K10C2.4，它编码的同源FAH的表征。针对K10C2.4的RNAi产生致死表型，其由青年期死亡、对肠道的广泛损伤、生育力受损以及氧化应激和内质应激反应途径的激活组成。这种表型是由于酪氨酸代谢的改变，因为饮食中酪氨酸的增加增强了它，并且用RNAi或遗传突变抑制酪氨酸降解中的上游酶降低了表型。我们还使用我们的模型来鉴定在试点遗传筛选中抑制K10C2.4 RNAi产生的损伤的基因。我们的研究结果建立蠕虫作为模型的研究I型酪氨酸血症。
In eukaryotes and many bacteria, tyrosine is degraded to produce energy via a five-step tyrosine degradation pathway. Mutations affecting the tyrosine degradation pathway are also of medical importance as mutations affecting enzymes in the pathway are responsible for type I, type II, and type III tyrosinemia. The most severe of these is type I tyrosinemia, which is caused by mutations affecting the last enzyme in the pathway, fumarylacetoacetate hydrolase ( FAH). So far, tyrosine degradation in the nematode Caenorhabditis elegans has not been studied; however, genes predicted to encode enzymes in this pathway have been identified in several microarray, proteomic, and RNA interference ( RNAi) screens as perhaps being involved in aging and the control of protein folding. We sought to identify and characterize the genes in the worm tyrosine degradation pathway as an initial step in understanding these findings. Here we describe the characterization of the K10C2.4, which encodes a homolog of FAH. RNAi directed against K10C2.4 produces a lethal phenotype consisting of death in young adulthood, extensive damage to the intestine, impaired fertility, and activation of oxidative stress and endoplasmic stress response pathways. This phenotype is due to alterations in tyrosine metabolism as increases in dietary tyrosine enhance it, and inhibition of upstream enzymes in tyrosine degradation with RNAi or genetic mutations reduces the phenotype. We also use our model to identify genes that suppress the damage produced by K10C2.4 RNAi in a pilot genetic screen. Our results establish worms as a model for the study of type I tyrosinemia.