Phosphoethanolamine N-methyltransferase (PMT-1) catalyses the first reaction of a new pathway for phosphocholine biosynthesis in Caenorhabditis elegans
Phosphoethanolamine N-methyltransferase (PMT-1) catalyses the first reaction of a new pathway for phosphocholine biosynthesis in Caenorhabditis elegans
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DOI：
10.1042/bj20061815
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发表时间：
2007-06-15
影响因子：
4.1
通讯作者：
Jez, Joseph M.
中科院分区：
文献类型：
--
作者：
Brendza, Katherine M.;Haakenson, William;Jez, Joseph M.
开发针对动植物寄生线虫的杀线虫剂，需要识别寄主生物中未发现的生化靶点。最近的研究表明，秀丽隐杆线虫通过PEAMT （s -腺苷- l-蛋氨酸：磷酸乙醇胺n -甲基转移酶）将磷酸乙醇胺转化为磷酸胆碱，从而合成磷酸胆碱。在这里，我们研究了秀丽隐杆线虫PEAMT（基因：pmt-1；蛋白：pmt-1）的功能。我们的分析表明，PMT-1只催化磷酸乙醇胺转化为磷酸单甲基乙醇胺，这是PEAMT途径的第一步。这与来自植物和疟原虫的多功能PEAMT形成对比，后者在该途径中使用单一酶进行多次甲基化。初始速度和产物抑制研究表明PMT-1采用随机顺序动力学机制，并受到磷胆碱的反馈抑制。为了研究去除PMT-1活性对秀丽隐杆线虫的影响，RNAi （RNA干扰）实验表明，PMT-1是线虫生长发育所必需的，并验证了PMT-1作为抑制的潜在靶点。此外，提供PMT-1下游的途径代谢物可逆转PMT-1的RNAi表型。由于PMT-1在哺乳动物中未发现，仅与植物PEAMT有远亲关系，并且在人类、动物和作物植物的多种寄生线虫中保守，因此针对它的抑制剂可能在人类、兽医学和农业中证明有价值。
The development of nematicides targeting parasitic nematodes of animals and plants requires the identification of biochemical targets not found in host organisms. Recent studies suggest that Caenorhabditis elegans synthesizes phosphocholine through the action of PEAMT (S-adenosyl-L-methionine:phosphoethanolamine N-methyltransferases) that convert: phosphoethanolamine into phosphocholine. Here, we examine the function of a PEAMT from C. elegans (gene: pmt-1; protein: PMT-1). Our analysis shows that PMT-1 only catalyses the conversion of phosphoethanolamine into phospho-monomethylethanolamine, which is the first step in the PEAMT pathway. This is in contrast with the multifunctional PEAMT from plants and Plasmodium that perform multiple methylations in the pathway using a single enzyme. Initial velocity and product inhibition studies indicate that PMT-1 uses a random sequential kinetic mechanism and is feedback inhibited by phosphocholine. To examine the effect of abrogating PMT-1 activity in C. elegans, RNAi (RNA interference) experiments demonstrate that pmt-1 is required for worm growth and development and validate PMT-1 as a potential target for inhibition. Moreover, providing pathway metabolites downstream of PMT-1 reverses the RNAi phenotype of pmt-1. Because PMT-1 is not found in mammals, is only distantly related to the plant PEAMT and is conserved in multiple parasitic nematodes of humans, animals and crop plants, inhibitors targeting it may prove valuable in human and veterinary medicine and agriculture.