PDF(Pubmed)
Abstract：
The micronutrient vitamin B12 is an essential cofactor for two enzymes: methionine synthase, which plays a key role in the one-carbon cycle; and methylmalonyl-CoA mutase, an enzyme in a pathway that breaks down branched-chain amino acids and odd-chain fatty acids. A second, vitamin B12-independent pathway that degrades propionic acid was recently described in Caenorhabditis elegans, the propionate shunt pathway. Activation of five shunt pathway genes in response to low vitamin B12 availability or high propionic acid levels is accomplished by a transcriptional regulatory mechanism involving two nuclear hormone receptors, NHR-10 and NHR-68. Here, we report that the C. elegans Mediator subunit mdt-15 is also essential for the activation of the propionate shunt pathway genes, likely by acting as a transcriptional coregulator for NHR-10. C. elegans mdt-15 mutants fed with a low vitamin B12 diet have transcriptomes resembling those of wild-type worms fed with a high vitamin B12 diet, with low expression of the shunt genes. Phenotypically, the embryonic lethality of mdt-15 mutants is specifically rescued by diets high in vitamin B12, but not by dietary polyunsaturated fatty acids, which rescue many other phenotypes of the mdt-15 mutants. Finally, NHR-10 binds to MDT-15 in yeast two-hybrid assays, and the transcriptomes of nhr-10 mutants share overlap with those of mdt-15 mutants. Our data show that MDT-15 is a key coregulator for an NHR regulating propionic acid detoxification, adding to roles played by NHR:MDT-15 partnerships in metabolic regulation and pinpointing vitamin B12 availability as a requirement for mdt-15 dependent embryonic development.
摘要：
微量营养素维生素B12是两种酶的必需辅因子：蛋氨酸合酶，在单碳循环中起关键作用；和甲基丙二酰辅酶A变位酶，分解支链氨基酸和奇数链脂肪酸的途径中的一种酶。一秒,最近在秀丽隐杆线虫中描述了不依赖维生素B12的降解丙酸的途径，丙酸分流途径.响应低维生素B12可用性或高丙酸水平的五个分流途径基因的激活是通过涉及两个核激素受体的转录调节机制完成的。NHR-10和NHR-68。这里,我们报道，秀丽隐杆线虫介体亚基mdt-15也是必不可少的丙酸分流途径基因的激活，可能是通过充当NHR-10的转录共调节因子。饲喂低维生素B12饮食的线虫mdt-15突变体的转录组类似于饲喂高维生素B12饮食的野生型蠕虫的转录组，分流基因的低表达。表型，mdt-15突变体的胚胎致死性特别是通过饮食中维生素B12高，而不是通过饮食多不饱和脂肪酸，这拯救了mdt-15突变体的许多其他表型。最后,NHR-10在酵母双杂交试验中与MDT-15结合，nhr-10突变体的转录组与mdt-15突变体的转录组重叠。我们的数据表明，MDT-15是NHR调节丙酸解毒的关键共调节剂，添加NHR：MDT-15伙伴关系在代谢调节中的作用，并确定维生素B12的可用性是mdt-15依赖性胚胎发育的必要条件。
