Pyrimidine ribonucleotide salvage pathways

Pyrimidine nucleotides are essential as components of nucleic acids, as substrates for amino acid synthesis and as energy sources, but defects in the de novo biosynthesis of pyrimidines are not lethal in S. cerevisiae cells. This is because salvage pathways are able to utilize preformed bases (either from exogenous sources or internal turnover sources) for the synthesis of pyrimidines. If the required substrates are available, salvage pathways are preferred over de novo synthesis pathways for pyrimidine biosynthesis. The salvage pathways of pyrimidine ribonucleotides consist of 1) importing exogenous bases into the cell, and 2) the interconversion of various bases. Three proteins are involved in the import of exogenous bases used by the salvage pathway for pyrimidine ribonucleotide biosynthesis. Uracil enters the cell via the Fur4p uracil permease, cytosine enters the cell via the Fcy2p purine-cytosine transporter, and uridine enters the cell via the Fui1p uridine permease. As with many of the metabolic pathways of S. cerevisiae, the pathways for the salvage of pyrimidine ribonucleotides are under both transcriptional and post-transcriptional catabolite repression at a variety of points. This pathway is of biomedical interest because cytosine deaminase (Fcy1p) is not found in mammals and is capable of catalyzing the deamination of the prodrug 5-fluorocytosine (5FC) to form the anticancer drug 5-fluorouracil (5FU). Expression of Fcy1p in tumor cells increases their sensitivity to 5FC, and expression of Fur1p increases tumor cell sensitivity to 5FU. Tumor cells expressing a novel chimeric protein, produced from a gene containing the FCY1 and FUR1 coding sequences fused in frame, display significantly increased sensitivity to 5-FC suggesting that this novel suicide gene may constitute an original and potent candidate therapeutic gene for cancer gene therapy. SOURCE: [https://pathway.yeastgenome.org YeastPathways Salvage pathways of pyrimidine ribonucleotides]

嘧啶核苷酸作为核酸的组成成分、氨基酸合成的底物以及能量来源，对生物体至关重要。然而，在酿酒酵母（S. cerevisiae）细胞中，嘧啶的从头合成途径的缺陷并不致命。这主要是因为补救途径能够利用预先形成的碱基（无论是来自外源来源还是内部周转来源）来合成嘧啶。如果所需的底物可用，补救途径相较于从头合成途径更优先用于嘧啶的生物合成。嘧啶核糖核苷酸的补救途径包括：1）将外源碱基导入细胞，以及2）各种碱基之间的相互转化。在嘧啶核糖核苷酸生物合成过程中，有三类蛋白质参与外源碱基的导入。尿嘧啶通过Fur4p尿嘧啶渗透酶进入细胞，胞嘧啶通过Fcy2p嘌呤-胞嘧啶转运蛋白进入细胞，尿苷则通过Fui1p尿苷渗透酶进入细胞。与酿酒酵母的许多代谢途径一样，嘧啶核糖核苷酸的补救途径在多个环节受到转录和转录后分解代谢产物抑制。这一途径具有生物医学价值，因为胞嘧啶脱氨酶（Fcy1p）在哺乳动物中不存在，并且能够催化前药5-氟胞嘧啶（5FC）的脱氨反应，形成抗癌药物5-氟尿嘧啶（5FU）。Fcy1p在肿瘤细胞中的表达增加了其对5FC的敏感性，而Fur1p的表达则提高了肿瘤细胞对5FU的敏感性。表达一种新型嵌合蛋白的肿瘤细胞，该蛋白由包含FCY1和FUR1编码序列融合的基因产生，对5-FC表现出显著增高的敏感性，这表明这种新型自杀基因可能成为癌症基因治疗中一种原创且高效的候选治疗基因。来源：[https://pathway.yeastgenome.org YeastPathways Salvage pathways of pyrimidine ribonucleotides]