Mammalians are devoid of autonomous biosynthesis of folates and hence must obtain them from the diet. Reduced folate cofactors are B9-vitamins which play a key role as donors of one-carbon units in the biosynthesis of purine nucleotides, thymidylate and amino acids as well as in a multitude of methylation reactions including DNA, RNA, histone and non-histone proteins, phospholipids, as well as intermediate metabolites. The products of these S-adenosylmethionine (SAM)-dependent methylations are involved in the regulation of key biological processes including transcription, translation and intracellular signaling. Folate-dependent one-carbon metabolism occurs in several subcellular compartments including the cytoplasm, mitochondria, and nucleus. Since folates are essential for DNA replication, intracellular folate cofactors play a central role in cancer biology and inflammatory autoimmune disorders. In this respect, various folate-dependent enzymes catalyzing nucleotide biosynthesis have been targeted by specific folate antagonists known as antifolates. Currently, antifolates are used in drug treatment of multiple human cancers, non-malignant chronic inflammatory disorders as well as bacterial and parasitic infections. An obligatory key component of intracellular folate retention and intracellular homeostasis is (anti)folate polyglutamylation, mediated by the unique enzyme folylpoly-γ-glutamate synthetase (FPGS), which resides in both the cytoplasm and mitochondria. Consistently, knockout of the FPGS gene in mice results in embryonic lethality. FPGS catalyzes the addition of a long polyglutamate chain to folates and antifolates, hence rendering them polyanions which are efficiently retained in the cell and are now bound with enhanced affinity by various folate-dependent enzymes. The current review highlights the crucial role that FPGS plays in maintenance of folate homeostasis under physiological conditions and delineates the plethora of the molecular mechanisms underlying loss of FPGS function and consequent antifolate resistance in cancer.

哺乳动物缺乏叶酸的自主生物合成，因此必须从饮食中获取它们。减少的叶酸辅因子是B9维生素，在嘌呤核苷酸，胸苷酸和氨基酸的生物合成以及包括DNA，RNA，组蛋白和非组蛋白的多种甲基化反应中，作为一碳单元的供体发挥关键作用，磷脂以及中间代谢产物。这些S的产品-腺苷甲硫氨酸（SAM）依赖性甲基化参与关键生物学过程的调控，包括转录，翻译和细胞内信号传导。叶酸依赖的一碳代谢发生在几个亚细胞区室，包括细胞质，线粒体和细胞核。由于叶酸对于DNA复制至关重要，因此细胞内叶酸辅因子在癌症生物学和炎性自身免疫性疾病中起着核心作用。在这方面，催化叶酸生物合成的各种叶酸依赖性酶已被称为抗叶酸剂的特定叶酸拮抗剂靶向。目前，抗叶酸药用于多种人类癌症，非恶性慢性炎症性疾病以及细菌和寄生虫感染的药物治疗。细胞内叶酸保留和细胞内稳态的必不可少的关键成分是（抗）叶酸多谷氨酰化，由独特的叶酸聚γ-谷氨酸合成酶（FPGS）介导，该酶同时存在于细胞质和线粒体中。一致地，敲除小鼠中的FPGS基因会导致胚胎致死性。FPGS催化向叶酸和抗叶酸中添加一条长的聚谷氨酸链，因此使它们成为有效保留在细胞中的聚阴离子，并且现在被各种叶酸依赖性酶以增强的亲和力结合。本综述强调了FPGS在生理条件下维持叶酸稳态中所起的关键作用，并描述了FPGS功能丧失和随之而来的抗叶酸耐药性的分子机制过多。