Scrimgeour K G
Biochem Cell Biol. 1986 Jul;64(7):667-74. doi: 10.1139/o86-092.
Folylpolyglutamate synthetase (FPGS) catalyzes the synthesis of the poly-gamma-glutamate forms of tetrahydrofolate and its co-enzyme adducts, as well as of the folate-analogue drugs. This paper reviews current knowledge of the preparations of FPGS from mammalian sources (rat, hog, mouse, and beef liver). Kinetic constants for the substrates and activators of FPGS are compared. Tetrahydrofolate and 5-formyltetrahydrofolate are excellent substrates for the enzyme. The Km values for the antifolates and their 7-hydroxy metabolites are much higher than those for the tetrahydrofolates. Aminopterin has higher activity with FPGS than does methotrexate, which partially explains its greater toxicity. 5-Formyltetrahydrofolate, which is used as a rescue agent in high-dose methotrexate-rescue chemotherapy, is a better alternate substrate of FPGS than is methotrexate and therefore is a potent competitive inhibitor of the glutamylation of methotrexate. Thus, low concentrations of the rescue agent prevent formation of cytotoxic polyglutamates of methotrexate. The pathway of the reaction is the addition of a glutamate residue to the terminal gamma-carboxyl of the pteridine substrate. That longer folylpolyglutamates are poorer substrates possibly is a result of this addition pathway. Pteroic acid activates FPGS by lowering the Km value of the pteridine substrate. It also greatly increases the activity of the synthetase at physiological pH values.
叶酰聚谷氨酸合成酶（FPGS）催化四氢叶酸及其辅酶加合物以及叶酸类似物药物的多聚γ-谷氨酸形式的合成。本文综述了从哺乳动物来源（大鼠、猪、小鼠和牛肝）制备FPGS的现有知识。比较了FPGS底物和激活剂的动力学常数。四氢叶酸和5-甲酰基四氢叶酸是该酶的优良底物。抗叶酸药物及其7-羟基代谢物的Km值远高于四氢叶酸的Km值。氨甲蝶呤对FPGS的活性高于甲氨蝶呤，这部分解释了其更大的毒性。在高剂量甲氨蝶呤解救化疗中用作解救剂的5-甲酰基四氢叶酸，是FPGS比甲氨蝶呤更好的替代底物，因此是甲氨蝶呤谷氨酰化的有效竞争性抑制剂。因此，低浓度的解救剂可防止甲氨蝶呤细胞毒性多聚谷氨酸的形成。反应途径是将一个谷氨酸残基添加到蝶啶底物的末端γ-羧基上。较长的叶酰聚谷氨酸是较差的底物，这可能是这种添加途径的结果。蝶酸通过降低蝶啶底物的Km值来激活FPGS。它还在生理pH值下大大增加合成酶的活性。
