Polyglutamyl derivatives of folate as substrates and inhibitors of thymidylate synthetase.
Polyglutamyl derivatives of folate as substrates and inhibitors of thymidylate synthetase.
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叶酸的聚谷氨酰衍生物作为胸苷酸合成酶的底物和抑制剂。
DOI：
10.1016/s0021-9258(19)42488-5
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发表时间：
1974
期刊：
影响因子：
--
通讯作者：
C. Baugh
中科院分区：
文献类型：
--
作者：
R. Kisliuk;Y. Gaumont;C. Baugh
制备（1）-四氢蝶酰三谷氨酸和（1）-四氢蝶酰六谷氨酸，并作为来自干酪乳杆菌的胸苷酸合成酶（EC 2.1.1.6）（亚甲基四氢叶酸：脱氧尿苷酸C-甲基转移酶）的底物进行测试。两种四氢蝶酰聚谷氨酸都是比（l）-四氢蝶酰谷氨酸更有效的底物，在10- 5 m时反应速率提高3倍，蝶酰聚谷氨酸及其相应的二氢和（d）-四氢形式都是该酶的抑制剂，抑制效力随谷氨酰残基的数目增加而增加。蝶酰谷氨酸盐的50%抑制浓度为1.5 × 10 - 4，蝶酰六谷氨酸盐的浓度为6 × 10 - 7。抑制pteroylhexaglutamate，但不是由pteroylglutamate，在0.4mNaCl的存在下被取消。用二氢蝶酰六谷氨酸盐和二氢蝶酰三谷氨酸盐获得的抑制（3.2x10- 6 m时为50%）足以证明这些化合物可以作为胸苷酸形成的生理调节剂。对氨基苯甲酰基六谷氨酸和六谷氨酸在10- 6 m时不抑制胸苷酸合成酶2表明在没有蝶啶的情况下，聚谷氨酸不与酶结合。作为二氢叶酸还原酶（EC 1.5.1.3）（5，6，7，8-四氢蝶酰谷氨酸盐：烟酰胺腺嘌呤二核苷酸磷酸氧化还原酶）的底物，casei。
(l)-Tetrahydropteroyltriglutamate and (l)-tetrahydropteroylhexaglutamate were prepared and tested as substrates for thymidylate synthetase (EC 2.1.1.6) (methylenetetrahydrofolate:deoxyuridylate C-methyltransferase) fromLactobacillus casei. Both tetrahydropteroylpolyglutamates were more effective substrates than (l)-tetrahydropteroylglutamate, enhancing the reaction rate 3-fold when compared at 10-5m.Pteroylpolyglutamates and their corresponding dihydro and (d)-tetrahydro forms were inhibitors of the enzyme, the inhibitory potency increasing with the number of glutamyl residues. The concentration for 50% inhibition with pteroylglutamate was 1.5x10-4mand for pteroylhexaglutamate 6x10-7m. Inhibition by pteroylhexaglutamate, but not that by pteroylglutamate, was abolished in the presence of 0.4mNaCl. Inhibition obtained with dihydropteroylhexaglutamate and dihydropteroyltriglutamate (50% at 3.2x10-6m) is sufficient to warrant consideration of these compounds as physiological regulators of thymidylate formation.p-Aminobenzoylhexaglutamate and hexaglutamate did not inhibit thymidylate synthetase at 10-2mindicating that polyglutamates do not bind to the enzyme in the absence of the pteridine.Dihydropteroyltriglutamate and dihydropteroylhexaglutamate were no more effective than dihydropteroylglutamate as substrates for dihydrofolate reductase (EC 1.5.1.3) (5, 6, 7, 8-tetrahydropteroylglutamate:nicotinamide adenine dinucleotide phosphate oxidoreductase) fromL. casei.