FOLATE AND COBALAMIN METABOLISM IN PLASMODIUM-FALCIPARUM
FOLATE AND COBALAMIN METABOLISM IN PLASMODIUM-FALCIPARUM
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DOI：
10.1016/0169-4758(90)90148-w
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发表时间：
1990-12-01
期刊：
影响因子：
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通讯作者：
YUTHAVONG, Y
中科院分区：
文献类型：
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作者：
KRUNGKRAI, J;WEBSTER, HK;YUTHAVONG, Y
在过去的几年中，Jerapan Krungkrai、H. Kyle Webster 和 Yongyuth Yuthavong 表征了体外生长的恶性疟原虫中叶酸生物合成和叶酸依赖性反应的代谢途径，包括甲硫氨酸合酶的钴胺素依赖性活性。在这篇综述中，他们讨论了这项工作对于理解乙胺嘧啶抗性机制的意义以及克隆二氢叶酸还原酶基因的重要性。此外，还将考虑钴胺素在恶性疟原虫中的作用。干扰钴胺的使用可能代表对抗寄生虫的新目标。叶酸辅酶在涉及嘌呤、嘧啶和氨基酸代谢以及蛋白质合成起始2'3的各种反应中充当一碳单位的受体或供体。维生素的辅酶形式是接受一碳单元的四氢衍生物。甲醛，作为 5, 10-亚甲基四氢蝶酰谷氨酸 [5, 10-亚甲基四氢叶酸 (H4PteGlu)]，用于从脱氧尿苷酸 (dUMP) 合成胸苷酸 (TMP)。 5、I 0-亚甲基四氢叶酸被还原为5-甲基四氢蝶酰谷氨酸（5-甲基四氢叶酸），随后甲基转移至同型半胱氨酸，形成蛋氨酸并重新生成四氢蝶酰谷氨酸（四氢叶酸）。该反应由同型半胱氨酸甲基转移酶（蛋氨酸合酶）催化，已知需要钴胺素（维生素 B I2）作为辅助因子。细胞内叶酸辅酶主要以具有γ-羧基和谷氨酰残基的氨基的肽键连接的聚谷氨酸衍生物的形式存在。对于许多叶酸依赖性酶 4，叶酰聚谷氨酸盐（或蝶酰聚谷氨酸盐）是比叶酸单谷氨酸盐形式更好的底物。大多数哺乳动物细胞使用外源叶酸作为 5-甲基四氢叶酸的单谷氨酸盐衍生物，5-甲基四氢叶酸是血浆中的循环形式。与哺乳动物宿主不同，疟原虫能够合成叶酸。尽管恶性疟原虫中的叶酸代谢尚不清楚 5-7，但战斗中化疗攻击的目标之一是
During the past several years, Jerapan Krungkrai, H. Kyle Webster and Yongyuth Yuthavong have characterized the metabolic pathway of folate biosynthesis and folate-dependent reactions, including the cobalamin-dependent activity of methionine synthase, in P. falciparum grown in vitro I. In this review, they discuss the implications of this work for understanding the mechanism of pyrimethamine resistance and the importance of cloning the dihydrofolate reductase gene. In addition, the role of cobalamin in P. falciparum will be considered. Interference with cobal-amin use may represent a new target for combating the parasite.Folate coenzymes serve as acceptors or donors of one-carbon units in a variety of reactions involved in purine, pyrimidine and amino acid metabolism and in the initiation of protein synthesis 2'3. The coenzyme forms of the vitamin are tetrahydro derivatives that accept one-carbon units. Formaldehyde, as 5, 10-methylenetetrahydropteroylglutamate [5, 10-methylenetetrahydrofolate (H4PteGlu)], is used in the synthesis of thymidylate (TMP) from deoxyuridylate (dUMP). 5, I 0-Methylenetetrahydrofolate is reduced to 5-methyltetrahydropteroylglutamate (5-methyltetrahydrofolate), followed by the transfer of the methyl group to homocysteine to form methionine and to regenerate tetrahydropteroylglutamate (tetrahydrofolate). This reaction, catalysed by homocysteine methyltransferase (methionine synthase), is known to require cobalamin (vitamin B I2) as a cofactor. The intracellular folate coenzymes are predominantly present as polyglutamate derivatives with peptide linkage of the gamma-carboxyl group and amino group of glutamyl residues. The folylpolyglutamates (or pteroylpolyglutamates) are better substrates than the monoglutamate form of folate for many folate-dependent enzymes 4. Most mammalian cells use exogenous folate as the monoglutamate derivative of 5-methyltetrahydrofolate, which is the circulating form in the plasma. In contrast to their mammalian hosts, malaria parasites are able to synthesize folate. Although folate metabolism in Plasmodium falciparum is not well understood 5-7, one target for chemotherapeutic attack in combat-