Structural basis of methotrexate and pemetrexed action on serine hydroxymethyltransferases revealed using plant models.
Structural basis of methotrexate and pemetrexed action on serine hydroxymethyltransferases revealed using plant models.
复制标题
使用植物模型揭示甲氨蝶呤和培美曲塞对丝氨酸羟甲基转移酶作用的结构基础。
DOI：
10.1038/s41598-019-56043-4
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发表时间：
2019
影响因子：
4.6
通讯作者：
Dauter,Zbigniew
中科院分区：
文献类型：
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作者：
Ruszkowski,Milosz;Sekula,Bartosz;Ruszkowska,Agnieszka;Contestabile,Roberto;Nogues,Isabel;Angelaccio,Sebastiana;Szczepaniak,Andrzej;Dauter,Zbigniew
丝氨酸羟甲基转移酶（SHMT）在伴随四氢叶酸（THF）转化为5，10-亚甲基-THF的反应中可逆地将丝氨酸转化为甘氨酸在体内，5，10-meTHF是一碳（1C）单元的主要载体，其用于核苷酸生物合成和对每个活细胞至关重要的其它过程，但在过度增殖的细胞（例如癌组织）中过度活化。SHMT正在成为开发新药的有希望的靶点，因为它似乎可以通过切断5，10-meTHF的供应来抑制癌细胞的生长。甲氨蝶呤（MTX）和培美曲塞（PTX）是抗叶酸剂的两个例子，多年来治愈了许多患者，但靶向叶酸循环的不同酶（分别主要是二氢叶酸还原酶和胸苷酸合成酶）。在这里，我们显示的晶体结构的MTX和PTX结合植物SHMT同工酶从胞质和拟南芥-人类同工酶存在于相同的亚细胞室。我们通过彻底的动力学分析验证所研究的同工酶的抑制。我们建议进一步利用抗叶酸支架开发SHMT抑制剂，因为似乎特别是聚谷氨酰化PTX在体内抑制SHMT。基于结构的优化有望产生新的抗叶酸剂，可能被用作化疗药物。
Serine hydroxymethyltransferases (SHMTs) reversibly transform serine into glycine in a reaction accompanied with conversion of tetrahydrofolate (THF) into 5,10-methylene-THF (5,10-meTHF).In vivo, 5,10-meTHF is the main carrier of one-carbon (1C) units, which are utilized for nucleotide biosynthesis and other processes crucial for every living cell, but hyperactivated in overproliferating cells (e.g. cancer tissues). SHMTs are emerging as a promising target for development of new drugs because it appears possible to inhibit growth of cancer cells by cutting off the supply of 5,10-meTHF. Methotrexate (MTX) and pemetrexed (PTX) are two examples of antifolates that have cured many patients over the years but target different enzymes from the folate cycle (mainly dihydrofolate reductase and thymidylate synthase, respectively). Here we show crystal structures of MTX and PTX bound to plant SHMT isozymes from cytosol and mitochondria—human isozymes exist in the same subcellular compartments. We verify inhibition of the studied isozymes by a thorough kinetic analysis. We propose to further exploit antifolate scaffold in development of SHMT inhibitors because it seems likely that especially polyglutamylated PTX inhibits SHMTsin vivo. Structure-based optimization is expected to yield novel antifolates that could potentially be used as chemotherapeutics.