THE BINDING OF TRIMETHOPRIM TO BACTERIAL DIHYDROFOLATE-REDUCTASE
THE BINDING OF TRIMETHOPRIM TO BACTERIAL DIHYDROFOLATE-REDUCTASE
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DOI：
10.1016/0014-5793(81)81030-7
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发表时间：
1981-01-01
期刊：
影响因子：
3.5
通讯作者：
STAMMERS, DK
中科院分区：
文献类型：
--
作者：
BAKER, DJ;BEDDELL, CR;STAMMERS, DK
二氢叶酸还原酶（DHFR、EC 1.5、1.3）催化 NADPH 依赖性二氢叶酸还原为四氢叶酸；四氢叶酸的其他代谢物参与单碳单元并入嘌呤、嘧啶和氨基酸 [1, 2]。因此，抑制 DHFR 可导致核酸和蛋白质成分的缺乏，最终导致 DNA 合成停止，从而导致细胞死亡。 DHFR 抑制剂用于控制许多疾病过程，包括各种肿瘤和细菌感染。在分子水平上了解抑制剂结合对于设计具有更大抑制潜力和改善对适当生物体的选择性的药物具有潜在价值。甲氧苄啶 (TMP) 是一种广泛使用的抗菌药物 [3-61]，是细菌 DHFR 的有效抑制剂，但对脊椎动物酶的抑制剂却较弱（例如，针对大肠杆菌和人类酶的 ICse 值 [7] 分别为 5 X lo-’M 和 3 X lo4 M）。为了在分子水平上提供该药物作用的信息，我们确定了 I 型大肠杆菌（RTSOO 菌株）DHFR 与 TMP 的二元复合物的结构，并将其与 DHFR 与甲氨蝶呤 (MTX) 的复合物进行了比较，MTX 是一种与细菌和脊椎动物 DHFR 紧密结合的药物。我们的 TMP-酶复合物的结构与[8]中来自不同大肠杆菌菌株 (MB1428) 的 MTX-酶复合物的结构不同。大肠杆菌。目前认为这两种酶的氨基酸序列有 3 个位置不同 [9]。
Dihydrofolate reductase (DHFR, EC 1.5. 1.3) catalyses the NADPH-dependent reduction of dihydrofolate to tetrahydrofolate; further metabolites of tetrahydrofolate are involved in the incorporation of singlecarbon units into purines, pyrimidines and amino acids [1, 2]. The inhibition of DHFR can therefore lead to a deficiency of the components of nucleic acids and proteins, to eventual cessation of DNA synthesis and hence to cell death. DHFR inhibitors are used in the control of a number of disease processes including various tumours and bacterial infections. Understanding of inhibitor binding at the molecular level is of potential value in the design of drugs having greater inhibitory potential and improved selectivity towards the appropriate organism. Trimethoprim (TMP), a widely used antibacterial drug [3-61, is a potent inhibitor of bacterial DHFRs but a much weaker inhibitor of the vertebrate enzymes (eg, ICse values against Escherichia coli and human enzyme [7] are, respectively, 5 X lo-’M and 3 X lo4 M). To provide information on the action of this drug at the molecular level, we have determined the structure of the binary complex of E. coli (strain RTSOO) form I DHFR with TMP and compared it with that of the complex of DHFR with methotrexate (MTX), a drug which binds tightly to both bacterial and vertebrate DHFR. The structure of our TMP-enzyme complex differs from that in [8] of an MTX-enzyme complex from a different strain (MB1428) ofE. coli. The amino acid sequences of the two enzymes are currently thought to differ at 3 positions [9].