染色体的结构比较和外生二氢叶酸还原酶金黄色葡萄球菌与强有力的抑制剂甲氧苄氨嘧啶在复杂。
文章的细节
-
引用
复制到剪贴板 -
Heaslet H,哈里斯M, Fahnoe K,萨维尔R,磨蹭H, Chang J, Subramanyam C,巴雷罗G,米勒JR
染色体的结构比较和外生二氢叶酸还原酶金黄色葡萄球菌与强有力的抑制剂甲氧苄氨嘧啶在复杂。
蛋白质。2009年8月15日,76(3):706 - 17所示。doi: 10.1002 / prot.22383。
- PubMed ID
-
19280600 (在PubMed]
- 文摘
-
二氢叶酸还原酶(DHFR)是酶负责NADPH-dependent减少5 6-dihydrofolate 5, 6, 7, 8-tetrahydrofolate,嘌呤的合成中不可缺少的辅助因子,thymidylate,蛋氨酸和其他关键代谢物。因为它的重要性在多个细胞功能DHFR一直是许多研究的主题定位与抗癌酶,抗菌,抗菌药物。临床使用目标化合物DHFR包括甲氨蝶呤治疗癌症和diaminopyrimidines (dap)如甲氧苄氨嘧啶(TMP)治疗细菌感染。DAP DHFR的抑制剂在临床上用于> 30年,抵抗这些代理已成为普遍。耐甲氧西林金黄色葡萄球菌(MRSA)的病原体许多严重的医院和社区获得性感染,和其他革兰氏阳性微生物可以显示阻力dap通过染色体基因的突变或收购另一个DHFR称为“S1 DHFR。”To develop new therapies for health threats such as MRSA, it is important to understand the molecular basis of DAP resistance. Here, we report the crystal structure of the wild-type chromosomal DHFR from S. aureus in complex with NADPH and TMP. We have also solved the structure of the exogenous, TMP resistant S1 DHFR, apo and in complex with TMP. The structural and thermodynamic data point to important molecular differences between the two enzymes that lead to dramatically reduced affinity of DAPs to S1 DHFR. These differences in enzyme binding affinity translate into reduced antibacterial activity against strains of S. aureus that express S1 DHFR.