Proteome-wide profiling of isoniazid targets in mycobacterium tuberculosis
Proteome-wide profiling of isoniazid targets in mycobacterium tuberculosis
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DOI：
10.1021/bi061874m
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发表时间：
2006-11-28
期刊：
影响因子：
2.9
通讯作者：
Blanchard, John S.
中科院分区：
文献类型：
--
作者：
Argyrou, Argyrides;Jin, Lianji;Blanchard, John S.
异烟肼（INH）是一种用于治疗结核病的基本药物。杀分枝杆菌剂是吡啶核苷酸辅酶的INH加合物[INH- nad (P)]，它在体内被INH激活后产生，结合并抑制必需酶。nadh依赖的烯酰acp还原酶（InhA）和nadph依赖的二氢叶酸还原酶（DfrA）都被具有纳米摩尔亲和力的INH-NAD(P)加合物所抑制。在本文中，我们使用与固体载体偶联的INH-NAD和INH-NADP加合物对结核分枝杆菌的蛋白质组进行了分析，并鉴定出除了InhA和DfrA外，还有16种高亲和力结合这些加合物的其他蛋白质。其中大多数被预测为依赖于吡啶核苷酸的脱氢酶/还原酶。它们参与许多细胞过程，包括s -腺苷甲硫氨酸依赖的甲基转移反应、嘧啶和缬氨酸分解代谢、精氨酸降解途径、质子和钾转运、应激反应、脂质代谢和核黄素生物合成。因此，多种酶的靶向性可以解释INH的多效性和强大的杀分枝杆菌特性。
Isoniazid (INH) is an essential drug used to treat tuberculosis. The mycobactericidal agents are INH adducts [INH-NAD(P)] of the pyridine nucleotide coenzymes, which are generated in vivo after INH activation and which bind to, and inhibit, essential enzymes. The NADH-dependent enoyl-ACP reductase (InhA) and the NADPH-dependent dihydrofolate reductase (DfrA) have both been shown to be inhibited by INH-NAD(P) adducts with nanomolar affinity. In this paper, we profiled the Mycobacterium tuberculosis proteome using both the INH-NAD and INH-NADP adducts coupled to solid supports and identified, in addition to InhA and DfrA, 16 other proteins that bind these adducts with high affinity. The majority of these are predicted to be pyridine nucleotide-dependent dehydrogenases/reductases. They are involved in many cellular processes, including S-adenosylmethionine-dependent methyl transfer reactions, pyrimidine and valine catabolism, the arginine degradative pathway, proton and potassium transport, stress response, lipid metabolism, and riboflavin biosynthesis. The targeting of multiple enzymes could, thus, account for the pleiotropic effects of, and powerful mycobactericidal properties of, INH.