Characterization and validation of Entamoeba histolytica pantothenate kinase as a novel anti-amebic drug target.
Characterization and validation of Entamoeba histolytica pantothenate kinase as a novel anti-amebic drug target.
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DOI：
10.1016/j.ijpddr.2018.02.004
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发表时间：
2018-04
期刊：
影响因子：
--
通讯作者：
Nozaki T
中科院分区：
文献类型：
--
作者：
Nurkanto A;Jeelani G;Yamamoto T;Naito Y;Hishiki T;Mori M;Suematsu M;Shiomi K;Hashimoto T;Nozaki T
辅酶A （CoA）作为参与bbb100代谢反应的辅助因子，对生命的基本生物化学至关重要。在这里，我们研究了溶组织内阿米巴（E. histolytica）的辅酶a生物合成途径，这是一种导致人类阿米巴病的肠道原生动物寄生虫。我们确定了参与辅酶a途径的四个关键酶：泛酸激酶（PanK, EC 2.7.1.33）、双功能磷酸磷酸腺苷-半胱氨酸连接酶/脱羧酶（PPCS-PPCDC）、磷酸蚁酸腺苷转移酶（PPAT）和去磷酸辅酶a激酶（DPCK）。胞质酶PanK被选择用于进一步的生化、遗传和系统发育表征。由于溶组织芽胞杆菌PanK （EhPanK）在生理上具有重要意义，并且与其人类同源物有充分的差异，因此该酶代表了开发新型抗阿米巴化疗药物的一个有吸引力的靶标。表观遗传基因PanK的沉默导致PanK活性显著降低，细胞内辅酶a浓度降低，体外生长迟缓，强化了该基因在溶组织芽胞杆菌中的重要性。此外，我们在Kitasato天然产物库中筛选了重组EhPanK的抑制剂，并鉴定了14个这样的化合物。其中一种化合物在低浓度下表现出适度抑制PanK活性和细胞生长，并对溶组织芽胞杆菌和人细胞具有不同的毒性。泛酸激酶（Pantothenate kinase, PanK）在溶组织内阿米巴原虫中是必需的。PanK基因沉默导致显著的生长缺陷、CoA水平和PanK活性。PanK代表了新药开发的一个有吸引力的目标。已经发现了对溶组织芽胞杆菌PanK的潜在抑制剂。
The Coenzyme A (CoA), as a cofactor involved in >100 metabolic reactions, is essential to the basic biochemistry of life. Here, we investigated the CoA biosynthetic pathway of Entamoeba histolytica (E. histolytica), an enteric protozoan parasite responsible for human amebiasis. We identified four key enzymes involved in the CoA pathway: pantothenate kinase (PanK, EC 2.7.1.33), bifunctional phosphopantothenate-cysteine ligase/decarboxylase (PPCS-PPCDC), phosphopantetheine adenylyltransferase (PPAT) and dephospho-CoA kinase (DPCK). Cytosolic enzyme PanK, was selected for further biochemical, genetic, and phylogenetic characterization. Since E. histolytica PanK (EhPanK) is physiologically important and sufficiently divergent from its human orthologs, this enzyme represents an attractive target for the development of novel anti-amebic chemotherapies. Epigenetic gene silencing of PanK resulted in a significant reduction of PanK activity, intracellular CoA concentrations, and growth retardation in vitro, reinforcing the importance of this gene in E. histolytica. Furthermore, we screened the Kitasato Natural Products Library for inhibitors of recombinant EhPanK, and identified 14 such compounds. One compound demonstrated moderate inhibition of PanK activity and cell growth at a low concentration, as well as differential toxicity towards E. histolytica and human cells. Pantothenate kinase (PanK) is essential in Entamoeba histolytica parasite. PanK gene silencing caused a significant growth defect, CoA level, and PanK activity. PanK represents an attractive target for new drug development. Potential inhibitors have been found against E. histolytica PanK.
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