Ilari Andrea, Fiorillo Annarita, Baiocco Paola, Poser Elena, Angiulli Gabriella, Colotti Gianni
CNR- Istituto di Biologia e Patologia Molecolari (IBPM), c/o Dipartimento di Scienze Biochimiche, Sapienza University of Roma, P.le A. Moro 5, 00185 Roma, Italy.
Mini Rev Med Chem. 2015;15(3):243-52. doi: 10.2174/138955751503150312141044.
Leishmaniasis is a neglected disease affecting more than 12 million people worldwide. The most used drugs are pentavalent antimonials that are very toxic and display the problem of drug resistance, especially in endemic regions such as Bihar in India. For this reason, it is urgent to find new and less toxic drugs against leishmaniasis. To this end, the understanding of pathways affecting parasite survival is of prime importance for targeted drug discovery. The parasite survival inside the macrophage is strongly dependent on polyamine metabolism. Polyamines are, in fact, very important for cell growth and proliferation. In particular, spermidine (Spd), the final product of the polyamine biosynthesis pathway, serves as a precursor for trypanothione (N1,N8- bis(glutathionyl)spermidine, T(SH)2) and hypusine (N(ε)-(4-amino-2-hydroxybutyl)lysine). T(SH)2 is a key molecule for parasite defense against the hydrogen peroxide produced by macrophages during the infection. Hypusination is a posttranslational modification occurring exclusively in the eukaryotic initiation factor 5A (eIF5A), which has an important role in avoiding the ribosome stalling during the biosynthesis of protein containing polyprolines sequences. The enzymes, belonging to the spermidine metabolism, i.e. arginase (ARG), ornithine decarboxylase (ODC), S-adenosylmethionine decarboxylase (AdoMetDC), spermidine synthase (SpdS), trypanothione synthetase (TryS or TSA), trypanothione reductase (TryR or TR), tryparedoxin peroxidase (TXNPx), deoxyhypusine synthase (DHS) and deoxyhypusine hydroxylase (DOHH) are promising targets for the development of new drugs against leishmaniasis. This minireview furnishes a picture of the structural, functional and inhibition studies on polyamine metabolism enzymes that could guide the discovery of new drugs against leishmaniasis.
利什曼病是一种被忽视的疾病，全球有超过1200万人受其影响。最常用的药物是五价锑化合物，这些药物毒性很强，且存在耐药性问题，尤其是在印度比哈尔邦等流行地区。因此，迫切需要找到针对利什曼病的新型低毒药物。为此，了解影响寄生虫存活的途径对于靶向药物研发至关重要。寄生虫在巨噬细胞内的存活强烈依赖于多胺代谢。事实上，多胺对细胞生长和增殖非常重要。特别是，多胺生物合成途径的终产物亚精胺（Spd）是三胺谷胱甘肽（N1,N8-双（谷胱甘肽基）亚精胺，T(SH)2）和hypusine（N(ε)-(4-氨基-2-羟基丁基)赖氨酸）的前体。T(SH)2是寄生虫在感染期间抵御巨噬细胞产生的过氧化氢的关键分子。Hypusination是一种仅发生在真核起始因子5A（eIF5A）中的翻译后修饰，它在避免核糖体在含有多聚脯氨酸序列的蛋白质生物合成过程中停滞方面具有重要作用。属于亚精胺代谢的酶，即精氨酸酶（ARG）、鸟氨酸脱羧酶（ODC）、S-腺苷甲硫氨酸脱羧酶（AdoMetDC）、亚精胺合酶（SpdS）、三胺谷胱甘肽合成酶（TryS或TSA）、三胺谷胱甘肽还原酶（TryR或TR）、三胺谷胱甘肽过氧化物酶（TXNPx）、脱氧hypusine合酶（DHS）和脱氧hypusine羟化酶（DOHH）是开发抗利什曼病新药的有前景的靶点。本综述提供了关于多胺代谢酶的结构、功能和抑制研究的概况，可为抗利什曼病新药的发现提供指导。
