Halogenated tryptophan derivatives disrupt essential transamination mechanisms in bloodstream form Trypanosoma brucei.
Halogenated tryptophan derivatives disrupt essential transamination mechanisms in bloodstream form Trypanosoma brucei.
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卤素色氨酸衍生物破坏了血液中的基本跨跨机制，形成了锥虫瘤。
DOI：
10.1371/journal.pntd.0008928
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发表时间：
2020-12
影响因子：
3.8
通讯作者：
Smith TK
中科院分区：
文献类型：
--
作者：
Cockram PE;Dickie EA;Barrett MP;Smith TK
布氏锥虫是人类非洲锥虫病的病原体，其体内的氨基酸代谢对寄生虫的存活和毒力至关重要。在这些代谢过程中，芳香族氨基酸的转氨作用是最重要的代谢过程之一。本研究对一系列卤代色氨酸类似物的抗寄生虫活性进行了研究。这些类似物中的几种显示出显著的杀锥虫活性。化合物处理的寄生虫的代谢组学分析揭示了在芳香族氨基酸代谢内发生的关键差异，特别是在该寄生虫的广泛报道和基本的转氨过程内。布氏锥虫（Trypanosoma brucei）是人类非洲锥虫病（HAT）的病原体，其对氨基酸，特别是芳香族氨基酸色氨酸、苯丙氨酸和酪氨酸的摄取和代谢，对该虫的生存至关重要。寄生虫和人类宿主细胞之间氨基酸代谢的显著差异提供了选择性化疗剂的潜在途径，其先前已在一线HAT药物依氟鸟氨酸的情况下被利用。我们已经研究了氨基酸色氨酸的类似物，发现几种类似物显示出选择性的杀锥虫效力，这与吲哚环的7-位处的卤化的结构修饰强烈相关。这些有效化合物的杀锥虫活性可以通过补充过量天然色氨酸的生长培养基来逆转，这表明化合物在色氨酸代谢中的竞争和直接参与。寄生虫代谢的调查时，治疗有效的类似物显示寄生虫的代谢功能的大干扰。重要的是，观察到芳香族氨基酸代谢的显著中断，为这些化合物直接中断该途径提供了证据。在未来，这些类似物可以作为重要的工具，以获得更深入的了解这些转氨过程中的功能意义的T。布鲁氏菌寄生虫
Amino acid metabolism within Trypanosoma brucei, the causative agent of human African trypanosomiasis, is critical for parasite survival and virulence. Of these metabolic processes, the transamination of aromatic amino acids is one of the most important. In this study, a series of halogenated tryptophan analogues were investigated for their anti-parasitic potency. Several of these analogues showed significant trypanocidal activity. Metabolomics analysis of compound-treated parasites revealed key differences occurring within aromatic amino acid metabolism, particularly within the widely reported and essential transamination processes of this parasite. The uptake and metabolism of amino acids, particularly the aromatic amino acids tryptophan, phenylalanine and tyrosine, is greatly important to the survival of Trypanosoma brucei, the causative agent of human African trypanosomiasis (HAT). Substantial differences in amino acid metabolism between parasite and human host cells provide a potential route to selective chemotherapeutic agents, which has previously been exploited in the case of the frontline HAT drug eflornithine. We have investigated analogues of the amino acid tryptophan and found that several analogues displayed selective trypanocidal potency, which strongly correlated to a structural modification of halogenation at the 7-position of the indole ring. The trypanocidal activity of these potent compounds could be reversed by supplementing growth media with excess levels of natural tryptophan, suggesting competition and direct involvement of the compounds in tryptophan metabolism. Investigation of parasite metabolism when treated with potent analogues revealed large disturbances of the parasites’ metabolic function. Importantly, significant disruptions to the metabolism of aromatic amino acids were observed, giving evidence for the direct disruption of this pathway by these compounds. In the future, these analogues could serve as vital tools to gain a deeper understanding of the functional significance of these transamination processes within T. brucei parasites.
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影响因子：
9.6
作者：
Baker N;de Koning HP;Mäser P;Horn D
通讯作者：
Horn D
DOI：
10.3390/pathogens7020036
发表时间：
2018-04-01
期刊：
Pathogens (Basel, Switzerland)
影响因子：
--
作者：
Marchese L;Nascimento JF;Damasceno FS;Bringaud F;Michels PAM;Silber AM
通讯作者：
Silber AM
DOI：
10.1111/j.1432-1033.1994.t01-1-01019.x
发表时间：
1994-12-15
期刊：
EUROPEAN JOURNAL OF BIOCHEMISTRY
影响因子：
--
作者：
HUNTER, KJ;LEQUESNE, SA;FAIRLAMB, AH
通讯作者：
FAIRLAMB, AH
影响因子：
8.9
作者：
Kappagoda, Shanthi;Singh, Upinder;Blackburn, Brian G.
通讯作者：
Blackburn, Brian G.
DOI：
10.1016/0305-0491(85)90130-0
发表时间：
1985-01-01
影响因子：
2.2
作者：
HALL, JE;SEED, JR;SECHELSKI, JB
通讯作者：
SECHELSKI, JB