Institute of Biology and Molecular Pathology, CNR, c/o Department of Biochemical Sciences, University Sapienza, P.le A. Moro 5, 00185, Rome, Italy.
Amino Acids. 2011 Feb;40(2):269-85. doi: 10.1007/s00726-010-0630-3. Epub 2010 May 29.
Polyamines (PAs) are essential metabolites in eukaryotes, participating in a variety of proliferative processes, and in trypanosomatid protozoa play an additional role in the synthesis of the critical thiol trypanothione. The PAs are synthesized by a metabolic process which involves arginase (ARG), which catalyzes the enzymatic hydrolysis of L-arginine (L-Arg) to L-ornithine and urea, and ornithine decarboxylase (ODC), which catalyzes the enzymatic decarboxylation of L-ornithine in putrescine. The S-adenosylmethionine decarboxylase (AdoMetDC) catalyzes the irreversible decarboxylation of S-adenosylmethionine (AdoMet), generating the decarboxylated S-adenosylmethionine (dAdoMet), which is a substrate, together with putrescine, for spermidine synthase (SpdS). Leishmania parasites and all the other members of the trypanosomatid family depend on spermidine for growth and survival. They can synthesize PAs and polyamine precursors, and also scavenge them from the microenvironment, using specific transporters. In addition, Trypanosomatids have a unique thiol-based metabolism, in which trypanothione (N1-N8-bis(glutathionyl)spermidine, T(SH)(2)) and trypanothione reductase (TR) replace many of the antioxidant and metabolic functions of the glutathione/glutathione reductase (GR) and thioredoxin/thioredoxin reductase (TrxR) systems present in the host. Trypanothione synthetase (TryS) and TR are necessary for the protozoa survival. Consequently, enzymes involved in spermidine synthesis and its utilization, i.e. ARG, ODC, AdoMetDC, SpdS and, in particular, TryS and TR, are promising targets for drug development.
多胺（PAs）是真核生物中必不可少的代谢物，参与各种增殖过程，在原生动物中还具有合成关键硫醇类物质——三肽硫醇（trypanothione）的额外作用。PAs 的合成涉及代谢过程，包括精氨酸酶（ARG），它催化 L-精氨酸（L-Arg）的酶促水解生成 L-鸟氨酸和尿素，以及鸟氨酸脱羧酶（ODC），它催化 L-鸟氨酸在腐胺中的酶促脱羧作用。S-腺苷甲硫氨酸脱羧酶（AdoMetDC）催化 S-腺苷甲硫氨酸（AdoMet）的不可逆脱羧作用，生成脱羧的 S-腺苷甲硫氨酸（dAdoMet），它与腐胺一起作为精脒合酶（SpdS）的底物。利什曼原虫寄生虫和其他所有原生动物家族的成员都依赖精脒来生长和存活。它们可以合成 PAs 和多胺前体，并且还可以使用特定的转运蛋白从微环境中摄取它们。此外，原生动物具有独特的基于硫醇的代谢途径，其中三肽硫醇（N1-N8-双（谷胱甘肽基）精脒，T（SH）（2））和三肽硫醇还原酶（TR）取代了许多抗氧化剂和代谢功能，这些功能原本由宿主中存在的谷胱甘肽/谷胱甘肽还原酶（GR）和硫氧还蛋白/硫氧还蛋白还原酶（TrxR）系统提供。三肽硫醇合成酶（TryS）和 TR 是原生动物生存所必需的。因此，涉及精脒合成及其利用的酶，即 ARG、ODC、AdoMetDC、SpdS 以及特别是 TryS 和 TR，是药物开发的有前途的靶点。
