Jaeger Timo, Flohé Leopold
MOLISA GmbH, Molecular Links Sachsen-Anhalt, Universitätsplatz 2, D-39106 Magdeburg, Germany.
Biofactors. 2006;27(1-4):109-20. doi: 10.1002/biof.5520270110.
Hydroperoxide metabolism in diverse pathogens is reviewed under consideration of involved enzymes as potential drug targets. The common denominator of the peroxidase systems of Trypanosoma, Leishmania, Plasmodium, and Mycobacterium species is the use of NAD(P)H to reduce hydroperoxides including peroxynitrite via a flavin-containing disulfide reductase, a thioredoxin (Trx)-related protein and a peroxidase that operates with thiol catalysis. In Plasmodium falciparum, thioredoxin- and glutathione dependent systems appear to be linked via glutaredoxin and plasmoredoxin to terminal thioredoxin peroxidases belonging to both, the peroxiredoxin (Prx) and glutathione peroxidase (GPx) family. In Mycobacterium tuberculosis, a catalase-type peroxidase is complemented by the typical 2-C-Prx AhpC that, in contrast to most bacteria, is reduced by TrxC, and an atypical 2-C-Prx reduced by TrxB or C. A most complex variation of the scheme is found in trypanosomatids, where the unique redox metabolite trypanothione reduces the thioredoxin-related tryparedoxin, which fuels Prx- and GPx-type peroxidases as well as ribonucleotide reductase. In Trypanosoma brucei and Leishmania donovani the system has been shown to be essential for viability and virulence by inversed genetics. It is concluded that optimum efficacy can be expected from inhibitors of the most upstream components of the redox cascades. For trypanosomatids attractive validated drug targets are trypanothione reductase and trypanothione synthetase; for mycobacteria thioredoxin reductase appears most appealing, while in Plasmodium simultaneous inhibition of both the thioredoxin and the glutathione pathway appears advisable to avoid mutual substitution in co-substrate supply to the peroxidases. Financial and organisational needs to translate the scientific progress into applicable drugs are discussed under consideration of the socio-economic impact of the addressed diseases.
在将相关酶作为潜在药物靶点的背景下，综述了多种病原体中的过氧化氢代谢。锥虫、利什曼原虫、疟原虫和分枝杆菌属过氧化物酶系统的共同特点是利用NAD(P)H，通过含黄素的二硫化物还原酶、硫氧还蛋白（Trx）相关蛋白和以硫醇催化作用的过氧化物酶来还原包括过氧亚硝酸盐在内的过氧化氢。在恶性疟原虫中，硫氧还蛋白和谷胱甘肽依赖性系统似乎通过谷氧还蛋白和质体硫氧还蛋白与属于过氧化物氧还蛋白（Prx）家族和谷胱甘肽过氧化物酶（GPx）家族的末端硫氧还蛋白过氧化物酶相联系。在结核分枝杆菌中，一种过氧化氢酶型过氧化物酶由典型的2-C-Prx AhpC（与大多数细菌不同，它由TrxC还原）和一种由TrxB或C还原的非典型2-C-Prx补充。在锥虫中发现了该模式的最复杂变体，其中独特的氧化还原代谢物锥虫硫醇还原与硫氧还蛋白相关的锥虫还蛋白，后者为Prx型和GPx型过氧化物酶以及核糖核苷酸还原酶提供燃料。在布氏锥虫和杜氏利什曼原虫中，通过反向遗传学已证明该系统对生存力和毒力至关重要。得出的结论是，氧化还原级联最上游成分的抑制剂有望产生最佳疗效。对于锥虫，经过验证的有吸引力的药物靶点是锥虫硫醇还原酶和锥虫硫醇合成酶；对于分枝杆菌，硫氧还蛋白还原酶似乎最具吸引力，而在疟原虫中，同时抑制硫氧还蛋白和谷胱甘肽途径似乎是可取的，以避免在过氧化物酶的共底物供应中相互替代。在考虑所涉疾病的社会经济影响的情况下，讨论了将科学进展转化为适用药物所需的资金和组织需求。
