Oxidative Stress: A Boon or Bane for Trypanosomatids Diseases?
01 Jan 2019-pp 175-183
TL;DR: This chapter has tried to give an outline of the significance of redox stress and its role in different cellular metabolisms of trypanosomatids, with a special focus on trypanothsione-trypanothione reductase (TR)-based redox system as a peculiar system to study trypano-parasite oxidative stress mechanism, also for drug designing.
Abstract: Infectious diseases are menace to the mankind, having a major contribution to the human morbidity and mortality. Trypanosomatids have a pervasive effect in the world, causing devastating but neglected diseases such as leishmaniasis, Chagas disease, and African sleeping sickness affecting 27 million people worldwide with 150,000 deaths annually. Trypanosomatids developing drug resistance is the current bottleneck in providing promising chemotherapeutics for these diseases which forces the continuous quest for new drugs and drug candidates. Balancing redox homeostasis is crucial for cell survival which has various implications in the biology of these parasites. Reactive oxygen species (ROS) act as signaling molecules, involving in various pathways and crucial for survival. Conversely, various chemotherapeutic drugs against trypanosomatids-caused ROS induction result in oxidative stress, eventually leading to apoptotic manifestations. Oxidative stress is one of the host defense mechanisms to control the infection, while detoxification is one of the crucial counteracts at the parasite front for successful host-parasite interaction. Therefore, oxidative stress is a good tool for better understanding of parasite biology, pathogenesis, and host-pathogen interactions. It is noteworthy that trypanosomatids have divergence from all other prokaryotes and eukaryotes at their redox system, majorly trypanothione-trypanothione reductase (TR)-based redox metabolism. The absence of this system in mammalians and structural/functional differences from host enzymes make it a lucrative target for studying its role in oxidative stress control and also to develop effective chemotherapeutics. One of the causes for drug resistance of trypanosomatids is due to their action of inducing oxidative stress which in turn activates repair mechanisms resulting in the development of drug resistance. Hence, studying oxidative stress mechanism of trypanosomatids gives insights into drug resistance, which is an impendence in attaining efficacious chemotherapy. In this chapter, we have tried to give an outline of the significance of redox stress and its role in different cellular metabolisms of trypanosomatids, with a special focus on trypanothione-trypanothione reductase (TR)-based redox system as a peculiar system to study trypanosomatids oxidative stress mechanism, also for drug designing.
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5,682 citations
TL;DR: This review describes the main mitochondrial sources of reactive species and the antioxidant defences that evolved to prevent oxidative damage in all the mitochondrial compartments and discusses various physiological and pathological scenarios resulting from an increased steady state concentration of mitochondrial oxidants.
Abstract: The reduction of oxygen to water proceeds via one electron at a time. In the mitochondrial respiratory chain, Complex IV (cytochrome oxidase) retains all partially reduced intermediates until full reduction is achieved. Other redox centres in the electron transport chain, however, may leak electrons to oxygen, partially reducing this molecule to superoxide anion (O2−•). Even though O2−• is not a strong oxidant, it is a precursor of most other reactive oxygen species, and it also becomes involved in the propagation of oxidative chain reactions. Despite the presence of various antioxidant defences, the mitochondrion appears to be the main intracellular source of these oxidants. This review describes the main mitochondrial sources of reactive species and the antioxidant defences that evolved to prevent oxidative damage in all the mitochondrial compartments. We also discuss various physiological and pathological scenarios resulting from an increased steady state concentration of mitochondrial oxidants.
4,282 citations
TL;DR: The purification and properties of three key enzymes (glutathionylspermidine synthetases, trypanothione synthetase, and trypanothsione reductase) are discussed, and the catalytic mechanism, substrate-specificity, andThe three-dimensional structure of trypanOTHione reduCTase are compared to that of glutathione reductor.
Abstract: Trypanosomatids differ from all other organisms in their ability to conjugate the sulfur-containing tripeptide, glutathione, and the polyamine, spermidine, to form trypanothione [N1,N8-bis(glutathionyl)spermidine]. Together with the NADPH-dependent flavoprotein, trypanothione reductase, the dithiol form of trypanothione provides an intracellular reducing environment in these parasites, substituting for glutathione and glutathione reductase found in the mammalian host. Trypanothione and its related enzymes are involved in defense against damage by oxidants, certain heavy metals, and possibly xenobiotics. Trypanothione and its metabolic precursor, glutathionylspermidine, are also implicated in the modulation of spermidine levels during growth. Several existing trypanocidal drugs interact with the trypanothione system, suggesting that trypanothione metabolism may be a good target for the development of new drugs. The purification and properties of three key enzymes (glutathionylspermidine synthetase, trypanothione synthetase, and trypanothione reductase) are discussed, and the catalytic mechanism, substrate-specificity, and the three-dimensional structure of trypanothione reductase are compared to that of glutathione reductase.
737 citations
TL;DR: The cofactor was purified from the insect trypanosomatid Crithidia fasciculata and identified as a novel glutathione-sperMidine conjugate, N1,N8-bis(L-gamma-glutamyl-L-hemicystinyl-glycyl)spermidine, for which the trivial name trypanothione is proposed.
Abstract: Glutathione reductase from trypanosomes and leishmanias, unlike glutathione reductase from other organisms, requires an unusual low molecular weight cofactor for activity. The cofactor was purified from the insect trypanosomatid Crithidia fasciculata and identified as a novel glutathione-spermidine conjugate, N1,N8-bis(L-gamma-glutamyl-L-hemicystinyl-glycyl)spermidine, for which the trivial name trypanothione is proposed. This discovery may open a new chemotherapeutic approach to trypanosomiasis and leishmaniasis.
627 citations
TL;DR: A whole-organism, proteomic analysis of the four life-cycle stages of Trypanosoma cruzi found that the four parasite stages appear to use distinct energy sources, including histidine for stages present in the insect vectors and fatty acids by intracellular amastigotes.
Abstract: To complement the sequencing of the three kinetoplastid genomes reported in this issue, we have undertaken a whole-organism, proteomic analysis of the four life-cycle stages of Trypanosoma cruzi. Peptides mapping to 2784 proteins in 1168 protein groups from the annotated T. cruzi genome were identified across the four life-cycle stages. Protein products were identified from >1000 genes annotated as "hypothetical" in the sequenced genome, including members of a newly defined gene family annotated as mucin-associated surface proteins. The four parasite stages appear to use distinct energy sources, including histidine for stages present in the insect vectors and fatty acids by intracellular amastigotes.
392 citations