Unique thiol metabolism in trypanosomatids: Redox homeostasis and drug resistance

Ali, Vahab; Behera, Sachidananda; Nawaz, Afreen; Equbal, Asif; Pandey, Krishna

doi:10.1016/bs.apar.2022.04.002

Cited by 7 publications

(8 citation statements)

References 408 publications

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“…Some of the druggable targets that have been more extensively studied are sterol biosynthesis, glycolysis, purine salvage pathway, DNA topoisomerases, folate metabolism, polyamine, and redox metabolism (Figure 1) [53][54][55][56]. Among these, redox metabolism and its relationship with oxidative stress are of particular interest due to the distinctive features of the redox-controlling system in trypanosomatids, which is based on trypanothione [57]. The main metabolic pathways that have been considered as potential drug targets are indicated in different colors: polyamine metabolism (blue color); methyl cycle metabolism (green color); modification of the topological state of DNA (yellow color); redox metabolism (red color); sterol biosyntyhesis (black color); folate metabolism (purple color); purine salvage pathway (orange color); folate metabolism (gray color).…”

Section: Current Treatments and Druggable Targets In Trypanosomatidsmentioning

confidence: 99%

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Targeting Trypanothione Metabolism in Trypanosomatids

González-Montero,

Andrés-Rodríguez,

García-Fernández

et al. 2024

Molecules

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Infectious diseases caused by trypanosomatids, including African trypanosomiasis (sleeping sickness), Chagas disease, and different forms of leishmaniasis, are Neglected Tropical Diseases affecting millions of people worldwide, mainly in vulnerable territories of tropical and subtropical areas. In general, current treatments against these diseases are old-fashioned, showing adverse effects and loss of efficacy due to misuse or overuse, thus leading to the emergence of resistance. For these reasons, searching for new antitrypanosomatid drugs has become an urgent necessity, and different metabolic pathways have been studied as potential drug targets against these parasites. Considering that trypanosomatids possess a unique redox pathway based on the trypanothione molecule absent in the mammalian host, the key enzymes involved in trypanothione metabolism, trypanothione reductase and trypanothione synthetase, have been studied in detail as druggable targets. In this review, we summarize some of the recent findings on the molecules inhibiting these two essential enzymes for Trypanosoma and Leishmania viability.

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Section: Current Treatments and Druggable Targets In Trypanosomatidsmentioning

confidence: 99%

“…Oxidative stress poses a fundamental challenge for trypanosomatids, impacting their survival and pathogenicity within the host organism. These parasites, responsible for some NTDs, have evolved unique mechanisms to mitigate oxidative stress and maintain redox balance [57].…”

Section: Oxidative Stress and The Unique Thiol Metabolism Of Trypanos...mentioning

confidence: 99%

Targeting Trypanothione Metabolism in Trypanosomatids

González-Montero,

Andrés-Rodríguez,

García-Fernández

et al. 2024

Molecules

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“…Instead of GSH itself, some organisms employ its precursors or derivates [ 3 , 59 , 120 ], such as γ-glutamyl-cysteine in halobacteria and halophilic archaea or trypanothione in kinetoplastid parasites [ 132 ]. They may also use other thiols, e.g., bacillithiol in Gram-positive Firmicutes [ 133 ] or mycothiol in many actinobacteria, such as the human pathogen Mycobacterium tuberculosis [ 134 ].…”

Section: Synthesis and Importance Of Glutathione In Living Organismsmentioning

confidence: 99%

The Glutathione System: A Journey from Cyanobacteria to Higher Eukaryotes

et al. 2023

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From bacteria to plants and humans, the glutathione system plays a pleiotropic role in cell defense against metabolic, oxidative and metal stresses. Glutathione (GSH), the γ-L-glutamyl-L-cysteinyl-glycine nucleophile tri-peptide, is the central player of this system that acts in redox homeostasis, detoxification and iron metabolism in most living organisms. GSH directly scavenges diverse reactive oxygen species (ROS), such as singlet oxygen, superoxide anion, hydrogen peroxide, hydroxyl radical, nitric oxide and carbon radicals. It also serves as a cofactor for various enzymes, such as glutaredoxins (Grxs), glutathione peroxidases (Gpxs), glutathione reductase (GR) and glutathione-S-transferases (GSTs), which play crucial roles in cell detoxication. This review summarizes what is known concerning the GSH-system (GSH, GSH-derived metabolites and GSH-dependent enzymes) in selected model organisms (Escherichia coli, Saccharomyces cerevisiae, Arabidopsis thaliana and human), emphasizing cyanobacteria for the following reasons. Cyanobacteria are environmentally crucial and biotechnologically important organisms that are regarded as having evolved photosynthesis and the GSH system to protect themselves against the ROS produced by their active photoautotrophic metabolism. Furthermore, cyanobacteria synthesize the GSH-derived metabolites, ergothioneine and phytochelatin, that play crucial roles in cell detoxication in humans and plants, respectively. Cyanobacteria also synthesize the thiol-less GSH homologs ophthalmate and norophthalmate that serve as biomarkers of various diseases in humans. Hence, cyanobacteria are well-suited to thoroughly analyze the role/specificity/redundancy of the players of the GSH-system using a genetic approach (deletion/overproduction) that is hardly feasible with other model organisms (E. coli and S. cerevisiae do not synthesize ergothioneine, while plants and humans acquire it from their soil and their diet, respectively).

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“…The major devastating protozoa-caused parasitic diseases are South American trypanosomiasis (Chagas disease), African trypanosomiasis (African sleeping sickness), malaria, and amoebiasis. Unicellular parasites of the trypanosomatidae family, responsible for Chagas diseases and sleeping sickness (Trypanosoma), respectively, as well as leishmaniasis (Leishmania), possess a redox system distinct from that of human cells [ 9 ]. These parasites heavily rely on the trypanothione, a thiol molecule that delivers electrons for the trypanothione-dependent pathways ( Figure 1 ).…”

Section: Introduction Scope and Aims Of This Reviewmentioning

confidence: 99%

“…The tryparedoxin plays an important role in catalyzing not only electron transfer from T(SH) 2 to different molecular targets, such as peroxidases, but also ribonucleotide reductase and protein disulfides. Importantly, trypanosomatid cells lack catalase, GPX, and GR; therefore, their redox homeostasis is maintained mainly by biosynthesis, regeneration, and utilization of trypanothione, which represents a potential target for the development of new drugs to treat these diseases [ 9 , 11 ]. Indeed, many proteins of the parasite-specific trypanothione metabolism have shown to be essential for the survival of the parasites.…”

Section: Introduction Scope and Aims Of This Reviewmentioning

confidence: 99%

Redox-Based Strategies against Infections by Eukaryotic Pathogens

Vallières

Golinelli-Cohen

Guittet

et al. 2023

Genes

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Redox homeostasis is an equilibrium between reducing and oxidizing reactions within cells. It is an essential, dynamic process, which allows proper cellular reactions and regulates biological responses. Unbalanced redox homeostasis is the hallmark of many diseases, including cancer or inflammatory responses, and can eventually lead to cell death. Specifically, disrupting redox balance, essentially by increasing pro-oxidative molecules and favouring hyperoxidation, is a smart strategy to eliminate cells and has been used for cancer treatment, for example. Selectivity between cancer and normal cells thus appears crucial to avoid toxicity as much as possible. Redox-based approaches are also employed in the case of infectious diseases to tackle the pathogens specifically, with limited impacts on host cells. In this review, we focus on recent advances in redox-based strategies to fight eukaryotic pathogens, especially fungi and eukaryotic parasites. We report molecules recently described for causing or being associated with compromising redox homeostasis in pathogens and discuss therapeutic possibilities.

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Unique thiol metabolism in trypanosomatids: Redox homeostasis and drug resistance

Cited by 7 publications

References 408 publications

Targeting Trypanothione Metabolism in Trypanosomatids

Targeting Trypanothione Metabolism in Trypanosomatids

The Glutathione System: A Journey from Cyanobacteria to Higher Eukaryotes

Redox-Based Strategies against Infections by Eukaryotic Pathogens

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