Low-Molecular-Mass Antioxidants in Parasites

Abstract

The current organism-wide RNA-interference and proteome analyses are supposed to reveal many more interesting candidates for future drug development approaches directed against the parasite antioxidant defense systems.

Mono- and Dithiol Glutaredoxins in the Trypanothione-Based Redox Metabolism of Pathogenic Trypanosomes

“…The dithiol form of 2-C-Grxs is regenerated by the spontaneous reaction of the intramolecular disulfide of the protein with two molecules of GSH, and the resulting GSSG is then reduced by NADPH and glutathione reductase (GR). Trypanosomatids lack GR, while containing about 300 lM of each free GSH and T(SH) 2 (for reviews see 44,45). Both thiols spontaneously reduce the parasite 2-C-Grxs.…”

“…Trypanosomatids display a number of morphological and metabolic peculiarities (50). For instance, the parasite thiol redox homeostasis is maintained by the unique trypanothione/trypanothione reductase couple, which substitutes for the glutathione/ glutathione reductase and the thioredoxin/thioredoxin reductase systems of the host (24,39,44,45). Trypanothione [T(SH) 2 ; Fig.…”

“…1A] is synthesized from glutathione and spermidine with monoglutathionylspermidine (Gsp) as intermediate (44). The dithiol T(SH) 2 constitutes the main low molecular mass thiol of trypanosomatids and acts as redox cofactor in a plethora of cellular functions (39,44,45). The transfer of reducing equivalents from T(SH) 2 to protein targets can be mediated by thioredoxin-(Trx), tryparedoxin-(TXN) and glutaredoxin-type oxidoreductases (12,20,63,77; Fig.…”

“…The parasite glutaredoxins (Grxs) probably have rather specialized functions and are the subject of this review. T(SH) 2 has also been shown to complex to electrophiles such as heavy metals and drugs or to ligate endobiotics (i.e., methylglyoxal) or nitro-iron complexes (7, for recent reviews see 44,45). On the other hand, iron is an essential element that trypanosomatids take up from the extracellular milieu by mechanisms that differ between species (reviewed in 55,83).…”

A cost-effective synthesis of enantiopure ovothiol A from L-histidine, its natural precursor

“…They act as protective antioxidants 9,10 in many parasitic protozoa. [11][12][13][14][15] These peculiarities have attracted pharmaceutical interest to create prospective antitrypanosomal chemotherapeutic agents. 16,17 Despite this, the commercial availability of ovothiol A is limited, and its isolation from marine algae 10 and sea urchin eggs 4 is a troublesome task.…”