Thiol Metabolism of the Trypanosomatids as Potential Drug Targets

Abstract

SummaryTrypanosomatids produce significant amounts of four major low molecular mass thiols, trypanothione, glutathionylspermidine, glutathione, and ovothiol A.

Molecular characterization of cytosolic and mitochondrial tryparedoxin peroxidase in Trypanosoma cruzi populations susceptible and resistant to benznidazole

“…Cells can develop resistance by increasing expression of genes that encode protective and repair system enzymes (Steenkamp 2002;Finzi et al 2004). Based on our results, we suggest that the T. cruzi population with in vitro resistance to BZ exhibits an increase in TcTXNPx protein levels together with other enzymes associated with peroxide metabolism, such as the previously described TcFeSOD (Nogueira et al 2006), protecting these resistant parasites against oxidative stress.…”

Oxidative stress and antioxidant defenses: a target for the treatment of diseases caused by parasitic protozoa

“…2). All trypanosomatids synthesize trypanothione, a dithiol derived from glutathione that is unique to the members of the order Kinetoplastida and that has been proposed as a suitable target to develop drugs for the treatment of leishmaniases and trypanosomiases (Fairlamb and Cerami, 1992;Flohe et al, 2003;Krauth-Siegel et al, 2003;Steenkamp, 2003). Trypanothione (bis(glutathiolnyl)spermidine) consists of two molecules of glutathione conjugated with a molecule of spermidine.…”

An Acyloxymethyl Ketone‐Based Probe to Monitor the Activity of Glutathionylspermidine Amidase in Escherichia coli

“…[3,4] In trypanosomatids, TSH deficiency decreases viability, suggesting that the enzymes involved in TSH synthesis are a potential drug target for parasitic diseases, such as, African sleeping disease and Chagas disease. [5] Intriguingly, in E. coli GspSA, the amidase domain (GspA), which is upstream of the synthetase domain, hydrolytically cleaves Gsp to GSH and Spd. [1] Given that two functionally opposing domains reside in one protein, how both functions are regulated to avert futile ATP consumption has attracted much attention.…”

“…Gsp also prevents the oxidation of protein cysteine thiols by Gspprotein cysteine disulfide formation. [5] Gsp accumulates because Cys59 is transiently oxidized under oxidative stress to a sulfenic acid. Therefore, the regulation of GspA activity is possi- bly linked to the redox state of Cys59, and consequently the ability to sensitively and specifically detect GspA activity in vivo would be a useful probe of the redox-mediated regulatory mechanism(s) of Gsp and the physiological roles of the enzymes involved.…”