Trypanothione reductase (TR) (TR)

Trypanothione reductase (TR) is a vital enzyme in the unique thiol-based antioxidant system of kinetoplastid parasites, including Leishmania and Trypanosoma species [1.4.1, 1.4.5]. Unlike their mammalian hosts, which rely on the glutathione/glutathione reductase system, these parasites use trypanothione [N1,N8-bis(glutathionyl)spermidine] to maintain redox homeostasis and defend against oxidative stress from host macrophages [1.3.1, 1.3.3]. TR catalyzes the NADPH-dependent reduction of trypanothione disulfide to its reduced form, which then serves as an electron donor for various antioxidant enzymes like tryparedoxin peroxidase [1.3.4, 1.4.5]. The target also encompasses related thiol-dependent reductases, such as tryparedoxin and thiol-dependent reductase 1 (TDR1), which function alongside TR to manage the parasite's redox environment [1.1.1, 1.1.3]. Because TR is essential for parasite survival and is absent in humans, it is a highly attractive target for drug development [1.2.1, 1.3.2]. Current treatments like pentavalent antimonials are thought to inhibit TR, but their use is limited by toxicity and emerging resistance, driving the search for more selective and potent TR inhibitors [1.3.2, 1.5.3].

Other names

TryRTPRtryRN(1),N(8)-bis(glutathionyl)spermidine reductaseThiol-dependent reductase 1TDR1TryparedoxinTXN

Inhibition of trypanothione reductase prevents the reduction of trypanothione disulfide, leading to the accumulation of reactive oxygen species and subsequent parasite death.