Proc. Natl. Acad. Sci. USA 109, 11693–11698 (2012)

Credit: BILL HUNTER

TDR1 is a thiol-dependent reductase in Leishmania and Trypanosoma parasites with a known role in redox regulation that is important for the activation of antimonial prodrugs. Fyfe et al. now report a crystal structure of TDR1 resolved to 2.3-Å resolution, revealing that TDR1 is a trimer with structural features reminiscent of glutaredoxins. TDR1 subunits consist of two glutathione-S-transferase (GST)-like domains fused by a linker with each domain containing a glutaredoxin-like subdomain. Typical GSTs are dimeric with the active site forming the dimer interface, whereas TDR1 is a trimer formed by intersubunit interactions. Each subunit contains two glutathione binding sites in which the cysteine of glutathione forms a disulfide with an active site cysteine as well as other structural features that mirror the situation in cysteine-type glutaredoxins. This observation prompted the authors to test TDR1 for various enzyme activities, including deglutathiolyzation. Biochemical and kinetic assays are consistent with TDR1 having glutaredoxin-like activity and show that it can catalyze the deglutathiolyzation of small-molecule mixed disulfides and protein-glutathione adducts. In these parasites, redox regulation has been thought to depend on trypanothione, but this unexpected activity for TDR1 raises the possibility that glutathione may also contribute to redox regulation in these organisms.