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. 2012 Feb 28;6(2):e1514. doi: 10.1371/journal.pntd.0001514

Figure 1. Overview of Leishmania pathways involved in response to SSG.

Figure 1

The defence against oxidative and nitrosative radicals imposed by macrophages relies on antioxidants here represented in the thiol pool with 3 major thiols: (a) cysteine with 2 synthesis pathways in trypanosomatids including transsulfuration pathway (as in vertebrates) via homocysteine with a key enzyme cystathione β-synthase (CBS) (#1), and de novo synthesis from serine (as in some prokaryotes and eukaryotes) catalysed by cysteine synthase (CS) (#2); with sulfide possibly provided by mercaptopyruvate sulfurtransferase (MST) (#3) [60], [61]; (b) glutathione (GSH) synthesised by condensation of cysteine and glutamate with the key enzyme γ-glutamylcysteine synthase (GCS) (#4) [62]; and (c) trypanothione (T(SH)2) which is synthesised by condensation of glutathione and spermidine; with ornithine decarboxylase (ODC) as key enzyme of spermidine synthesis (#5) [63]. Maintenance of redox balance is centred around the strong reductant T(SH)2 and the flavo-enzyme trypanothione reductase (TR) which keeps the T(SH)2 pool reduced and the redox potential low (#6) [40], [63]–[65]; MST possibly also has an antioxidant role via thioredoxin (#7) [61]. The drug SbV can be taken up by the parasite via an unidentified transporter (#8) [66] and the reduced form SbIII gains access via aquaglyceroporin (AQP1) (#9) [67]. The reduction of SbV to SbIII involves thiols and can be a non-enzymatical spontaneous reduction [68]–[71], or enzymatically catalyzed by thiol dependent reductase 1 (TDR1) [72] or arsenate reductase 2 (ACR2) [73] (#10). The resulting SbIII can form conjugates with thiols and inhibit TR (#12), together leading to increase of redox potential [12]–[14], [39]. The SbIII/thiol conjugates can be sequestered by ABC transporter multidrug resistance protein A (MRPA) or possibly pentamidine resistance protein 1 (PRP1) [74], [75] into intracellular organelles (#13), or can be directly pumped out by an uncharacterised transporter (#14) [76] (boxed names = proteins of which the corresponding genes were chosen for DNA sequencing and gene expression profiling in this study, unboxed names = metabolites; used abbreviations: ROI = reactive oxygen intermediates, RNI = reactive nitrogen intermediates).