Figure 2.
Figure 2. Pathogen antioxidant networks: The examples of Mtb and T. cruzi. (A) Mtb. NADPH oxidase-derived (O2•−) and iNOS-derived (•NO) radicals can react with specific enzymes (Fe- or Cu-containing SODs to form H2O2; trHbN to form nitrate) or recombine to form peroxynitrite. H2O2, peroxynitritous acid (ONOOH), and organic hydroperoxides (ROOH) are reduced particularly by KatG and peroxiredoxins (Prx). Most Mtb Prx (AhpC, TPx, PrxQB) can use Trx as reducing substrate. AhpC can also be reduced by AhpD, an adaptor protein that links antioxidant with metabolic enzymes and NADH. NADPH—derived from the pentose phosphate pathway (PPP), isocitrate dehydrogenase (IDH), malic enzyme (ME), and H+-transhydrogenases (TH)—is the final electron donor for TrxR and MshR. TrxR reduces Trx B and C (collectively indicated herein as Trx’s). The one-Cys Prx AhpE is reduced by Mrx-1 either directly (data not shown) or through the formation of a mixed disulfide with MSH, which is reduced by Mrx-1 in a monothiolic mechanism that leads to mycothiolated Mrx-1 (Mrx-1-SM) and is resolved by MSH/MshR/NADPH. MsrA and B reduce S– and R–Met-SO, respectively, and accept electrons from the Trx/TrxR/NADPH system. (B) T. cruzi. Enzymatic and nonenzymatic redox-active molecules use reducing equivalents from NADPH—derived from the PPP, IDH, ME, and TH—are funneled through the T(SH)2, GSH, ascorbate (ASC), and/or TXN-I/II redox systems. H2O2 is metabolized by APxCcP at the endoplasmic reticulum, mitochondria, and plasma membrane using ASC/Cyt cII as the electron donors. Dehidroascorbate (DHA) is reduced by a direct reaction with T(SH)2. Organic hydroperoxides (ROOH) are substrates for GPX-II that uses GSH. T(SH)2 reduces oxidized GSH (GSSG), while TR reduces TS2. Mitochondrial O2•− formation by the electron transport chain (mainly at complex III) is detoxified by Fe-SODA with H2O2 generation. •NO can reach the mitochondria and inhibit respiration at complex IV (CIV; with an enhanced O2•− generation). Fe-SODA outcompetes for O2•− inhibiting ONOO− formation. Mitochondrial peroxiredoxin (MPX) decomposes H2O2 and/or ONOO−, probably using reduced TXN-II and T(SH)2 as the reducing substrate (dashed arrows). Met-SO is repaired by the action of MsrB at the expense of TXN. In the cytosol, cytosolic peroxiredoxin (CPX) detoxifies ROOH. T(SH)2 is synthesized from two molecules of GSH and one spermidine in a reaction catalyzed by the enzyme trypanothione synthetase (TS). Met-SO is repaired by the presence of MsrA and B in the different compartments.

Pathogen antioxidant networks: The examples of Mtb and T. cruzi. (A) Mtb. NADPH oxidase-derived (O2•−) and iNOS-derived (•NO) radicals can react with specific enzymes (Fe- or Cu-containing SODs to form H2O2; trHbN to form nitrate) or recombine to form peroxynitrite. H2O2, peroxynitritous acid (ONOOH), and organic hydroperoxides (ROOH) are reduced particularly by KatG and peroxiredoxins (Prx). Most Mtb Prx (AhpC, TPx, PrxQB) can use Trx as reducing substrate. AhpC can also be reduced by AhpD, an adaptor protein that links antioxidant with metabolic enzymes and NADH. NADPH—derived from the pentose phosphate pathway (PPP), isocitrate dehydrogenase (IDH), malic enzyme (ME), and H+-transhydrogenases (TH)—is the final electron donor for TrxR and MshR. TrxR reduces Trx B and C (collectively indicated herein as Trx’s). The one-Cys Prx AhpE is reduced by Mrx-1 either directly (data not shown) or through the formation of a mixed disulfide with MSH, which is reduced by Mrx-1 in a monothiolic mechanism that leads to mycothiolated Mrx-1 (Mrx-1-SM) and is resolved by MSH/MshR/NADPH. MsrA and B reduce S– and R–Met-SO, respectively, and accept electrons from the Trx/TrxR/NADPH system. (B) T. cruzi. Enzymatic and nonenzymatic redox-active molecules use reducing equivalents from NADPH—derived from the PPP, IDH, ME, and TH—are funneled through the T(SH)2, GSH, ascorbate (ASC), and/or TXN-I/II redox systems. H2O2 is metabolized by APxCcP at the endoplasmic reticulum, mitochondria, and plasma membrane using ASC/Cyt cII as the electron donors. Dehidroascorbate (DHA) is reduced by a direct reaction with T(SH)2. Organic hydroperoxides (ROOH) are substrates for GPX-II that uses GSH. T(SH)2 reduces oxidized GSH (GSSG), while TR reduces TS2. Mitochondrial O2•− formation by the electron transport chain (mainly at complex III) is detoxified by Fe-SODA with H2O2 generation. •NO can reach the mitochondria and inhibit respiration at complex IV (CIV; with an enhanced O2•− generation). Fe-SODA outcompetes for O2•− inhibiting ONOO− formation. Mitochondrial peroxiredoxin (MPX) decomposes H2O2 and/or ONOO−, probably using reduced TXN-II and T(SH)2 as the reducing substrate (dashed arrows). Met-SO is repaired by the action of MsrB at the expense of TXN. In the cytosol, cytosolic peroxiredoxin (CPX) detoxifies ROOH. T(SH)2 is synthesized from two molecules of GSH and one spermidine in a reaction catalyzed by the enzyme trypanothione synthetase (TS). Met-SO is repaired by the presence of MsrA and B in the different compartments.

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