Trypanothione reductase

Chibale K, Visser M, van Schalkwyk D, Smith PJ, Saravanamuthu A, Fairlamb AH (2003) Exploring the potential of xanthene derivatives as trypanothione reductase inhibitors and chloroquine potentiating agents. Tetrahedron 59 2289-2296... 

Enzymes unique to the parasite and not found in humans (e.g., dihydropteroate synthesis enzymes, trypanothione reductase)... 

From Table 2 it is evident that only for three proteins, TIM, GAPDH, and trypanothione reductase the structures of the parasite and host enzymes are... 

Bradley, M., Bucheler, U. S. Walsh, C. T. (1991). Redox enzyme engineering conversion of human glutathione reductase into a trypanothione reductase. Biochemistry, 30,6124-7. 

DNA circles in 219 mitochondria of 14 Trypanothione 552 Trypanothione reductase 785 Tryparsamide 597s... 

Figure 3-7. Sequence alignment of various enzymes in the flavopro-tein disulfide oxidoreductase family. The sequences of the NADP4-dependent enzymes are the glutathione reductase from E. coli (E-GR), human (H-GR), Pseudomonas aeruginosa (P-GR), mercuric reductase from Staphylococcus aureus (S-MR), P. aeruginosa Tn 501 (P-GR), and trypanothione reductase from Trypanosoma congolense (T-TR). The NAD+-dependent enzymes are dihydrolipoamide dehydrogenase from E. coli (E-DD), B. stearothermophilus (B-DD), yeast (Y-DD), and human (H-DD). Residue positions marked with an asterisk correspond to those that were targets of site-directed mutagenesis in the text.

Tetragonal crystals of trypanothione reductase. Space group P4, cell parameters 0=6=128.6 A, c=92.5 A, o=P—y=90°. Typical largest dimension 1 mm. Photograph kindly provided by W. N. Hunter with permission. 

Polyamine metabolism by parasites differs in several significant ways from the mammalian host these include, but are not limited to, enzyme half-life, turnover, substrate specificity, types and quantities of polyamines produced. The production of the novel bis glutathionyl spermidine adduct by trypanosomatids, its role as an antioxidant and the protein structure of trypanothione reductase is discussed with respect to the more conventional glutathione reductase system. The role of S-adenosylmethionine and decarboxylated S-adenosylmethionine as critical precursors in the biosynthesis of the higher polyamines is explored with respect to differences in the function and control of the pathway by various parasites. Polyamine biosynthesis in parasites is sufficiently different from that of the host to afford multiple opportunities for drug development, these may be aimed directly at circumventing polyamine biosynthesis or at inhibiting precursors necessary for polyamine synthesis. 

The cloned trypanothione reductase genes from T. congolense (60) and T. cruzi (61) have been expressed in E. coli, and the enzymes overproduced and purified. The trypanothione reductase genes from Crithidia fasciculata (62,63) and T. brucei (63) have also been cloned and sequenced. Site-directed mutagenesis of either the E. coli glutathione reductase (64) or the T. congolense trypanothione reductase expressed in E. coli (60) has been used to evaluate the role of different residues in the mutually exclusive specificities of trypanothione reductase and glutathione reductase. 

Shames, S. L., Fairlamb, A. H., Cerami, A. and Walsh, C. T. (1986) Purification and characterization of trypanothione reductase from Crithidia fasciculata, a newly discovered member of the family of disulfide-containing flavoprotein reductases. Biochemistry 25 3519-3526. 

Krauth-Siegel, R. L., Enders, B., Henderson, G. B., Fairlamb, A. H. and Schirmer, R. H. (1987) Trypanothione reductase from Trypanosoma cruzi. Purification and characterization of the crystalline enzyme. Eur. J. Biochem. 164 123-128. 

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