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• W2017019216 abstract "The parasitic protozoan Trypanosoma brucei maintains redox balance by synthesizing a conjugate of glutathione and spermidine termed trypanothione. The first committed step in the biosynthesis of glutathione, and thereby trypanothione, is catalyzed by the enzyme γ-glutamylcysteine synthetase (γGCS). We have cloned and sequenced the 2037-base pair gene coding for the catalytic subunit of T. brucei γGCS. T. brucei γGCS appears to be encoded by a single copy gene. A transcript of about 2.3 kilobases was observed in procyclic trypomastigotes. The deduced amino acid sequence of 679 amino acids shares 45, 41, and 36% sequence identity with mammalian, Caenorhabditis elegans, and yeast γGCS, respectively. The T. brucei γGCS gene was expressed in E. coli; the purified 77.4-kDa enzyme catalyzes the ligation of L-Glu to L-Cys with a kcat of 10 s−1, confirming that the gene encodes the functional catalytic subunit of γGCS. The apparent Km values measured for the three natural substrates L-Glu, L-Cys, and ATP are 0.24, 0.69, and 0.07 mM, respectively. Unlike the mammalian enzyme, L-α-aminobutyrate (apparent Km = 10 mM) is a poor substitute for L-Cys in the T. brucei γGCS-catalyzed reaction. T. brucei γGCS is feedback-inhibited by glutathione (apparent KI = 1.1 mM), and it is inactivated by cystamine and buthionine sulfoximine. The kinetic properties of recombinant T. brucei γGCS suggest that the substrate binding pocket and the mechanism of enzyme regulation differ from the mammalian enzyme, providing evidence that T. brucei γGCS could be a selective chemotherapeutic target for the treatment of trypanosomiasis. The parasitic protozoan Trypanosoma brucei maintains redox balance by synthesizing a conjugate of glutathione and spermidine termed trypanothione. The first committed step in the biosynthesis of glutathione, and thereby trypanothione, is catalyzed by the enzyme γ-glutamylcysteine synthetase (γGCS). We have cloned and sequenced the 2037-base pair gene coding for the catalytic subunit of T. brucei γGCS. T. brucei γGCS appears to be encoded by a single copy gene. A transcript of about 2.3 kilobases was observed in procyclic trypomastigotes. The deduced amino acid sequence of 679 amino acids shares 45, 41, and 36% sequence identity with mammalian, Caenorhabditis elegans, and yeast γGCS, respectively. The T. brucei γGCS gene was expressed in E. coli; the purified 77.4-kDa enzyme catalyzes the ligation of L-Glu to L-Cys with a kcat of 10 s−1, confirming that the gene encodes the functional catalytic subunit of γGCS. The apparent Km values measured for the three natural substrates L-Glu, L-Cys, and ATP are 0.24, 0.69, and 0.07 mM, respectively. Unlike the mammalian enzyme, L-α-aminobutyrate (apparent Km = 10 mM) is a poor substitute for L-Cys in the T. brucei γGCS-catalyzed reaction. T. brucei γGCS is feedback-inhibited by glutathione (apparent KI = 1.1 mM), and it is inactivated by cystamine and buthionine sulfoximine. The kinetic properties of recombinant T. brucei γGCS suggest that the substrate binding pocket and the mechanism of enzyme regulation differ from the mammalian enzyme, providing evidence that T. brucei γGCS could be a selective chemotherapeutic target for the treatment of trypanosomiasis." @default.
• W2017019216 created "2016-06-24" @default.
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• W2017019216 date "1996-07-01" @default.
• W2017019216 modified "2023-09-28" @default.
• W2017019216 title "Characterization of γ-Glutamylcysteine Synthetase, an Essential Enzyme in the Biosynthesis of Trypanothione (Diglutathionylspermidine)" @default.
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• W2017019216 doi "https://doi.org/10.1074/jbc.271.29.17485" @default.
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