Catalysis and Structural Properties of Leishmania infantum Glyoxalase II: Trypanothione Specificity and Phylogeny

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• 作者：Marta Sousa Silva ; Lí ; dia Barata ; Antó ; nio E. N. Ferreira ; Susana Romã ; o ; Ana M. Tom&aacute ; s ; Ana Ponces Freire ; Carlos Cordeiro
• 刊名：Biochemistry
• 出版年：2008
• 出版时间：January 8, 2008
• 年：2008
• 卷：47
• 期：1
• 页码：195 - 204
• 全文大小：1072K
• 年卷期：v.47,no.1(January 8, 2008)
• ISSN：1520-4995

文摘

The glyoxalase pathway catalyzes the formation of D-lactate from methylglyoxal, a toxicbyproduct of glycolysis. In trypanosomatids, trypanothione replaces glutathione in this pathway, makingit a potential drug target, since its selective inhibition might increase methylglyoxal concentration in theparasites. Two glyoxalase II structures were solved. One with a bound spermidine molecule (1.8 Å) andthe other with D-lactate at the active site (1.9 Å). The second structure was obtained by crystal soakingwith the enzyme substrate (S)-D-lactoyltrypanothione. The overall structure of Leishmania infantumglyoxalase II is very similar to its human counterpart, with important differences at the substrate bindingsite. The crystal structure of L. infantum glyoxalase II is the first structure of this enzyme fromtrypanosomatids. The differential specificity of glyoxalase II toward glutathione and trypanothione moietieswas revealed by differential substrate binding. Evolutionary analysis shows that trypanosomatid glyoxalasesII diverged early from eukaryotic enzymes, being unrelated to prokaryotic proteins.