Catalysis and structural properties of Leishmania infantum glyoxalase II: trypanothione specificity and phylogeny.
The glyoxalase pathway catalyzes the formation of d-lactate from methylglyoxal, a toxic byproduct of glycolysis. In trypanosomatids, trypanothione replaces glutathione in this pathway, making it a potential drug target, since its selective inhibition might increase methylglyoxal concentration in the parasites. Two glyoxalase II structures were solved. One with a bound spermidine molecule (1.8 A) and the other with d-lactate at the active site (1.9 A). The second structure was obtained by crystal soaking with the enzyme substrate (S)-d-lactoyltrypanothione. The overall structure of Leishmania infantum glyoxalase II is very similar to its human counterpart, with important differences at the substrate binding site. The crystal structure of L. infantum glyoxalase II is the first structure of this enzyme from trypanosomatids. The differential specificity of glyoxalase II toward glutathione and trypanothione moieties was revealed by differential substrate binding. Evolutionary analysis shows that trypanosomatid glyoxalases II diverged early from eukaryotic enzymes, being unrelated to prokaryotic proteins.
Silva
Marta Sousa
MS
Centro de Química e Bioquímica, Departamento de Química e Bioquímica, Faculdade de Ciências da Universidade de Lisboa, Portugal.
Barata
Lídia
L
Ferreira
António E N
AE
Romão
Susana
S
Tomás
Ana M
AM
Freire
Ana Ponces
AP
Cordeiro
Carlos
C
D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D002384:Catalysis; D018360:Crystallography, X-Ray; D005978:Glutathione / Q000031:analogs & derivatives* / Q000378:metabolism; D007700:Kinetics; D018314:Leishmania infantum / Q000145:classification / Q000201:enzymology* / Q000235:genetics; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010802:Phylogeny; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D013095:Spermidine / Q000031:analogs & derivatives* / Q000378:metabolism; D013379:Substrate Specificity; D013869:Thiolester Hydrolases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D000099301:Hydroxyacylglutathione Hydrolase
D005978:Glutathione; D011994:Recombinant Proteins; D013095:Spermidine; D013869:Thiolester Hydrolases; D000099301:Hydroxyacylglutathione Hydrolase; C044809:trypanothione