Stereospecific mechanism of DJ-1 glyoxalases inferred from their hemithioacetal-containing crystal structures

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DJ-1 family proteins have recently been characterized as novel glyoxalases, although their cofactor-free catalytic mechanisms are not fully understood. Here, we obtained crystals of Arabidopsisthaliana DJ-1d (atDJ-1d) and Homosapiens DJ-1 (hDJ-1) covalently bound to glyoxylate, an analog of methylglyoxal, forming a hemithioacetal that presumably mimics an intermediate structure in catalysis of methylglyoxal to lactate. The deuteration level of lactate supported the proton transfer mechanism in the enzyme reaction. Differences in the enantiomeric specificity of d/l-lactacte formation observed for the DJ-1 superfamily proteins are explained by the presence of a His residue in the active site with essential Cys and Glu residues. The model for the stereospecificity was further evaluated by a molecular modeling simulation with methylglyoxal hemithioacetal superimposed on the glyoxylate hemithioacetal. The mechanism of DJ-1 glyoxalase provides a basis for understanding the His residue-based stereospecificity. DatabaseStructural data have been submitted to the Protein Data Bank under accession numbers (structure of atDJ-1d), (structure of hDJ-1 with glyoxylate) and (structure of atDJ-1d with glyoxylate).
Publisher
WILEY-BLACKWELL
Issue Date
2014-12
Language
English
Article Type
Article
Keywords

OXIDATIVE ENERGY SUBSTRATE; GLYCATION END-PRODUCTS; ESCHERICHIA-COLI; D-LACTATE; DIABETIC COMPLICATIONS; PARKINSONS-DISEASE; PROTEIN; METHYLGLYOXAL; SYSTEM; RESOLUTION

Citation

FEBS JOURNAL, v.281, no.24, pp.5447 - 5462

ISSN
1742-464X
DOI
10.1111/febs.13085
URI
http://hdl.handle.net/10203/194476
Appears in Collection
CH-Journal Papers(저널논문)BS-Journal Papers(저널논문)
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