Glyoxalase I--structure, function and a critical role in the enzymatic defence against glycation.
Glyoxalase I is part of the glyoxalase system present in the cytosol of cells. The glyoxalase system catalyses the conversion of reactive, acyclic alpha-oxoaldehydes into the corresponding alpha-hydroxyacids. Glyoxalase I catalyses the isomerization of the hemithioacetal, formed spontaneously from alpha-oxoaldehyde and GSH, to S -2-hydroxyacylglutathione derivatives [RCOCH(OH)-SG-->RCH(OH)CO-SG], and in so doing decreases the steady-state concentrations of physiological alpha-oxoaldehydes and associated glycation reactions. Physiological substrates of glyoxalase I are methylglyoxal, glyoxal and other acyclic alpha-oxoaldehydes. Human glyoxalase I is a dimeric Zn(2+) metalloenzyme of molecular mass 42 kDa. Glyoxalase I from Escherichia coli is a Ni(2+) metalloenzyme. The crystal structures of human and E. coli glyoxalase I have been determined to 1.7 and 1.5 A resolution. The Zn(2+) site comprises two structurally equivalent residues from each domain--Gln-33A, Glu-99A, His-126B, Glu-172B and two water molecules. The Ni(2+) binding site comprises His-5A, Glu-56A, His-74B, Glu-122B and two water molecules. The catalytic reaction involves base-catalysed shielded-proton transfer from C-1 to C-2 of the hemithioacetal to form an ene-diol intermediate and rapid ketonization to the thioester product. R - and S-enantiomers of the hemithioacetal are bound in the active site, displacing the water molecules in the metal ion primary co-ordination shell. It has been proposed that Glu-172 is the catalytic base for the S-substrate enantiomer and Glu-99 the catalytic base for the R-substrate enantiomer; Glu-172 then reprotonates the ene-diol stereospecifically to form the R-2-hydroxyacylglutathione product. By analogy with the human enzyme, Glu-56 and Glu-122 may be the bases involved in the catalytic mechanism of E. coli glyoxalase I. The suppression of alpha-oxoaldehyde-mediated glycation by glyoxalase I is particularly important in diabetes and uraemia, where alpha-oxoaldehyde concentrations are increased. Decreased glyoxalase I activity in situ due to the aging process and oxidative stress results in increased glycation and tissue damage. Inhibition of glyoxalase I pharmacologically with specific inhibitors leads to the accumulation of alpha-oxoaldehydes to cytotoxic levels; cell-permeable glyoxalase I inhibitors are antitumour and antimalarial agents. Glyoxalase I has a critical role in the prevention of glycation reactions mediated by methylglyoxal, glyoxal and other alpha-oxoaldehydes in vivo.
Thornalley
P J
PJ
Department of Biological Sciences, University of Essex, Central Campus, Wivenhoe Park, Colchester, Essex CO4 3SQ, U.K. thorp@essex.ac.uk
D002384:Catalysis; D004926:Escherichia coli / Q000201:enzymology; D005947:Glucose / Q000378:metabolism*; D006801:Humans; D007791:Lactoylglutathione Lyase / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D008958:Models, Molecular; D011110:Polymorphism, Genetic; D011487:Protein Conformation
D007791:Lactoylglutathione Lyase; D005947:Glucose