Departments of Molecular Biology and Biochemistry, Uppsala University, Biomedical Center, Box 590, S-751 24 Uppsala, Sweden
The zinc metalloenzyme, glyoxalase I catalyses the glutathione dependent inactivation of toxic methylglyoxal. We have solved the structure of the dimeric human enzyme by MIR and refined it at a resolution of 2.2Å. The structure does not display any homology with the glutathione-binding domain found in all other glutathione-linked proteins. Instead each monomer is built of two very similar domains that appear to have arisen by gene duplication. 'Domain swapping' of the N and C-terminal domains has resulted in the active site being situated at the dimer interface with the inhibitor and essential zinc ion interacting with both subunits. Two structurally equivalent residues from each domain contribute to a square pyramidal coordination of the zinc, rarely seen in zinc enzymes. Comparison of glyoxalase I with other known structures shows the enzyme to belong to a new strucural family which includes the Fe2+ dependent biphenyl-cleaving extradiol dioxygenase and the bleomycin resistance protein. This family appears to allow members to form with or without domain swapping.