Structural relationship between glutathione reductase and lipoamide dehydrogenase.
The elucidation of the primary structure of the Escherichia coli lipoamide dehydrogenase (EC 1.8.1.4) by sequencing the corresponding structural gene (lpd) has enabled a detailed structural comparison between lipoamide dehydrogenase and the related disulphide oxido-reductase, human erythrocyte glutathione reductase (EC 1.6.4.2). Some 28% of the amino acid residues were found to be identical and a striking degree of homology was apparent throughout the polypeptide chains. It was concluded that the two enzymes possess very similar three-dimensional structures with particularly strong conservation of residues around the FAD and NAD(P) binding sites and at the redox centres of the molecules. Significant amino acid substitutions occur in the substrate binding pocket and these include an extra 18 amino acid residues at the C terminus of lipoamide dehydrogenase. Under physiological conditions, lipoamide dehydrogenase and glutathione reductase act in opposite directions, passing reducing equivalents to NAD+ or from NADPH (respectively), and two key substitutions near the redox centre could be associated with this difference in function. This study represents the first direct structural comparison between two related enzymes that are NADP+-linked (glutathione reductase) and NAD+-linked (lipoamide dehydrogenase). The differential recognition of these two cofactors could be explained in terms of amino acid substitutions. A divergent evolutionary relationship between the two enzymes including their NAD and NADP binding domains is fully supported by this analysis.
D000595:Amino Acid Sequence; D001665:Binding Sites; D002384:Catalysis; D008058:Dihydrolipoamide Dehydrogenase; D005182:Flavin-Adenine Dinucleotide; D005980:Glutathione Reductase; D008958:Models, Molecular; D009243:NAD; D009249:NADP; D011485:Protein Binding; D011487:Protein Conformation
D009243:NAD; D005182:Flavin-Adenine Dinucleotide; D009249:NADP; D008058:Dihydrolipoamide Dehydrogenase; D005980:Glutathione Reductase