Convergent evolution of similar function in two structurally divergent enzymes.
An example of two related enzymes that catalyse similar reactions but possess different active sites is provided by comparing the structure of Escherichia coli thioredoxin reductase with glutathione reductase. Both are dimeric enzymes that catalyse the reduction of disulphides by pyridine nucleotides through an enzyme disulphide and a flavin. Human glutathione reductase contains four structural domains within each molecule: the flavin-adenine dinucleotide (FAD)- and nicotinamide-adenine dinucleotide phosphate (NADPH)-binding domains, the 'central' domain and the C-terminal domain that provides the dimer interface and part of the active site. Although both enzymes share the same catalytic mechanism and similar tertiary structures, their active sites do not resemble each other. We have determined the crystal structure of E. coli thioredoxin reductase at 2 A resolution, and show that thioredoxin reductase lacks the domain that provides the dimer interface in glutathione reductase, and forms a completely different dimeric structure. The catalytically active disulphides are located in different domains on opposite sides of the flavin ring system. This suggests that these enzymes diverged from an ancestral nucleotide-binding protein and acquired their disulphide reductase activities independently.
Kuriyan
J
J
Rockefeller University, New York 10021.
Krishna
T S
TS
Wong
L
L
Guenther
B
B
Pahler
A
A
Williams
C H
CH
Model
P
P
D000595:Amino Acid Sequence; D001665:Binding Sites; D005075:Biological Evolution; D003460:Crystallization; D004220:Disulfides / Q000737:chemistry; D004926:Escherichia coli / Q000201:enzymology*; D005182:Flavin-Adenine Dinucleotide / Q000378:metabolism; D005980:Glutathione Reductase / Q000737:chemistry*; D046911:Macromolecular Substances; D008969:Molecular Sequence Data; D009249:NADP / Q000378:metabolism; D011487:Protein Conformation; D012689:Sequence Homology, Nucleic Acid; D013880:Thioredoxin-Disulfide Reductase / Q000737:chemistry*
D004220:Disulfides; D046911:Macromolecular Substances; D005182:Flavin-Adenine Dinucleotide; D009249:NADP; D005980:Glutathione Reductase; D013880:Thioredoxin-Disulfide Reductase