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Convergent evolution of similar function in two structurally divergent enzymes
J Kuriyan1, T S Krishna, L Wong
1Rockefeller University, New York 10021.
Nature
|July 11, 1991
Summary
Comparing Escherichia coli thioredoxin reductase and human glutathione reductase reveals distinct active site structures despite similar catalytic functions. This structural divergence suggests independent evolution of their disulfide reductase activities from a common ancestor.
Area of Science:
- Enzymology
- Structural Biology
- Biochemistry
Background:
- Thioredoxin reductase and glutathione reductase are dimeric enzymes catalyzing disulfide reduction via pyridine nucleotides, flavin, and an enzyme disulfide.
- Human glutathione reductase possesses four distinct structural domains, including FAD- and NADPH-binding domains, a central domain, and a C-terminal domain crucial for dimerization and active site formation.
- Despite sharing catalytic mechanisms and overall tertiary structures, these enzymes exhibit significant differences in their active site configurations.
Purpose of the Study:
- To elucidate the structural basis for the differences in active sites between Escherichia coli thioredoxin reductase and human glutathione reductase.
- To compare the quaternary structure and domain organization of E. coli thioredoxin reductase with that of human glutathione reductase.
Main Methods:
- Determination of the crystal structure of E. coli thioredoxin reductase at 2 Angstrom resolution.
- Comparative structural analysis of E. coli thioredoxin reductase and human glutathione reductase.
Main Results:
- The crystal structure reveals that E. coli thioredoxin reductase lacks the C-terminal domain present in human glutathione reductase, which forms the dimer interface.
- E. coli thioredoxin reductase forms a distinct dimeric structure compared to human glutathione reductase.
- The catalytically essential disulfide groups are situated in different domains and are positioned on opposite sides of the flavin ring system in the two enzymes.
Conclusions:
- The structural differences, particularly in domain composition and active site arrangement, indicate that E. coli thioredoxin reductase and human glutathione reductase have evolved distinct mechanisms for disulfide reduction.
- These findings support the hypothesis that these enzymes diverged from an ancestral nucleotide-binding protein and independently acquired their respective disulfide reductase functions.