User:Sarah Abdalla/Thioredoxin Reductase: Difference between revisions
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Thioredoxin reductase is a | '''General Description''' | ||
Thioredoxin reductase (TR)<applet load='1h6v' size='300' frame='true' align='right' caption='Insert caption here' /> is a 55 kDa enzyme that belongs to the family of pyridine nucleotide disulfide oxidoreductases. Also included in this family are glutathione reductases, with which TRs have high homology. TR is ubiquitous from humans to archaea, however TR from higher eukaryotes is distinct from its prokaryotic counterpart and is thought to have evolved from gluthathione reductases due to similarities in catalytic activity of both enzymes. TRs are unique from GRs in that they contain a 16 amino acid C-terminal extension. Mammalian TRs fall into the class of selenium containing enzymes due to the presence of its penultimate selenocysteine residue that has been shown to be essential for reduction of its cognate substrate, thioredoxin. The C-terminal redox center (which contains the selenocysteine residue) is notable because a number of high molecular weight TRs contain cysteine in place of selenocysteine. TR from Drosophila melanogaster falls under this category and has a vicinal cysteine dyad in the redox center. A large decrease in the catalytic activity of mammalian TRs upon replacement of the selenocysteine residue with cysteine has been reported in the literature. This result together with others not mentioned here suggests that selenocysteine plays a special role and has lead to controversies in the role of the amino acid when cysteine is the functional residue in other forms of the enzyme. | |||
'''Structure''' | |||
The functional unit of TR is a homodimer, typical of proteins in the family of glutathione reductases. Each monomer exhibits a three domain modular architecture, containing a NADP binding domain, a N-terminal FAD binding domain, and an interface domain. Both the FAD and NADP binding domains have similar folds, and are variants of the Rossman fold, characterized by a β sheet linked by several alpha helices which in the enzyme is composed of 5 strands surrounded by helices. The two domains are positioned in a head to tail orientation allowing for electron transfer that leads to the reduction of the enzyme’s redox active center. The active site of the enzyme is located at the interface domain formed by two subunits, deeming the physiological significance of the dimeric form. This domain is composed of a five stranded β sheet flanked on either side by two helices. | |||
A unique feature of mammalian TR, distinguishing the enzyme from GR, is the C-terminal extension containing the essential selenocysteine residue that is part of the characteristic Gly-Cys-SeCys-Gly motif. This region runs antiparallel to the edge of the β sheet strand at the interface domain, with the last residues of the extension forming an arm that protrudes into the interface domain, allowing for interaction with groups at the active site interface which is located at the N-terminus. | |||
<applet load='1h6v' size='300' frame='true' align='right' caption='Insert caption here' /> | |||
Revision as of 06:19, 15 April 2009
General Description
Thioredoxin reductase (TR)
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is a 55 kDa enzyme that belongs to the family of pyridine nucleotide disulfide oxidoreductases. Also included in this family are glutathione reductases, with which TRs have high homology. TR is ubiquitous from humans to archaea, however TR from higher eukaryotes is distinct from its prokaryotic counterpart and is thought to have evolved from gluthathione reductases due to similarities in catalytic activity of both enzymes. TRs are unique from GRs in that they contain a 16 amino acid C-terminal extension. Mammalian TRs fall into the class of selenium containing enzymes due to the presence of its penultimate selenocysteine residue that has been shown to be essential for reduction of its cognate substrate, thioredoxin. The C-terminal redox center (which contains the selenocysteine residue) is notable because a number of high molecular weight TRs contain cysteine in place of selenocysteine. TR from Drosophila melanogaster falls under this category and has a vicinal cysteine dyad in the redox center. A large decrease in the catalytic activity of mammalian TRs upon replacement of the selenocysteine residue with cysteine has been reported in the literature. This result together with others not mentioned here suggests that selenocysteine plays a special role and has lead to controversies in the role of the amino acid when cysteine is the functional residue in other forms of the enzyme.
Structure
The functional unit of TR is a homodimer, typical of proteins in the family of glutathione reductases. Each monomer exhibits a three domain modular architecture, containing a NADP binding domain, a N-terminal FAD binding domain, and an interface domain. Both the FAD and NADP binding domains have similar folds, and are variants of the Rossman fold, characterized by a β sheet linked by several alpha helices which in the enzyme is composed of 5 strands surrounded by helices. The two domains are positioned in a head to tail orientation allowing for electron transfer that leads to the reduction of the enzyme’s redox active center. The active site of the enzyme is located at the interface domain formed by two subunits, deeming the physiological significance of the dimeric form. This domain is composed of a five stranded β sheet flanked on either side by two helices.
A unique feature of mammalian TR, distinguishing the enzyme from GR, is the C-terminal extension containing the essential selenocysteine residue that is part of the characteristic Gly-Cys-SeCys-Gly motif. This region runs antiparallel to the edge of the β sheet strand at the interface domain, with the last residues of the extension forming an arm that protrudes into the interface domain, allowing for interaction with groups at the active site interface which is located at the N-terminus.
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