User:Sarah Abdalla/Thioredoxin Reductase: Difference between revisions

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== '''Thioredoxin Reductase''' ==

Thioredoxin reductase (TR) is a 55 kDa enzyme that belongs to the family of pyridine nucleotide disulfide oxidoreductases <ref>PMID: 11481439</ref>. Also included in this family are lipoamide dehydrogenases and glutathione reductases, with which TRs share 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 the catalytic activity of both enzymes <ref>PMID: 10801974</ref>. Compared with gluthathione reductases, TRs are unique in that they contain a 16 amino acid C-terminal extension which mediates the catalytic activity of the enzyme <ref>PMID: 17661444</ref>. 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 ~~<scene name='User:Sarah_Abdalla/Thioredoxin_Reductase/Residue498_edited/1'>~~selenocysteine~~</scene>~~ at this site <ref>PMID: 11481439</ref>. TR from ''Drosophila melanogaster'' falls under this category and has a vicinal cysteine dyad in the redox center. Mammalian TR is known for having decreased catalytic activity upon replacement of the selenocysteine residue with cysteine <ref>PMID: 17385893</ref>. This aspect together with other findings not mentioned here suggests that selenocysteine plays a special role in the enzyme. For this reason, the role of selenocysteine in TR is controversial considering that cysteine is the functional residue in other forms of the enzyme.

Thioredoxin reductase (TR) is a 55 kDa enzyme that belongs to the family of pyridine nucleotide disulfide oxidoreductases <ref>PMID: 11481439</ref>. Also included in this family are lipoamide dehydrogenases and glutathione reductases, with which TRs share 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 the catalytic activity of both enzymes <ref>PMID: 10801974</ref>. Compared with gluthathione reductases, TRs are unique in that they contain a 16 amino acid C-terminal extension which mediates the catalytic activity of the enzyme <ref>PMID: 17661444</ref>. 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 at this site <ref>PMID: 11481439</ref>. TR from ''Drosophila melanogaster'' falls under this category and has a vicinal cysteine dyad in the redox center. Mammalian TR is known for having decreased catalytic activity upon replacement of the selenocysteine residue with cysteine <ref>PMID: 17385893</ref>. This aspect together with other findings not mentioned here suggests that selenocysteine plays a special role in the enzyme. For this reason, the role of selenocysteine in TR is controversial considering that cysteine is the functional residue in other forms of the enzyme.

===Structure===

The functional unit of TR is a <scene name='User:Sarah_Abdalla/Thioredoxin_Reductase/Homodimer/2'>homodimer</scene>, typical of proteins in the family of glutathione reductases, with each subunit composed of mainly <scene name='User:Sarah_Abdalla/Thioredoxin_Reductase/Single_subunit/3'>alpha helices</scene> (yellow) and <scene name='User:Sarah_Abdalla/Thioredoxin_Reductase/Single_subunit/3'>beta sheets</scene> (blue). Each monomer is exhibits a three domain modular architecture, containing a NADP binding domain, a N-terminal FAD binding domain, and an interface domain. Both the <scene name='User:Sarah_Abdalla/Thioredoxin_Reductase/Fad_domain/1'>FAD and NADP </scene> 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 <scene name='User:Sarah_Abdalla/Thioredoxin_Reductase/Active_site/1'>active site</scene> of the enzyme is located at the interface domain formed by two subunits, deeming the physiological significance of the dimeric form of the enzyme. This domain is composed of a five stranded β sheet flanked on either side by two helices. The C- terminal extension of TR runs parallel 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 <ref>PMID: 11481439</ref>.

The functional unit of TR is a <scene name='User:Sarah_Abdalla/Thioredoxin_Reductase/Homodimer/2'>homodimer</scene>, typical of proteins in the family of glutathione reductases, with each subunit composed of mainly <scene name='User:Sarah_Abdalla/Thioredoxin_Reductase/Single_subunit/3'>alpha helices</scene> (yellow) and <scene name='User:Sarah_Abdalla/Thioredoxin_Reductase/Single_subunit/3'>beta sheets</scene> (blue). 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 <scene name='User:Sarah_Abdalla/Thioredoxin_Reductase/Fad_domain/1'>FAD and NADP </scene> 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 <scene name='User:Sarah_Abdalla/Thioredoxin_Reductase/Active_site/1'>active site</scene> of the enzyme is located at the interface domain formed by two subunits, deeming the physiological significance of the dimeric form of the enzyme. This domain is composed of a five stranded β sheet flanked on either side by two helices. The C- terminal extension of TR runs parallel 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 <ref>PMID: 11481439</ref>.

===Function and Mechanism===

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 == '''Thioredoxin Reductase''' ==
-Thioredoxin reductase (TR) is a 55 kDa enzyme that belongs to the family of pyridine nucleotide disulfide oxidoreductases <ref>PMID: 11481439</ref>.  Also included in this family are lipoamide dehydrogenases and glutathione reductases, with which TRs share 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 the catalytic activity of both enzymes <ref>PMID: 10801974</ref>.  Compared with gluthathione reductases, TRs are unique in that they contain a 16 amino acid C-terminal extension which mediates the catalytic activity of the enzyme <ref>PMID: 17661444</ref>.  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 <scene name='User:Sarah_Abdalla/Thioredoxin_Reductase/Residue498_edited/1'>selenocysteine</scene> at this site <ref>PMID: 11481439</ref>.  TR from ''Drosophila melanogaster'' falls under this category and has a vicinal cysteine dyad in the redox center.  Mammalian TR is known for having decreased catalytic activity upon replacement of the selenocysteine residue with cysteine <ref>PMID: 17385893</ref>.  This aspect together with other findings not mentioned here suggests that selenocysteine plays a special role in the enzyme.  For this reason, the role of selenocysteine in TR is controversial considering that cysteine is the functional residue in other forms of the enzyme.
+Thioredoxin reductase (TR) is a 55 kDa enzyme that belongs to the family of pyridine nucleotide disulfide oxidoreductases <ref>PMID: 11481439</ref>.  Also included in this family are lipoamide dehydrogenases and glutathione reductases, with which TRs share 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 the catalytic activity of both enzymes <ref>PMID: 10801974</ref>.  Compared with gluthathione reductases, TRs are unique in that they contain a 16 amino acid C-terminal extension which mediates the catalytic activity of the enzyme <ref>PMID: 17661444</ref>.  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 at this site <ref>PMID: 11481439</ref>.  TR from ''Drosophila melanogaster'' falls under this category and has a vicinal cysteine dyad in the redox center.  Mammalian TR is known for having decreased catalytic activity upon replacement of the selenocysteine residue with cysteine <ref>PMID: 17385893</ref>.  This aspect together with other findings not mentioned here suggests that selenocysteine plays a special role in the enzyme.  For this reason, the role of selenocysteine in TR is controversial considering that cysteine is the functional residue in other forms of the enzyme.
 ===Structure===
-The functional unit of TR is a <scene name='User:Sarah_Abdalla/Thioredoxin_Reductase/Homodimer/2'>homodimer</scene>, typical of proteins in the family of glutathione reductases, with each subunit composed of mainly <scene name='User:Sarah_Abdalla/Thioredoxin_Reductase/Single_subunit/3'>alpha helices</scene> (yellow) and <scene name='User:Sarah_Abdalla/Thioredoxin_Reductase/Single_subunit/3'>beta sheets</scene> (blue).  Each monomer is exhibits a three domain modular architecture, containing a NADP binding domain, a N-terminal FAD binding domain, and an interface domain. Both the <scene name='User:Sarah_Abdalla/Thioredoxin_Reductase/Fad_domain/1'>FAD and NADP </scene> 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 <scene name='User:Sarah_Abdalla/Thioredoxin_Reductase/Active_site/1'>active site</scene> of the enzyme is located at the interface domain formed by two subunits, deeming the physiological significance of the dimeric form of the enzyme.  This domain is composed of a five stranded β sheet flanked on either side by two helices.  The C- terminal extension of TR runs parallel 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 <ref>PMID: 11481439</ref>.
+The functional unit of TR is a <scene name='User:Sarah_Abdalla/Thioredoxin_Reductase/Homodimer/2'>homodimer</scene>, typical of proteins in the family of glutathione reductases, with each subunit composed of mainly <scene name='User:Sarah_Abdalla/Thioredoxin_Reductase/Single_subunit/3'>alpha helices</scene> (yellow) and <scene name='User:Sarah_Abdalla/Thioredoxin_Reductase/Single_subunit/3'>beta sheets</scene> (blue).  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 <scene name='User:Sarah_Abdalla/Thioredoxin_Reductase/Fad_domain/1'>FAD and NADP </scene> 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 <scene name='User:Sarah_Abdalla/Thioredoxin_Reductase/Active_site/1'>active site</scene> of the enzyme is located at the interface domain formed by two subunits, deeming the physiological significance of the dimeric form of the enzyme.  This domain is composed of a five stranded β sheet flanked on either side by two helices.  The C- terminal extension of TR runs parallel 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 <ref>PMID: 11481439</ref>.
 ===Function and Mechanism===