Thioredoxin functions

SH)2 (with opening and relaxation of the 14-membered polypeptide ring.) As a reductant, thioredoxin functions as an electron transport protein between NADPH and the reduction of ribonucleotides to deoxyribonucleotides, as a general catalyst for the reduction of protein disulphides, in other reductive processes and in the regulation of the hormonal response . ... 

Nishiyama A, Matsui M, Iwata S, Hirota K, Masutani H, Nakamura H, Takagi Y, Sono H, Gon Y, Yodoi J. Identification of thioredoxin-bindlng protein-2/vitamin D3 up-regulated protein 1 as a negative regulator of thioredoxin function and expression. J Biol Chem 1999 274 21645-21650. 

A dithiol protein, thioredoxin, functions in the transport of electrons from reduced nicotinamide adoiine dinucleotide phosphate (NADPH) to ribonucleotides in the biosynthesis of 2 -deoxyribonucleotides. A thioredoxin type carrier is involved in both vitamin dependent and independent type systems. Thioredoxin is frequently described as a polypeptide cofactor rather than an enzyme because its activity is not destroyed... 

There are other substrates for the E. coli Met(0) peptide reductase, one of which is Met(0)-a-l-PI. The native protein is the major serum elastase inhibitor that functions by forming a binary complex with elastase which inhibits its activity. Met(0)-a-l-PI, on the other hand, which can be formed by treatment of the protein with TV-chlorosuccinimide, cannot form a complex with elastase and therefore is not able to inhibit elastase activity117,118. Table 6 shows, however, that when Met(0)-a-l-PI is incubated in the presence of Met(0)-peptide reductase and dithiothreitol the protein regains its ability to form a complex with elastase and inhibit elastase activity119. Similar to results found with Met(0)-L12 reduced thioredoxin could replace the dithiothreitol as reductant in the enzymatic reaction. 

PiaRigobello, M., Messori, L., Marcon, G., Cinellu, M.A., Bragadin, M., Folda, A., Scutari, G. and Bindoli, A. (2004) Gold complexes inhibit mitochondrial thioredoxin reductase consequences on mitochondrial functions. Journal of Inorganic Biochemistry, 98, 1634—1641. 

N. Brot, H. Fliss and H. Weissbach, in Thioredoxin and Glutaredoxin Systems Structure and Function (Ed. A. Holmgren, C.-I. Branden, H. Jbrnvall and B.-M. Sjoberg), Raven Press, New York, 1986, pp. 141-153. 

In addition to its role as the P-subunit of PHY, PDI acts independently by catalysing thiol/protein disulphide interchange. The role of PDI as the P-subunit in prolyl 4-hydroxylase is not related to its disulphide isomerase activity and experiments where the vertebrate PDI was mutated in both thioredoxin-like active domains had no effect on tetramer assembly (Vuori et al., 1992). PDI appears to function as a molecular chaperone, retaining the a-subunits in the correct catalytically active, non-aggregated form in the ER-lumen (John et al, 1993). Dissociation of the P-subunits results in insoluble aggregates of the a-subunits, analogous to a-subunits expressed in the absence of PDI. An additional function of PDI in the complex is to maintain the ER luminal location of the a-subunits, since deletion of the ER retention signal from PDI results in the secretion of the complex (Vuori et al., 1992). 

Mammalian thioredoxin reductases are a family of selenium-containing pyridine nucleotide-disulfide oxidoreductases. These enzymes catalyze NADPH-dependent reduction of the redox protein thioredoxin (Trx), which contains a redox-active disulfide and dithiol group and by itself may function as an efficient cytosolic antioxidant [77]. One of the functions of Trx/ thioredoxin reductase system is the NADPH-catalyzed reduction of protein disulfide [78] ... 

Regeneration of reduced thioredoxin Thioredoxin must be converted back to its reduced form in order to continue to perform its function. The necessary reducing equivalents are provided by NADPH + H+, and the reaction is catalyzed by thioredoxin reductase (see Figure 22.12). 

However, the two proteins have significantly different specificities and functions. The disulfide loop in glutaredoxin, whose eukaryotic forms are often called thioltransferases/ has the sequence CPYC. Although glutaredoxins are weaker reductants of mixed disulfides of proteins with glutathione than are thioredoxins/1 sthey are more specific. 

A recently discovered human selenoprotein is a thioredoxin reductase which is present in the T cells of the immune system as well as in placenta and other tissues.189 547-549 The 55-kDa protein has one selenocysteine as the penultimate C-terminal residue. Another mammalian selenoprotein, of uncertain function, is the 57-kDa selenoprotein P. It contains over 60% of the... 

Lu, Z., Murray, K. S., Van Cleave, V., LaVallie, E. R., Stahl, M. L., and McCoy, J. M. (1995) Expression of thioredoxin random peptide libraries on the Escherichia coli cell surface as functional fusions to flagellin a system designed for exploring protein-protein interactions. Biotechnology 13, 366-372. 

Recently, active recombinant a-LTX has been generated using bacteria in which both thioredoxin reductase and glutathione reductase are inactivated to improve the formation of disulphide bonds in expressed proteins (Li et al. 2005). The toxin is expressed as a fusion with glutathione-S-transferase (GST), which is used for affinity purification of the recombinant toxin and can be subsequently removed by selective proteolysis. Considering the relative ease of generating recombinant proteins in bacteria, this approach will facilitate structure-function studies of a-LTX. 

Fernandes, A.P., and Holmgren, A. 2004. Glutaredoxins glutathione-dependent redox enzymes with functions far beyond a simple thioredoxin backup system. Antioxid. Redox Signal. 6 63-74. 

Zhou, J., Damdimopoulos, A.E., Spyrou, G., and Brune, B. 2007. Thioredoxin 1 and thioredoxin 2 have opposed regulatory functions on hypoxia inducible factor-lalpha. J. Biol. Chem. 282 7482-7490. 

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