Vitamin Thioredoxin

Mammalian thioredoxin reductase is able to reduce many substances in addition to thioredoxin such as insulin, vitamin K, alloxan, and others, while Escherichia coli enzyme is a... 

Small-molecule antioxidants include glutathione, ascorbic acid (vitamin C), vitamin E and a number of dietary flavonoids. Because humans, in contrast to most other animals, are unable to synthesize vitamin C, this important antioxidant must be supplied entirely from dietary intake. Other proteins, such as thioredoxin and metallothionein, may also contribute to some extent to the cellular antioxidant pool. 

Finally the analogue of vitamin shows interesting inhibition characteristics towards thioredoxin reductase. 

Ribonucleotides are reduced to the 2 -deoxyribo-nucleotides (Eq. 16-21) that are needed for DNA synthesis by enzymes that act on either the di- or triphosphates of the purine and pyrimidine nucleosides348-351 (Chapter 25). These ribonucleotide reductases utilize either thioredoxin or glutaredoxin (Box 15-C) as the immediate hydrogen donors (Eq. 16-22). The pair of closely spaced -SH groups in the reduced thioredoxin or glutaredoxin are converted into a disulfide bridge at the same time that the 2 -OH of the ribonucleotide di- (or tri-) phosphate is converted to H20. While some organisms employ a vitamin B12-... 

Ribonucleotide reductase and the thioredoxin system. In some lactobacilli, vitamin B12 is involved in the reduction of ribonucleotide triphosphate to deoxyribonucleotide. 

These differences are correlated with differing functions. The intracellular reduced thioredoxins are thermodynamically the best reductants of disulfide linkages in proteins and they help keep intracellular proteins reduced. Glutaredoxin can be reduced efficiently by reduced glutathione or by NADPH and glutathione reductase and can, in turn, reduce cysteine and the oxidized form of vitamin C, dehydroascorbic acid (Box The peri-... 

The diaryl telluride, alkyl aryl telluride, and dialkyl telluride carrying sulfopropyl groups were prepared and were found to be the most efficient tellurium based inhibitors of thioredoxin reductase ever tested. The results clearly showed that of the four cyclic aryl alkyl chalcogenides 162-165, all primitive analogues of vitamin E, only the tellurium compound, 165, showed interesting inhibition characteristics. 

FIGURE 4.2 The vitamin K cycle as it functions in protein glutamyl carboxylation reaction. The conversion of protein-bound glutamic acid into Y-carboxyglutamic acid is catalysed by a carboxylase. During the carboxylation reaction vitamin K hydroquinone (KH2) is converted to vitamin K epoxide (KO). X—(SH)2 and X—S2 represent, respectively, the reduced and oxidised forms of thioredoxin. The NADH-dependent and dithiol-dependent vitamin K reductases are different enzymes. Both the dithiol-dependent K- and KO-reductases are inhibited by dicoumarol (1) and warfarin (11). 

E. coli mutants unable to synthesize thioredoxin are still able to form deoxyribonucleotides. In these bacteria, a related substance, glutaredoxin, and two molecules of glutathione carry out the reduction. In Lactobacillus, the triphosphate is reduced and vitamin is an essential coenzyme. Another example of this use of vitamin Bi2 is in Euglena, where the diphosphates are reduced. The mammalian system is nearly identical to that of E. coli. 

In ischemia, the endogenous free radical quenching capability of the neurons diminishes further adding to cell stress. Consequently, free radical scavengers such as extract of Ginkgo biloba (Szabo et al., 1991), a-lipoic acid (Block and Schwarz 1997), vitamin E (Celebi et al., 2002), thioredoxin (Shibuki et al., 2000), an ascorbic acid derivative (Kuriyama et al., 2001), mannitol (Gupta and Marmor, 1993), and the iron chelator desferrioxamine (Ophir et al., 1994) have all been shown to be neuroprotective in ischemia-reperfusion injury. 

The redox state of a cell is mediated by the ratios of reduced and oxidized pyridine nucleotides (NADH/NAD/NADPH/NADP) and thiols such as reduced and oxidized GSH (GSH/GSSG) and thioredoxin/thior-edoxin disulphide. In addition, anti-oxidants such as vitamin E (tocopherol) and ascorbate (vitamin C) can reduce ROS non-enzymatically. 

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... 

RecycHng of ascorbic acid from its oxidised forms is required to maintain intracellular stores of the vitamin in most cells. Since the ubiquitous sele-noenzyme thioredoxin reductase can recycle dehydroascorbic acid to ascorbate. May et al. (1998) presented evidence that mammalian thioredoxin can catalyse a one-electron reduction of the ascorbyi free radical to ascorbate, using NADPH as the electron donor. 

Nishinaka Y, Masutani H, Oka S, Matsuo Y, Yamaguchi Y, Nishio K, Ishii Y, Yodoi J. 2004a. Importin alphal (Rchl) mediates nuclear translocation of thioredoxin-binding pro-tein-2/vitamin D(3)-up-regulated protein 1. J Biol Chem 279 37559-37565. 

Nishinaka Y, Nishiyama A, Masutani H, Oka S, Ahsan KM, NakayamaY, Ishii Y, Nakamura H, Maeda M, Yodoi J. 2004b. Loss of thioredoxin-binding protein-2/vitamin D3 up-reg-ulated protein 1 in human T-cell leukemia virus type I-dependent T-cell transformation Implications for adult T-cell leukemia leukemogenesis. Cancer Res 64 1287-1292. 

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