Thioredoxin nature

Figure 6.8 Schematic diagram of the enzyme DsbA which catalyzes disulfide bond formation and rearrangement. The enzyme is folded into two domains, one domain comprising five a helices (green) and a second domain which has a structure similar to the disulfide-containing redox protein thioredoxin (violet). The N-terminal extension (blue) is not present in thioredoxin. (Adapted from J.L. Martin et al.. Nature 365 464-468, 1993.)...

Arsenic trioxide is a chemotheraputic agent used to treat leukemia that is unresponsive to first line agents. It is suspected that arsenic trioxide induces cancer cells to undergo apoptosis. The enzyme thioredoxin reductase has recently been identified as a target for arsenic trioxide. Due to the toxic nature of arsenic, this drug carries signihcant risks. 

Fig. 11.1. Multiple sequence alignment of the deduced amino acid sequence of thioredoxin peroxidase 1 (Peroxiredoxin 2, TSA, natural killer cell enhancing factor B) from the snail host B. glabrata clone BgTPx (GenBank Accession AAK26236), the parasites S. mansoni (GenBank Accession ...

Thus, Nature has integrated thiol/disulfide exchange reactions in the regulation of its metabolic and antioxidant networks. The potentially cytotoxic effects of protein S-thiolation will remain controversial until the relationship between the systems of glutathione reductase, thioredoxin, glutaredoxin and thioltransferase are better understood. 

The lack of reactivity of the semiquinone per se with either thioredoxin or NADPH shows that it cannot be involved in catalysis. The rapid production of semiquinone by irradiation of partially reduced enzyme is a light-activated disproportionation since it is totally dependent upon the presence of some oxidized enzyme. Enzyme fully reduced by dithionite forms no semiquinone, while enzyme partially reduced by dithionite rapidly forms semiquinone upon irradiation. Furthermore, the light-activated disproportionation of enzyme first reduced with NADPH results in the reduction of NADP. Thus, FAD catalyzes the disproportionation in keeping with the known photosensitizing nature of free flavins. This reaction is reversed slowly (half-time ca. 150 min 25°) in the dark. The semiquinone is rapidly reoxidized by oxygen to yield an enzyme with unaltered spectral and catalytic properties (58). Similar reactions have been very briefly reported for lipoamide dehydrogenase the dark reverse reaction is comparatively rapid, being complete in 30 min (16S). 

The most important recent results obtained by means of time-resolved techniques (pulse radiolysis and laser flash photolysis) on model peptides containing single or multiple Met-residues and in selected naturally occurring peptides (Met-enkephalin and amyloid peptide) and proteins (thioredoxin and calmodulin) have been recently reviewed. ... 

Selenium is an essential trace element. As an important constituent of glutathion peroxydase and thioredoxin reductase, it must be considered an extremely valuable antioxidant. The daily requirement of 75 gg is very often not achieved, especially by tumour patients, so that substitution is necessary. In addition, malignant diseases generally show a reduction in the serum value of selenium. Moreover, it intensifies the cytotoxicity of T lymphocytes and natural killer cells, leading to a corresponding effect on tumour cells. This effect can be enhanced through the stimulation of IFNy. The application of cytostatics thus becomes more favourable in every respect. A daily dose of 200 qg (-1,000 qg) selenium is recommended. Even in acute infections, i.v. administration of selenite has proved extremely useful, (s. p. 304)... 

In the present context, we are currently studying peptidomimetic polycyclic structures derived from the thioredoxin reductase active site [56,57], which consist of a domain of peptidic nature containing the sequence for the recognition and of a domain of non-peptidic nature. In the present case, this last domain is formed by an unnatural amino acid of the size (i.e. isosteric) of a bi- or tri-peptide that can undergo cis— trans photoisomerization. Such isomerization induces conformational changes in... 

The actual process, which is catalyzed by ribonucleotide reductase, is more complex than the preceding equation would indicate and involves some intermediate electron carriers. The ribonucleotide reductase system from E. coli has been extensively studied, and its mode of action gives some clues to the nature of the process. Two other proteins are required, thioredoxin and thioredoxin reductase. Thioredoxin contains a disulfide (S—S) group in its oxidized form and two sulfhydryl (—SH) groups in its reduced form. NADPH reduces thioredoxin in a reaction catalyzed by thioredoxin reductase. The reduced thioredoxin in turn reduces a ribonucleoside diphosphate (NDP) to a deoxyribonucleoside diphosphate (dNDP), shown in Figure 23.31b, and this reaction is actually catalyzed by ribonucleotide reductase. Note that this reaction produces dADP, dGDP, dCDP, and dUDP. The first three are phosphorylated to... 

Wiita AP, Perez-Jimenez R, Walther KA, Grater F, Berne BJ, Holmgren A, Sanchez-Ruiz JM, Fernandez JM (2007) Probing the chtanistry of thioredoxin catalysis with force. Nature 450 124-127... 

Fig. 2. Superposition of PfPDO N and C units. The active site disulfides are shown in ball-and-stick representation. The secondary structure elements belonging to the thioredoxin fold are mimbeied with Roman numerals. Adapted om B. Ren, G. Tibbelin, D. de Pascale, M. Rossi, S. Baitolucci, and R. Ladenstein, Nature Struct. Biol. 5,602 (1998).

Results of experiments using the stromal fraction of isolated spinach chloroplasts are presented. Incubation of a stroma extract with DTT in the absence of O2 allows to estimate the maximum rate of reductive activation with the natural amounts of the respective thioredoxins. The effect of metabolites on the rate of activation of some enzymes is summarized in Fig. 3. The types of regulatory strategy pertinent for the individual chloroplast enzymes can be stated as follows ... 

Wiita AP et al (2007) Probing the chemistry of thioredoxin catalysis with force. Nature 450 124-127... 

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