Thioredoxin reductase and

An additional topic for anticancer research involving organotellnrium compounds was thioredoxin reductase. Since in several human cancers thioredoxin expression is increased, several organotellurium compounds have been tested. 4,4 -Disubstituted dior-ganyl tellurides have been shown to be effective inhibitors of thioredoxin reductase and also to inhibit the growth of human cells in culture. ... 

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. 

Thioredoxin is used by ribonucleotide reductase as reducing agent to reduce such diphosphonucleotides as ADP and UDP. NADPH is a substrate for thioredoxin reductase, and GTP is not used at all. 

Thioredoxin was shown to reduce the two interchain disulfides of insulin very efficiently around neutral pH and in the presence of either thioredoxin reductase and NADPH or lipoamide, lipoamide dehydrogenase and NADH [277,278], This reduction may be important in hormone action since the reduction of insulin disulfides is a prerequisite of proteolytic degradation of insulin. Thioredoxin has also been identified as the endogenous activator of the rat glucocorticoid receptor to a steroid-binding state [279]. Finally, recent data suggest that thioredoxin is secreted by immunocompetent cells and then behaves as an autocrine growth factor [280]. 

In this section on mechanism and in the section to follow on structure, the comparisons will show that the relationship between lipoamide dehydrogenase and glutathione reductase is more marked than is the relationship of either to thioredoxin reductase. Thus, in catalysis, lipoamide dehydrogenase and glutathione reductase cycle between the oxidized state and a spectrally characteristic state in which the enzyme has accepted two electrons and these are shared between the FAD and the active center disulfide. This intermediate does not seem to be operative in thioredoxin reductase, and in this enzyme the FAD and disulfide interact in a different way. The oxidized forms of these enzsrmes can then be represented as... 

Chloroethanol, catalase and, 401 p-Chloromercuriphenyl sulfonate glutathione reductase and, 141 small NADH dehydrogenase and, 203 thioredoxin reductase and, 146 ubiquinone reductase and, 197 Chloroplasts, transhydrogenase of, 66 Chlorosuccinate, succinate dehydrogenase and, 237-238 Cholate... 

D-lactate dehydrogenase and, 271 lipoamide dehydrogenase and, 126 NADH dehydrogenase and, 206 succinate dehydrogenase and, 247 thioredoxin reductase and, 147, 148 Ethyl hydrogen peroxide, catalase and, 391-392, 395 iV-Ethylmaleimide c> tochrome b, reductase and, 163,... 

Glutathione reductase, thioredoxin reductase, and lipoamide dehydrogenase are members of a group of flavoproteins that contain an active site disulfide as well as FAD. They catalyze the NAD(P)H dependent reduction of a disulfide... 

Telluranthrene 158 and compound 159 demonstrated bacterial cytotoxicity and a capacity to induce apoptotic cell death in eukaryotic HL-60 cells. The EC50 values for telluranthrene 158 and diphenyl ditelluride 160 were 196 and 33 pM, respectively. The series of organotellurium compounds 142, 144, 151, and 161 function as selective inhibitors of thioredoxin reductase and have potential antitumor effects. They were good noncompetitive inhibitors of thioredoxin reductase. 

Little is known about the specific biochemical mechanism(s) by which selenium and selenium compounds exert their acute toxic effects. Long-term effects on the hair, skin, nails, liver, and nervous system are also well documented, and a general theory has been developed to explain the toxicity of exposure to excess selenium, as discussed below. Generally, water-soluble forms are more easily absorbed and are generally of greater acute toxicity. Mechanisms of absorption and distribution for dermal and pulmonary uptake are unknown and subject to speculation, but an active transport mechanism for selenomethionine absorption in the intestine has been described (Spencer and Blau 1962). The mechanisms by which selenium exerts positive effects as a component of glutathione peroxidase, thioredoxin reductase, and the iodothyronine 5 -deiodinases are better understood, but the roles of other selenium-containing proteins in mammalian metabolism have not been clarified. 

Powis, G University of Arizona Thioredoxin reductases and cancer CRISP 2001... 

C. H. Williams, Jr., Lipoamide Dehydrogenase, Glutathione Reductase, Thioredoxin Reductase, and Mercuric Reductase - A Family of Flavoenzyme Transhydrogenases. In Chemistry and Biochemistry of Fiavoenzymes F. Muller, Ed. CRC Press Boca Raton, 1992 Vol. III. 

FIGURE 23.31 Conversion of ribonucleoside diphosphates to deoxyribonucleoside diphosphates, (a) The (—S—S—) / (—SH HS—) oxidation-reduction cycle involving ribonucleotide reductase, thioredoxin, thioredoxin reductase, and NADPH. (b) The structures of NDP and dNDP. 

Knapp KG, Swartz JR (2004) Cell-free production of active E. coli thioredoxin reductase and glutathione reductase. EEBS Lett 559 66-70... 

Corn leaf NADP- malate dehydrogenase (NADP- MDH), spinach ferredoxin, ferredoxin thioredoxin reductase and thioredoxin m were purified to homogeneity as described earlier (1). Pig ad enal ferredoxin was prepared as in (1). Human lymphocyte thioredoxin was cloned, overexpressed and purified from E coli as described in (2). 

Spinach ferredoxin, thioredoxin m, ferredoxin-thioredoxin-reductase and com NADP-MDH were purified as previously described (4). Light activation of NADP-MDH, labeling of thiols and purification of the labeled protein... 

---