Disease relevance of dhd

• Using recombinant proteins expressed in Escherichia coli, we demonstrated the activity of the Trx domain of TMX to cleave the interchain disulfide bridges in insulin in vitro [1].

High impact information on dhd

• Active sites of thioredoxin reductases: why selenoproteins [2]?
• Thioredoxin reductase has an N-terminal redox-active disulfide (Cys57-Cys62) adjacent to the flavin and a redox-active C-terminal cysteine pair (Cys489'-Cys490' in the other subunit) that transfer electrons from Cys57-Cys62 to the substrate thioredoxin [3].
• Recombinant thioredoxin peroxidase-1 (subunit molecular mass = 23 kDa) was found to be a decameric protein that can efficiently use Trx-2 but not Trx-1 as a reducing substrate [4].
• As Drosophila melanogaster does not contain glutathione reductase, the thioredoxin system has a key function for glutathione disulfide reduction in insects (Kanzok, S. M., Fechner, A., Bauer, H., Ulschmid, J. K., Müller, H. M., Botella-Munoz, J., Schneuwly, S., Schirmer, R. H., and Becker, K. (2001) Science 291, 643-646) [4].
• They transfer reducing equivalents from NADPH to thioredoxin (Trx) and glutathione disulfide (GSSG), respectively, resulting in Trx(SH)(2) and glutathione (GSH), which act as effective intracellular antioxidants [5].

Biological context of dhd

• TrxT and dhd are arranged as a gene pair, transcribed in opposite directions and sharing a 471 bp regulatory region [6].
• The phenotypic analysis of two different mutations which eliminate function suggests that dhd is essential for female meiosis [7].
• In most living cells, redox homeostasis is based both on the glutathione and the thioredoxin system [8].
• Thioredoxin peroxidases can foster cytoprotection or cell death in response to different stressors: over- and under-expression of thioredoxin peroxidase in Drosophila cells [9].
• In Drosophila, the maternal-effect gene deadhead encodes a thioredoxin-like protein that is required for initiation of embryonic development [10].

Anatomical context of dhd

• Among the five ICs in Ciona, three are orthologs of those in sea urchin dynein: two are WD-repeat proteins and the third one, unique to metazoan sperm flagella, contains both thioredoxin and nucleoside diphosphate kinase modules [11].
• Although bPDI shows a relatively low amino acid homology with other PDIs, in which both sites of the two thioredoxin active sites and the endoplasmic reticulum (ER) retention signal are completely conserved, it was successfully recognized by anti-rat PDI antibodies [12].

Associations of dhd with chemical compounds

• Site-directed mutagenesis of C91 in DmGPx abrogated Trx peroxidase activity, but increased the rate constant for glutathione by two orders of magnitude [13].
• Molecular modeling and homology considerations based on 450 GPxs suggest peculiar features to determine Trx specificity: (i) a non-aligned second Cys within the fourth helix that acts as C(R); (ii) deletions of the subunit interfaces typical of tetrameric GPxs leading to flexibility of the C(R)-containing loop [13].
• This activity was abolished when two Cys residues in the active site sequence were mutated to Ser, suggesting that the Trx-like activity of TMX may help relieve ER stress caused by brefeldin A [1].
• The purified recombinant BmTPx was shown to reduce H(2)O(2) in the presence of electrons donated by dithiothreitol and shown to be active in the presence of thioredoxin as electron donor [14].
• The catalytic activity of selenocysteine-containing thioredoxin reductases can be mimicked by cysteine-variants if the local environment at the C-terminal redox center supports thiol activation [15].

Other interactions of dhd

• The ThioredoxinT and deadhead gene pair encode testis- and ovary-specific thioredoxins in Drosophila melanogaster [6].
• The fruit fly Drosophila lacks a functional GR, suggesting that the thioredoxin system is the major source for recycling glutathione [16].

Analytical, diagnostic and therapeutic context of dhd

• However, as demonstrated by gel-filtration analyses, DmTrx does not dimerize under quasi in vivo conditions and there is no redox control of a putative monomer/dimer equilibrium [17].
• DmTrx-2 is capable of reducing glutathione disulfide with a second order rate constant of 170 m(-1) s(-1) at pH 7.4 and 25 degrees C. Western blot analysis indicated that this thioredoxin represents up to 1% of the extractable protein of D. melanogaster Schneider cells or whole fruit flies [4].

References