Disease relevance of Dihydrothioctamide

• The autoepitope of the 74-kD mitochondrial autoantigen of primary biliary cirrhosis corresponds to the functional site of dihydrolipoamide acetyltransferase [1].
• Particularly striking is the conservation of sequence in the active site region of the dihydrolipoamide dehydrogenases from E. coli, yeast, and pig heart [2].
• Based on these data, we attempted an 8-month study to induce antibodies and liver dysfunction by immunizing AKR/J, C3H/J and CBA/HeJ mice as well as rats, guinea pigs, rabbits and rhesus monkeys with purified recombinant human dihydrolipoamide acetyltransferase [3].
• Dihydrolipoamide acetyltransferase is well-known to mitochondrial biochemistry and, similar to identified autoantigens in other autoimmune diseases, is highly conserved in evolution [4].
• The high-resolution structure of the peripheral subunit-binding domain of dihydrolipoamide acetyltransferase from the pyruvate dehydrogenase multienzyme complex of Bacillus stearothermophilus [5].

Psychiatry related information on Dihydrothioctamide

• In addition, a possible relationship between dihydrolipoamide succinyltransferase and familial Alzheimer's disease is discussed [6].

High impact information on Dihydrothioctamide

• This recombinant protein was identified as the 74-kD M2 mitochondrial inner membrane autoantigen, now known to be dihydrolipoamide acetyltransferase [1].
• Of particular interest was the finding that this peptide contains the lipoic acid binding site KATIGF of the dihydrolipoamide acetyltransferase found in the inner mitochondrial membrane [1].
• In addition to binding to mitochondria, patients' autoantibodies to the assumed major autoantigen pyruvate dehydrogenase complex (PDC) dihydrolipoamide acetyltransferase (E2) bind to the plasma membrane of biliary epithelial cells (BECs) specifically in PBC [7].
• Membrane dihydrolipoamide acetyltransferase (E2) on human biliary epithelial cells in primary biliary cirrhosis [8].
• We have demonstrated that three genes (dihydrolipoamide succinyltransferase, S31iii125, and S20i15), which are linked to FOS in the familial Alzheimer disease focus (AD3) on human chromosome 14, have homologues in the Fugu genome adjacent to Fugu cFOS [9].

Chemical compound and disease context of Dihydrothioctamide

• Close to 95% of patients with established clinical, biochemical and histologic features of primary biliary cirrhosis (PBC) possess antimitochondrial M2 antibodies reacting with the E2 component, dihydrolipoamide acetyltransferase, of the pyruvate dehydrogenase complex [10].
• Three different dihydrolipoamide dehydrogenases were purified to homogenity from the anaerobic glycine-utilizing bacteria Clostridium cylindrosporum, Clostridium sporogenes, and Peptostreptococcus glycinophilus, and their basic properties were determined [11].
• The nucleotide sequence of the sucB gene, which encodes the dihydrolipoamide succinyltransferase component (E2o) of the 2-oxoglutarate dehydrogenase complex of Escherichia coli K12, has been determined by the dideoxy chain-termination method [12].
• Rhodanese from Thiobacillus A2 was shown by proton nuclear magnetic resonance (NMR) spectroscopy to use dihydrolipoate or dihydrolipoamide as acceptor of the sulphane moiety of thiosulphate with the formation of alpha-lipoate or lipoamide respectively [13].
• Rhodanese from Thiobacillus A2: catalysis of reactions of thiosulphate with dihydrolipoate and dihydrolipoamide [14].

Biological context of Dihydrothioctamide

• Comparison of the deduced amino acid sequences of yeast protein X and dihydrolipoamide acetyltransferase indicates that the two proteins evolved from a common ancestor [15].
• Here we report that noa is deficient for dihydrolipoamide S-acetyltransferase (Dlat), the PDH E2 subunit, and exhibits phenotypes similar to human patients with PDH deficiency [16].
• Human dihydrolipoamide dehydrogenases with selected amino acid substitutions were then tested in the null strain for their ability to restore function [17].
• Dihydrolipoamide succinyltransferase (E2, EC 2.3.1.61, chromosome 14q24.2-3) is a specific subunit of human alpha-ketoglutarate dehydrogenase complex (KGDHC) [18].
• In primary biliary cirrhosis the predominant manifestation of autoimmunity is antimitochondrial antibodies that react with dihydrolipoamide transacetylase [19].

Anatomical context of Dihydrothioctamide

• Distribution of dihydrolipoamide acetyltransferase (E2) in the liver and portal lymph nodes of patients with primary biliary cirrhosis: an immunohistochemical study [20].
• In isolated rat heart mitochondria, dihydrolipoamide was found to be a better antioxidant than dihydrolipoic acid [21].
• The cDNA sequence of hamster testes dihydrolipoamide dehydrogenase does not show any variation from the already reported mammalian dihydrolipoamide dehydrogenases [22].
• The favored use of GSH and dihydrolipoamide indicated that MIF may be involved in the regulation of cellular redox processes and was supported further by the finding that MIF expression by the cell lines COS-1 and RAW 264.7 was significantly induced upon treatment with the oxidant hydrogen peroxide [23].
• A polypeptide derived from mitochondrial dihydrolipoamide succinyltransferase is located on the plasma membrane in skeletal muscle [24].

Associations of Dihydrothioctamide with other chemical compounds

• This study was designed to determine whether the increase in intensity of pyruvate dehydrogenase dihydrolipoamide acetyltransferase in biliary epithelial cells is accounted for by an increase in the number of mitochondria in the same cells [25].
• The availability of recombinant dihydrolipoamide transacetylase and the development of a rapid and reproducible enzyme-linked immunosorbent assay for autoantibodies has allowed us to address the affinity of autoantibodies using thiocyanate inhibition [19].
• The oxidation-reduction potential, E2, for the couple oxidized lipoamide dehydrogenase/2-electron reduced lipoamide dehydrogenase has been determined by measurement of equilibria of these enzyme species with lipoamide and dihydrolipoamide or with oxidized and reduced azine dyes [26].
• The dihydrolipoyl transacetylase component of the pyruvate dehydrogenase complex catalyzes a reversible reaction between acetyl-CoA and dihydrolipoamide that results in the formation of S-acetyldihydrolipoamide [27].
• Trypanothione reductase belongs to the family of flavoprotein disulphide oxidoreductases that include glutathione reductases, dihydrolipoamide dehydrogenases and mercuric reductases [28].

Gene context of Dihydrothioctamide

• Mutations in DLAT, the gene encoding dihydrolipoamide acetyltransferase, the E2 core component of the complex, have not been described previously [29].
• The maximum activation by dihydrolipoamide acetyltransferase was demonstrated by PDK3 [30].
• The activity of the four PDKs was stimulated to a different extent by the reduction and acetylation state of the lipoyl moieties of dihydrolipoamide acetyltransferase with the maximum stimulation of PDK2 [30].
• The Brucella melitensis sucB gene encoding the dihydrolipoamide succinyltransferase (E2o) enzyme (previously identified as an immunogenic protein in infected sheep) was cloned and sequenced [31].
• Since lipoic acids inhibited PDKs activity both when reconstituted in PDC and in the presence of E1 alone, dissociation of PDK from the lipoyl domains of dihydrolipoamide acetyltransferase in the presence of lipoic acids is not a likely explanation for inhibition [32].

Analytical, diagnostic and therapeutic context of Dihydrothioctamide

• We used this property to inhibit the binding by enzyme-linked immunosorbent assay of human recombinant dihydrolipoamide transacetylase with serum autoantibodies from 55 patients with primary biliary cirrhosis [19].
• We have imaged by negative stain and cryoelectron microscopy the truncated dihydrolipoamide acetyltransferase core (60 subunits; M(r) = 2.7 x 10(6)) of the Saccharomyces cerevisiae pyruvate dehydrogenase complex [33].
• Structural studies by three-dimensional electron microscopy of the Saccharomyces cerevisiae truncated dihydrolipoamide acetyltransferase (tE(2)) component of the pyruvate dehydrogenase complex reveal an extraordinary example of protein dynamics [34].
• Incubation of human or pig PDC with Q(0) followed by matrix-assisted laser desorption ionization time-of-flight and liquid chromatography/electrospray ionization mass spectrometry analyses of chymotrypsin-digested peptides of PDC E2 confirmed that Q(0) bonds to the dihydrolipoamide in these proteins [35].
• Protein expression of mitochondrial LipDH and mitochondrial branched chain alpha-ketoacid dihydrolipoamide transacylase in these parasite stages was confirmed by Western blotting [36].

References