Disease relevance of DLST

• Other studies have associated specific forms of one of the genes encoding KGDHC (namely the DLST gene) with AD, Parkinson's disease, as well as other neurodegenerative diseases [1].
• The immunodominant antimitochondrial antibody (AMA) response in primary biliary cirrhosis (PBC) is directed against the E2 component of pyruvate dehydrogenase (PDC-E2) [2].
• The human papillomavirus (HPV) 16 E2 protein (hE2) binds to four sites present upstream of the P97 promoter and regulates transcription of the viral E6 and E7 oncogenes [3].
• Highly assembled bovine E2 devoid of prosthetic lipoic acid has been overexpressed in Escherichia coli [4].
• Maple syrup urine disease: domain structure, mutations and exon skipping in the dihydrolipoyl transacylase (E2) component of the branched-chain alpha-keto acid dehydrogenase complex [4].

Psychiatry related information on DLST

• While studying how the DLST genotype contributes to the pathogenesis of Alzheimer's disease (AD), we found a novel mRNA that is transcribed starting from intron 7 in the DLST gene [5].
• No association between DLST gene and Alzheimer's disease or Wernicke-Korsakoff syndrome [6].
• E1/E2 dimers and the HCV-LPs of 1b did not bind CD81-LEL, consistent with the notion that CD81 recognition by E2 is strain-specific and does not correlate with permissiveness of infection [7].

High impact information on DLST

• The core DNA-binding domain, which comprises both the dimerization domain and a helix predicted to bind the inner portion of the EBNA1 DNA recognition element, was remarkably similar to the structure of the papillomavirus E2 protein, despite a complete lack of sequence conservation [8].
• Hepatitis C virus, the E2 envelope protein, and alpha-interferon resistance [9].
• Consistent with the hypothesis of selective pressure by the host immune system, the sequence changes occurred almost exclusively within the hypervariable region 1 of the E2 gene and were temporally correlated with antibody seroconversion [10].
• The papillomavirus E2 protein regulates viral transcription and DNA replication through interactions with cellular and viral proteins [11].
• The transcriptional enhancer sequences of the papillomaviruses are regulated by trans-acting factors encoded by the viral E2 open reading frame [12].

Chemical compound and disease context of DLST

• In this report, we confirm that primary biliary cirrhosis sera react with dihydrolipoamide succinyltransferase, the E2 component of alpha-ketoglutarate dehydrogenase complex [13].
• Large-scale epidemiological case-control studies suggest the involvements of dihydrolipoamide succinyltransferase (DLST) of the mitochondrial Krebs cycle and mitochondrial aldehyde dehydrogenase-2 (ALDH2) in Alzheimer's disease (AD) [14].
• A case of a 19-year-old man with ulcerative colitis (UC) developed multiple pulmonary nodular shadows with cavity formation, elevated perinuclear antinuclear cytoplasmic antibody (pANCA) and positive lymphocyte stimulation test by drug (DLST) for mesalazine suggesting mesalazine induced Wegener's granulomatosis (WG) [15].
• The reason for the close association between primary biliary cirrhosis and the appearance of antibodies that recognize the E2 component of pyruvate dehydrogenase complex is not understood [16].
• An expression system for analysis of the synthesis and processing of the E2 glycoprotein of a hepatitis C virus (HCV) genotype 1a strain was developed in transiently transfected cells [17].

Biological context of DLST

• Dihydrolipoamide succinyltransferase (DLST) is a subunit enzyme of the alpha-ketoglutarate dehydrogenase complex of the Krebs cycle [5].
• Thus, the DLST gene is bifunctional and MIRTD transcribed from the gene contributes to the biogenesis of the mitochondrial respiratory complexes [5].
• Polymorphisms of DLST (A19,117G and T19,183C), shown to be of interest in previous studies, were analyzed by restriction fragment length polymorphism analysis after polymerase chain reaction amplification [18].
• Mutation analysis of the chromosome 14q24.3 dihydrolipoyl succinyltransferase (DLST) gene in patients with early-onset Alzheimer disease [19].
• The 15 exons and the promoter region of the DLST gene were analysed for mutations in chromosome 14 linked AD cases and in two series of unrelated early-onset AD cases (onset age < 55 years) [19].

Anatomical context of DLST

• Dihydrolipoamide succinyltransferase (DLST) is the core-enzyme of 2-oxoglutarate dehydrogenase complex which is located in mitochondria [20].
• The DLST gene is a candidate for the AD3 gene since deficiencies in KGDHC activity have been observed in brain tissue and fibroblasts of AD patients [19].
• The U2OS-ERalpha and U2OS-ERbeta cell lines were treated with Dox and either vehicle control or E2 for 24 h [21].
• Estrogen (17beta-estradiol, E2) plays pivotal roles in the function and maintenance of the skeleton, including the bone-forming osteoblasts (OBs) [21].
• A peripheral blood lymphocytes stimulating test (DLST) with TS-1 demonstrated a substantial positive reaction [22].

Associations of DLST with chemical compounds

• Another candidate is the dihydrolipoyl succinyltransferase (DLST) gene, one of three components of thiamine-dependent mitochondrial alpha-ketoglutarate dehydrogenase complex (KGDHC), because KGDHC activity is reported reduced in AD patients [6].
• Very-low-density lipoprotein (VLDL) cholesterol and triglyceride levels were significantly higher in carriers of both apo E2 and apo E4 in white men only [23].
• Finally, alpha-ketoglutarate dehydrogenase complex-E2 specific affinity-purified antisera did not react on immunoblot with any component enzymes of pyruvate dehydrogenase complex or branched chain alpha-ketoacid dehydrogenase complex.(ABSTRACT TRUNCATED AT 250 WORDS)[13]
• Using site-directed mutagenesis we demonstrate that an arginine at position 304 of the hE2 protein is responsible for the recognition of specific base pairs at this position [3].
• Among the PDC components, the activity of the dihydrolipoamide acetyltransferase-E3-binding protein subcomplex (E2-E3BP) only was decreased by HNE [24].

Regulatory relationships of DLST

• Similarly 76% of the ERbeta-regulated genes were upregulated whereas 24% were inhibited by E2 [21].

Other interactions of DLST

• The dihydrolipoamide succinyltransferase (DLST) gene of the alpha-ketoglutarate dehydrogenase complex (alpha-KGDC) was isolated from a rat genomic DNA library and sequenced [25].
• There were no significant gender or age differences in tested genotypic and allelic distribution except for the DLST and apolipoprotein E [26].
• The functions of E2 are largely mediated through two distinct estrogen receptor isoforms, ERalpha and ERbeta, both of which are expressed in OBs [21].
• The distinct patterns of E2-dependent gene regulation in the U2OS cells by ERalpha and ERbeta shown here suggest that during OB differentiation, when either isoform dominates, a unique pattern of gene responses will occur, partially due to the differentiation state and the ER isoform present [21].
• Results demonstrate that the AR activation plays a pivotal role in the inhibitory action of DHEA on the E2-induced MCF-7 growth [27].

Analytical, diagnostic and therapeutic context of DLST

• Furthermore, subcellular fractionation analysis coupled with Western blotting demonstrated that the antigen of the anti-DLST antibody is distributed on the plasma membrane fraction in addition to the mitochondria fraction in skeletal muscle and that it is free from the complex [20].
• Association of the candidate gene DLST with late-onset Alzheimer's disease (LOAD) risk has been suggested on the basis of case-control studies [28].
• Sequence analysis of the promoter-regulatory region of the rat DLST gene-(Dlst) showed the possible presence of a CAAT box-sequence and of the sequences for an AP-2 site and three Sp1 sites, but no TATA box-sequence was evidenced [25].
• At the genetic level, the human E2 gene (DBT) has been regionally assigned to chromosome 1p31, and a related E2 pseudogene to chromosome 3q24 by in situ hybridization [4].
• The assembly of 24 E2 subunits into a cubic structure, forming the core of the mammalian BCKAD complex, was established by electron microscopy and sedimentation equilibrium analysis [4].

References