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PubMed2000

Lipids and retroviruses.

The role that lipids may play in enveloped viruses is reviewed. Small lipid molecules can influence retrovirus binding to cell receptors, plasma membrane fusion, and transcription. Palmitoylation following myristoylation of viral glycoproteins is required at the transmembrane level for signal transduction as well as for virion budding and maturation. Cholesterol, ether lipids, phospholipids, platelet-activating factor, phosphatidic acids, diacylglycerols, and several analogs and derivatives influence human immunodeficiency virus (HIV) activity; when conjugated with inhibitors of the viral reverse transcriptase (RT) or aspartyl protease these compounds increase drug effectiveness. On the other hand, L-carnitine, in association with the mitochondrial cardiolipins, inhibits myopathy due to continued prescription of drugs [AZT (zidovudine), ddl (didanoside), or ddC (zalcitabine)], and the redox couple of alpha-lipoic-dihydrolipoic acid prevents production of the reactive oxygen species that trigger apoptosis of infected cells, with sphingomyelin breakdown to ceramides. Retroviral infection induces a shift from phospholipid to neutral fat synthesis in host cells, and a long antiviral, i.e., antiprotease, treatment may lead to lipodystrophy. Multitherapy involving lipids and their analogs in association with anti-RT and antiproteases might enhance the inhibition of growth and proliferation of retroviruses.

Anti-HIV Agents↗
PubMed1984

Oxidation of glycine by Pseudomonas putida requires a specific lipoamide dehydrogenase.

Pseudomonas putida produces two lipoamide dehydrogenases with molecular weights of 49,000 and 56,000 designated LPD-val and LPD-glc, respectively. LPD-val is required for oxidation of valine, since it is specifically utilized as the E3 component of branched-chain keto acid dehydrogenase. Since glycine oxidation by bacteria and mammals also requires lipoamide dehydrogenase, we desired to determine which lipoamide dehydrogenase would be used by the P. putida glycine oxidation system. When grown in a medium with glycine as the sole nitrogen source, P. putida produced a single lipoamide dehydrogenase with a molecular weight of 56,000 and which reacted with antiserum to LPD-glc. The partially purified glycine oxidation system from P. putida was stimulated by LPD-glc but not by LPD-val and was inhibited by anti-LPD-glc, but not by anti-LPD-val. It was not possible to detect LPD-val in extracts of cells grown in glucose-glycine medium by the use of anti-LPD-val. LPD-glc was five times as active as LPD-val in catalyzing the oxidation of purified protein H, the heat-stable, lipoic acid-containing protein of the glycine oxidation system. These results indicate that LPD-glc is specifically utilized for glycine oxidation in P. putida.

Antibody Specificity↗
PubMed1999

Characterization of the autoantibody responses to recombinant E3 binding protein (protein X) of pyruvate dehydrogenase in primary biliary cirrhosis.

Autoantibodies to the pyruvate dehydrogenase complex (PDC) are present in the serum of more than 95% of patients with primary biliary cirrhosis (PBC), the major epitope being the inner lipoyl domain of the E2 component. Immunoblotting suggests a similar prevalence of antibodies to a tightly associated lipoic acid-containing protein, E3 binding protein (E3BP). Attempts to resolve E3BP from E2 have been unsuccessful, restricting study of the nature and significance of antibody responses to the individual proteins. In particular, it is unclear (1) whether there is true cross-reactivity between E3BP and E2 and, if so, which is the originating response and (2) whether autoantibodies preferentially bind a lipoylated epitope on E3BP as is the case with PDC-E2. In this study, complementary DNAs encoding rE2, full-length rE3BP, its single lipoyl domain (rLip), and core domain (rE3BPCore) were cloned, and the proteins were expressed in Escherichia coli. Sera from 47 PBC patients were studied by immunoblotting and enzyme-linked immunosorbent assay (ELISA) against rE2, rE3BP, rE3BPCore, and both unlipoylated (U) and lipoylated (L) rLip. All sera were reactive by ELISA to some degree with all recombinant proteins except rE3BPCore, to which only 6 of 47 showed any reactivity. Significant correlations (P <.0001) were observed when comparing absorbance values for rE3BP with both rLip (U) (r = 0.793) and (L) (r = 0.963). The mean absorbance for rLip (U, 0.26 +/- 0.05) was, however, significantly lower than the absorbance for rLip (L) (0.78 +/- 0.12; P <.0001). After probing by immunoblotting and elution of antibodies from rE2 and rE3BP, subsequent reprobing against the components in whole PDC revealed true cross-reactivity. In summary, the response to E3BP is primarily directed against the lipoylated domain of the protein. It still remains unclear, however, whether the initial breakdown of tolerance is to E2 or E3BP.

Antibody Formation↗
PubMed1989

Characterisation of the reactivity of autoantibodies in primary biliary cirrhosis.

Autoantibodies in the sera of patients with primary biliary cirrhosis, shown previously to recognise the E2 polypeptide of the mammalian pyruvate dehydrogenase complex (PDC), have been demonstrated to react with the E2 component of PDC from bacteria (E. coli) and yeast (S. cerevisiae). Limited tryptic digestion, which cleaves E2 into well-characterised domains, followed by Western blotting indicates that the main immunodominant region of PDC E2 lies within the lipoic acid-containing domains of the polypeptide.

Acetylation↗
PubMed2000

Autoreactive responses to pyruvate dehydrogenase complex in the pathogenesis of primary biliary cirrhosis.

Primary biliary cirrhosis (PBC) is a cholestatic liver disease characterised by immune-mediated destruction of the biliary epithelial cells (BEC) lining the intrahepatic bile ducts (non-suppurative destructive cholangitis (NSDC)). Autoantibody and autoreactive T-cell responses specific for the self-antigen pyruvate dehydrogenase complex (PDC) are almost ubiquitous in PBC patients, leading to the view that the disease has an autoimmune aetiology. Autoreactive responses in PBC appear to be directed at the E2 and at the E3-binding protein (E3BP) (protein X) components of PDC, with the dominant B-cell and T-cell epitopes in E2 (fewer data are available for E3BP) spanning the inner (of two) lipoic acid-binding domains. The causal link between the breakdown of self-tolerance to PDC (particularly at the T-cell level) and the development of NSDC has been emphasised by the demonstration, in a murine model (experimental autoimmune cholangitis), that sensitisation with PDC of mammalian origin results in a breakdown of both B-cell and T-cell tolerance to murine PDC accompanied by the development of NSDC. An increasing understanding of the role played by PDC-specific autoreactive T cells in the pathogenesis of PBC has led us to examine the role played by the target cells in PBC (BEC) in both the inducer and effector mechanisms responsible for PBC.

Acyltransferases↗
PubMed2002

The impact of oxidative stress on Arabidopsis mitochondria.

Treatment of Arabidopsis cell culture for 16 h with H2O2, menadione or antimycin A induced an oxidative stress decreasing growth rate and increasing DCF fluorescence and lipid peroxidation products. Treated cells remained viable and maintained significant respiratory rates. Mitochondrial integrity was maintained, but accumulation of alternative oxidase and decreased abundance of lipoic acid-containing components during several of the treatments indicated oxidative stress. Analysis of the treatments was undertaken by IEF/SDS-PAGE, comparison of protein spot abundances and tandem mass spectrometry. A set of 25 protein spots increased >3-fold in H2O2/menadione treatments, a subset of these increased in antimycin A-treated samples. A set of 10 protein spots decreased significantly during stress treatments. A specific set of mitochondrial proteins were degraded by stress treatments. These damaged components included subunits of ATP synthase, complex I, succinyl CoA ligase, aconitase, and pyruvate and 2-oxoglutarate dehydrogenase complexes. Nine increased proteins represented products of different genes not found in control mitochondria. One is directly involved in antioxidant defense, a mitochondrial thioredoxin-dependent peroxidase, while another, a thioredoxin reductase-dependent protein disulphide isomerase, is required for protein disulfide redox homeostasis. Several others are generally considered to be extramitochondrial but are clearly present in a highly purified mitochondrial fraction used in this study and are known to play roles in stress response. Using H2O2 as a model stress, further work revealed that this treatment induced a protease activity in isolated mitochondria, putatively responsible for the degradation of oxidatively damaged mitochondrial proteins and that O2 consumption by mitochondria was significantly decreased by H2O2 treatment.

Antimycin A↗
PubMed1992

Interaction of avidin with the lipoyl domains in the pyruvate dehydrogenase multienzyme complex: three-dimensional location and similarity to biotinyl domains in carboxylases.

Avidin can form intermolecular cross-links between particles of the pyruvate dehydrogenase multienzyme complex from various sources. Avidin does this by binding to lipoic acid-containing regions of the dihydrolipoamide acetyltransferase polypeptide chains that comprise the structural core of the complex. It is inferred that the lipoyl domains of the acetyltransferase chain extend outwards from the interior of the enzyme particle, interdigitating between the subunits of the other two enzymes bound peripherally in the assembled structure, with the lipoyl-lysine residues capable of reaching to within at least 1-2 nm of the outer surface of the enzyme complex (diameter ca. 37 nm). The distribution of enzymic activities between different domains of the dihydrolipoamide acetyltransferase chain implies that considerable movement of the lipoyl domains is a feature of the catalytic activity of the enzyme complex. There is evidence that the lipoyl domain of the 2-oxo acid dehydrogenase complexes is similar in structure to a domain that binds the cofactor biotin, also in amide linkage with a specific lysine residue, in the biotin-dependent class of carboxylases.

Amidohydrolases↗
PubMed1973

Incorporation of radioactive acetate into diacetyl by Streptococcus diacetilactis.

Streptococcus diacetilactis was grown in a partially defined, lipoic acid-free medium containing radioactive acetate with and without addition of 0.1% unlabeled sodium pyruvate. Labeled carbon was incorporated into diacetyl, but neither the amount of diacetyl produced nor its specific activity was influenced by addition of pyruvate. Acetoin had low specific activity, indicating that it was a mixture of radioactive and nonradioactive acetoin. The specific activity of acetoin was lower when pyruvate, a precursor of unlabeled acetoin, was added to the medium, which indicated that the radioactive acetoin was produced from radioactive diacetyl by diacetyl reductase. Results substantiate condensation of acetyl-coenzyme A with hydroxyethylthiamine pyrophosphate as the in vivo mechanism for synthesis of diacetyl.

Acetates↗