Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.6.1.3 (ATPase)
65,361 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Epidermal Langerhans cells (LCs) possess surface markers and functional attributes which identify them as being of macrophage/monocyte lineage, and recent evidence documents their participation in certain immune process which occur in skin. To assess the role of LCs in lupus erythematosus (LE), a disease in which immune system dysfunction predominates, human epidermis from patients with cutaneous LE was studied with 3 LC surface markers: ATPase activity, HLA-DR and OKT-6 antigens. Suction blister top epidermal skin biopsies from patients with 3 clinical types of cutaneous LE exhibited similar features: LCs were less dendritic, they were more irregularly distributed, and they were present in fewer numbers when compared with those in adjacent normal skin. These changes contrasted with those observed in diseases with similar lichenoid histopathological features. LCs appeared increased in number in lichen planus. LCs in skin lesions from one patient with dermatomyositis exhibited similar morphologic alterations, but surface densities and distributions were preserved. Disaggregated epidermal cells from skin lesions of patients with cutaneous LE induced allogeneic lymphocyte proliferation as efficiently as did cells from nonlesional skin, indicating that the morphologic alterations observed were not associated with a decreased alloantigen presenting capacity. These studies have demonstrated that epidermal LC populations in 3 clinical types of cutaneous LE are perturbed in a manner not seen in 2 other lichenoid skin diseases, although these changes were not associated with an altered capacity of such cells to stimulate proliferation by allogeneic lymphocytes.
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PMID:Epidermal Langerhans cell involvement in cutaneous lupus erythematosus. 621 51

We studied the TCR/CD3 complex-mediated signal transduction pathway in freshly isolated T cells and T cell lines from patients with systemic lupus erythematosus (SLE). The peak and 5-min anti-CD3 mAb-mediated free intracytoplasmic Ca2+ concentration ([Ca2+]i) increase was statistically significant higher in fresh T cells from SLE patients than in control T cells. Increased CD3-mediated [Ca2+]i responses were observed in T cells from patients with SLE but not in T cells from other rheumatic diseases. Furthermore, significantly increased CD3-mediated [Ca2+]i responses were observed in T cell lines from SLE patients but not from controls. Although the [Ca2+]i response did not correlate with the global SLE disease activity or individual clinical manifestations, it was significantly higher in the group of patients who were not on treatment. Both CD4+ and CD8+ T cell subsets from peripheral blood cells and T cell lines displayed higher CD3-mediated [Ca2+]i responses than their normal counterparts. The peak of the response occurred earlier in the patient than in the normal group. The amount of Ca2+ that was released from the intracellular stores was higher in lupus than control T cells. The TCR/CD3-induced production of inositol phosphate metabolites in SLE cells was comparable with controls. The sarcoplasmic and endoplasmic reticulum Ca(2+)-ATPase inhibitor thapsigargin-induced [Ca2+]i response was similar in both SLE and normal T cells. Our experiments demonstrate for the first time a definite abnormality in the early steps of the TCR/CD3-mediated signal transduction pathway in T cells from SLE patients that involves increased release of Ca2+ from intracellular stores.
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PMID:TCR/CD3 complex-mediated signal transduction pathway in T cells and T cell lines from patients with systemic lupus erythematosus. 763 73

Human DNA helicase II (HDH II) is a novel ATP-dependent DNA unwinding enzyme, purified to apparent homogeneity from HeLa cells, which (i) unwinds exclusively DNA duplexes, (ii) prefers partially unwound substrates and (iii) proceeds in the 3' to 5' direction on the bound strand. HDH II is a heterodimer of 72 and 87 kDa polypeptides. It shows single-stranded DNA-dependent ATPase activity, as well as double-stranded DNA binding capacity. All these activities comigrate in gel filtration and glycerol gradients, giving a sedimentation coefficient of 7.4S and a Stokes radius of approximately 46 A, corresponding to a native molecular weight of 158 kDa. The antibodies raised in rabbit against either polypeptide can remove from the solution all the activities of HDH II. Photoaffinity labelling with [alpha-32P]ATP labelled both polypeptides. Microsequencing of the separate polypeptides of HDH II and cross-reaction with specific antibodies showed that this enzyme is identical to Ku, an autoantigen recognized by the sera of scleroderma and lupus erythematosus patients, which binds specifically to duplex DNA ends and is regulator of a DNA-dependent protein kinase. Recombinant HDH II/Ku protein expressed in and purified from Escherichia coli cells showed DNA binding and helicase activities indistinguishable from those of the isolated protein. The exclusively nuclear location of HDH II/Ku antigen, its highly specific affinity for double-stranded DNA, its abundance and its newly demonstrated ability to unwind exclusively DNA duplexes, point to an additional, if still unclear, role for this molecule in DNA metabolism.
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PMID:Human DNA helicase II: a novel DNA unwinding enzyme identified as the Ku autoantigen. 795 65

The isoprenoid pathway produces three key metabolites--digoxin (membrane Na(+)-K+ ATPase inhibitor, regulator of neurotransmitter transport, and immunomodulatory agent), dolichol (regulatory of N-glycosylation of proteins), and ubiquinone (free-radical scavenger). The pathway was assessed in systemic lupus erythematosis with neuropsychiatric manifestations, slow viral diseases (subacute sclerosing panencephalitis [SSPE], and Creutzfeldt-Jakob disease [CJD]) and patients with recurrent respiratory infections. This was also studied for comparison in patients with right hemispheric and left hemispheric dominance. The isoprenoid pathway was upregulated with increased digoxin synthesis in patients with neurolupus, SSPE, and CJD, and in those with right hemispheric dominance. The tryptophan catabolites were increased and the tyrosine catabolites reduced. In these patients the dolichol and glycoconjugate levels were elevated and lysosomal stability was reduced. The ubiquinone levels were low and free-radical levels increased in these patients. The membrane cholesterol:phospholipid ratios were increased and membrane glycoconjugates reduced. On the other hand, in patients with recurrent respiratory infection and left hemispheric dominance, the reverse patterns and hypodigoxinemia with a downregulated isoprenoid pathway were noticed. The isoprenoid pathway is important in the pathogenesis of neurolupus, CJD, SSPE, and recurrent respiratory infections. Hypothalamic digoxin and chemical hemispheric dominance play an important role in the regulation of immunity.
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PMID:Hypothalamic digoxin, hemispheric dominance, and neuroimmune integration. 1232 97

Systemic lupus erythematosus (SLE) is characterized by abnormal activation and cell death signaling within the immune system. Activation, proliferation, or death of cells of the immune system are dependent on controlled reactive oxygen intermediate (ROI) production and ATP synthesis in mitochondria. The mitochondrial transmembrane potential (Delta(Psi)m) reflects the energy stored in the electrochemical gradient across the inner mitochondrial membrane, which in turn is used by F0F1-ATPase to convert adenosine 5'-diphosphate to ATP during oxidative phosphorylation. Mitochondrial hyperpolarization and transient ATP depletion represent early and reversible steps in T-cell activation and apoptosis. By contrast, T lymphocytes of patients with SLE exhibit elevated Delta(Psi)m, that is, persistent mitochondrial hyperpolarization, cytoplasmic alkalinization, increased ROI production, as well as diminished levels of intracellular glutathione and ATP. Oxidative stress affects signaling through the T-cell receptor as well as the activity of redox-sensitive caspases. ATP depletion may be responsible for diminished activation-induced apoptosis and sensitize lupus T cells to necrosis. Mitochondrial dysfunction is identified as a key mechanism in the pathogenesis of SLE.
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PMID:Apoptosis and mitochondrial dysfunction in lymphocytes of patients with systemic lupus erythematosus. 1528 82

Bz-423 is a 1,4-benzodiazepine that suppresses disease in lupus-prone mice by selectively killing pathogenic lymphocytes, and it is less toxic compared to current lupus drugs. Cells exposed to Bz-423 rapidly generate O(2)(-) within mitochondria, and this reactive oxygen species is the signal initiating apoptosis. Phage display screening revealed that Bz-423 binds to the oligomycin sensitivity conferring protein (OSCP) component of the mitochondrial F(1)F(0)-ATPase. Bz-423 inhibited the F(1)F(0)-ATPase in vitro, and reconstitution experiments demonstrated that inhibition was mediated by the OSCP. This target was further validated by generating cells with reduced OSCP expression using RNA interference and studying the sensitivity of these cells to Bz-423. Our findings help explain the efficacy and selectivity of Bz-423 for autoimmune lymphocytes and highlight the OSCP as a target to guide the development of novel lupus therapeutics.
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PMID:Identification and validation of the mitochondrial F1F0-ATPase as the molecular target of the immunomodulatory benzodiazepine Bz-423. 1585 Sep 77

Myc proteins regulate cell growth and are oncogenic in many cancers. Although these proteins are validated molecular anticancer targets, new therapies aimed at modulating myc have yet to emerge. A benzodiazepine (Bz-423) that was discovered in efforts to find new drugs for lupus was found recently to have antiproliferative effects on Burkitt's lymphoma cells. We now show that the basis for the antiproliferative effects of Bz-423 is the rapid and specific depletion of c-myc protein, which is coupled to growth-suppressing effects on key regulators of proliferation and cell cycle progression. c-Myc is depleted as a result of signals coupled to Bz-423 binding its molecular target, the oligomycin sensitivity-conferring protein subunit of the mitochondrial F(1)F(o)-ATPase. Bz-423 inhibits F(1)F(o)-ATPase activity, blocking respiratory chain function and generating superoxide, which at growth-inhibiting concentrations triggers proteasomal degradation of c-myc. Bz-423-induced c-myc degradation is independent of glycogen synthase kinase but is substantially blocked by mutation of the phosphosensitive residue threonine 58, which when phosphorylated targets c-myc for ubiquitination and subsequent proteasomal degradation. Collectively, this work describes a new lead compound, with drug-like properties, which regulates c-myc by a novel molecular mechanism that may be therapeutically useful.
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PMID:The immunomodulatory benzodiazepine Bz-423 inhibits B-cell proliferation by targeting c-myc protein for rapid and specific degradation. 1645 38

Transport ATPases can be lumped into four distinct types, P, F, V, and ABC, with the first three designated 20 years ago (Pedersen, P.L. and Carafoli, E., Trends Biochem. Sci. 12, 146-150, 1987) and the ABC type included more recently. The mini-reviews (>20) that comprise this volume of the Journal of Bioenergetics and Biomembranes describe work presented at the 2007 FASEB Conference (6th) on Transport ATPases (Kathleen Sweadner, Chair; Rajini Rao, Co-Chair). Since these conferences began in 1997, the "transport ATPase field" has seen tremendous progress. Advances include a much better understanding of the structure, mechanism, and regulation of each of the four major ATPase types as well as their physiological and medical relevance. In fact, the transport ATPase field has entered a new era in which work on these enzymes is likely to contribute to new therapies for multiple diseases that affect both people and animals. Among these are cancer and heart disease, mitochondrial diseases, osteoporosis, macromolecular degeneration, immune deficiency, cystic fibrosis, diabetes, ulcers, nephro-toxicity, hearing loss, skin disorders, lupus, and malaria. In addition, as several members of the transport ATPase family include those involved in drug resistance their study may help alleviate this recurring problem in drug development. Finally, the transport ATPase field is also paving the way for nanotechnology focused on nano-motors with work on the F-type ATPases (F(0)F(1)) leading the way. These ATPases driven in reverse by a proton gradient have the capacity to interconvert electrochemical energy into mechanical energy and finally into chemical energy conserved in the terminal bond of ATP. In mammalian mitochondria these events occur on a larger complex or "nano-machine" called the "ATP synthasome" that consists of the ATP synthase in complex formation with carriers for P(i) and ADP/ATP.
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PMID:Transport ATPases into the year 2008: a brief overview related to types, structures, functions and roles in health and disease. 1817 9

Bz-423 is a proapoptotic 1,4-benzodiazepine with potent therapeutic properties in murine models of lupus and psoriasis. Bz-423 modulates the F(1)F(0)-ATPase, inducing the formation of superoxide within the mitochondrial respiratory chain, which then functions as a second messenger initiating apoptosis. Herein, we report the signaling pathway activated by Bz-423 in mouse embryonic fibroblasts containing knockouts of key apoptotic proteins. Bz-423-induced superoxide activates cytosolic ASK1 and its release from thioredoxin. A mitogen-activated protein kinase cascade follows, leading to the specific phosphorylation of JNK. JNK signals activation of Bax and Bak which then induces mitochondrial outer membrane permeabilization to cause the release of cytochrome c and a commitment to apoptosis. The response of these cells to Bz-423 is critically dependent on both superoxide and JNK activation as antioxidants and the JNK inhibitor SP600125 prevents Bax translocation, cytochrome c release, and cell death. These results demonstrate that superoxide generated from the mitochondrial respiratory chain as a consequence of a respiratory transition can signal a sequential and specific apoptotic response. Collectively, these data suggest that the selectivity of Bz-423 observed in vivo results from cell-type specific differences in redox balance and signaling by ASK1 and Bcl-2 proteins.
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PMID:Bz-423 superoxide signals apoptosis via selective activation of JNK, Bak, and Bax. 1871 27

Bz-423 is a pro-apoptotic 1,4-benzodiazepine with therapeutic properties in murine models of lupus demonstrating selectivity for autoreactive lymphocytes. Bz-423 modulates the F(1)F(0)-ATPase, inducing the formation of superoxide within the mitochondrial respiratory chain, which then functions as a second messenger initiating apoptosis. In order to understand some of the features that contribute to the increased sensitivity of lymphocytes, we report the signaling pathway engaged by Bz-423 in a Burkitt lymphoma cell line (Ramos). Following the generation of superoxide, Bz-423-induced apoptosis requires the activation of Bax and Bak to induce mitochondrial outer membrane permeabilization and cytochrome c release. Knockdown of the BH3-only proteins Bad, Bim, Bik, and Puma inhibits Bz-423 apoptosis, suggesting that these proteins serve as upstream sensors of the oxidant stress induced by Bz-423. Treatment with Bz-423 results in superoxide-dependent Mcl-1 degradation, implicating this protein as the link between Bz-423-induced superoxide and Bax and Bak activation. In contrast to fibroblasts, B cell death induced by Bz-423 is independent of c-Jun N-terminal kinase. These results demonstrate that superoxide generated from the mitochondrial respiratory chain as a consequence of a respiratory transition can signal a specific apoptotic response that differs across cell types.
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PMID:Bz-423 superoxide signals B cell apoptosis via Mcl-1, Bak, and Bax. 1948 Oct 66


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