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:3.6.3.14 (ATP synthase)
7,042 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Five protein kinases are shown to serve as specific phosphatases in the absence of ADP. Although the rates of hydrolysis are very slow compared to the forward phosphorylation rates under optimal conditions, they are of the same order as the reverse reaction in the presence of ADP. Because cells contain approximately equal to 3 mM ATP, neither the reverse reaction nor the phosphatase is likely to play a physiological role. beta-casein B phosphorylated by the catalytic subunit of cAMP-dependent protein kinase (protein kinase A) is specifically dephosphorylated by protein kinase A but not by polypeptide-dependent protein kinase (protein kinase P). beta-casein B phosphorylated by protein kinase P is specifically dephosphorylated by protein kinase P but not by protein kinase A. Histone H1 phosphorylated by protein kinase C is dephosphorylated by the same enzyme in the absence of ADP. In all cases tested addition of ADP and F1-ATPase accelerates moderately the rate of dephosphorylation. Native H+-ATPase from yeast plasma membranes is isolated mainly in the phosphorylated form. It is dephosphorylated and rephosphorylated by protein kinase P but not by protein kinase A. Protein-tyrosine kinase of the epidermal growth factor receptor phosphorylates the random synthetic polypeptide poly(Glu80Tyr20). The phosphorylated polymer is specifically dephosphorylated in the absence of ADP by epidermal growth factor receptor preparations but not by insulin receptor preparations. The same polymer phosphorylated by insulin receptor is dephosphorylated by insulin receptor but not by epidermal growth factor receptor preparations. By using a cycle of dephosphorylation-rephosphorylation, it is possible to identify proteins that are phosphorylated by these protein kinases in vivo. Should this method be applicable to additional protein kinases, it should be possible to estimate the quantitative contribution of each protein kinase to a single phosphoprotein.
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PMID:Specific dephosphorylation of phosphoproteins by protein-serine and -tyrosine kinases. 290 Oct 92

Widely held theories of the pathogenesis of obesity-associated NIDDM have implicated apparently incompatible events as seminal: 1) insulin resistance in muscle, 2) abnormal secretion of insulin, and 3) increases in intra-abdominal fat. Altered circulating or tissue lipids are characteristic features of obesity and NIDDM. The etiology of these defects is not known. In this perspective, we propose that the same metabolic events, elevated malonyl-CoA and long-chain acyl-CoA (LC-CoA), in various tissues mediate, in part, the pleiotropic alterations characteristic of obesity and NIDDM. We review the evidence in support of the emerging concept that malonyl-CoA and LC-CoA act as metabolic coupling factors in beta-cell signal transduction, linking fuel metabolism to insulin secretion. We suggest that acetyl-CoA carboxylase, which synthesizes malonyl-CoA, a "signal of plenty," and carnitine palmitoyl transferase 1, which is regulated by it, may perform as fuel sensors in the beta-cell, integrating the concentrations of all circulating fuel stimuli in the beta-cell as well as in muscle, liver, and adipose tissue. The target effectors of LC-CoA may include protein kinase C sub-types, complex lipid formation, genes encoding metabolic enzymes or transduction factors, and protein acylation. We support the concept that only under conditions in which both glucose and lipids are plentiful will the metabolic abnormality, which may be termed glucolipoxia, become apparent. If our hypothesis is correct that common signaling abnormalities in the metabolism of malonyl-CoA and LC-CoA contribute to altered insulin release and sensitivity, it offers a novel explanation for the presence of variable combinations of these defects in individuals with differing genetic backgrounds and for the fact that it has been difficult to determine whether one or the other is the primary event.
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PMID:Are the beta-cell signaling molecules malonyl-CoA and cystolic long-chain acyl-CoA implicated in multiple tissue defects of obesity and NIDDM? 859 30

Preconditioning is an effective mean of protecting the heart against prolonged ischemia by pretreating it with a minor insult, and the present paper reviews various controversies in this highly active field of research. In many models, adenosine plays a role by triggering the activation of protein kinase C. It may work in conjunction with other agents, such as bradykinin, but the putative role of noradrenaline is uncertain. Regulation of the enzyme producing adenosine (i.e., 5'-nucleotidase) has been reported during preconditioning but, because its activity does not seem to be associated with infarct size, it is unlikely that the hydrolase plays a pivotal role. Controversial data have been published on the involvement of mitochondrial ATPase, which may be ascribed to the poor time resolution of the experiments described; however, we do not believe that either acidosis or tissue ATP are important factors in triggering preconditioning. The role of glycolysis in the preconditioning effect remains to be firmly established; opposite mechanisms are activated in low-flow and stop-flow protocols. Although species differences regarding preconditioning exist, they seem to be more of a quantitative than a qualitative nature. The phenomenon could be clinically relevant because evidence is accumulating that preconditioning may take place during bypass surgery and coronary angioplasty if longer balloon-occlusion times are used.
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PMID:Controversies in preconditioning. 911 Jan 21

Atypical protein kinase C-iota (aPKCiota) plays an important role in mitogenic signaling, actin cytoskeleton organization, and cell survival. Apart from the differences in the regulatory domain, the catalytic domain of aPKCiota differs considerably from other known kinases, because it contains a modification within the glycine-rich loop motif (GXGXXG) that is found in the nucleotide-binding fold of virtually all nucleotide-binding proteins including PKCs, Ras, adenylate kinase, and the mitochondrial F1-ATPase. We have used site-directed mutagenesis and kinetic analysis to investigate whether these sequence differences affect the nucleotide binding properties and catalytic activity of aPKCiota. When lysine 274, a residue essential for ATP binding and activity conserved in most protein kinases, was replaced by arginine (K274R mutant), aPKCiota retained its normal kinase activity. This is in sharp contrast to results published for any other PKC or even distantly related kinases like phosphoinositide 3-kinase gamma, where the same mutation completely abrogated the kinase activity. Furthermore, the sensitivity of aPKCiota for inhibition by GF109203X, a substance acting on the ATP-binding site, was not altered in the K274R mutant. In contrast, replacement of Lys-274 by tryptophan (K274W) completely abolished the kinase activity of PKCiota. In accordance with results obtained with other kinase-defective PKC mutants, in cultured cells aPKCiota-K274W acted in a dominant negative fashion on signal transduction pathways involving endogenous aPKCiota, whereas the effect of the catalytically active K274R mutant was identical to the wild type enzyme. In summary, aPKCiota differs from classical and novel PKCs also in the catalytic domain. This information could be of significant value for the development of specific inhibitors of aPKCiota as a key factor in central signaling pathways.
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PMID:Unique structural and functional properties of the ATP-binding domain of atypical protein kinase C-iota. 1090 26

Glucose depletion results in cellular stress and reactive oxygen species (ROS) production, which evokes adaptive and protective responses. One such protective response is the induction of haem oxygenase 1 (HO-1), which catalyses the rate-limiting step in haem degradation, liberating iron, CO and biliverdin. The present study evaluated the role of ROS and the mitochondrial electron-transport chain in the induction of HO-1 by glucose deprivation in HepG2 hepatoma cells. Either N-acetylcysteine, an antioxidant, or deferoxamine, an iron chelator, resulted in a dose-dependent inhibition of HO-1 mRNA and protein induction during glucose deprivation, suggesting a redox- and iron-dependent mechanism. Inhibitors of electron-transport chain complex III, antimycin A and myxothiazol, the ATP synthase inhibitor oligomycin and ATP depletion with 2-deoxyglucose or glucosamine also blocked HO-1 induction. To address the involvement of ROS further, specifically H(2)O(2), we showed that overexpression of catalase completely blocked HO-1 activation by glucose deprivation. In contrast, inhibition of nuclear factor kappa B, mitogen-activated protein kinase (MAPK), protein kinase A, protein kinase C, phosphoinositide 3-kinase, cyclo-oxygenase or cytosolic phospholipase A(2), did not prevent HO-1 induction. These results demonstrate that activation of the HO-1 gene by glucose deprivation is mediated by a 'glucose metabolic response' pathway via generation of ROS and that the pathway requires a functional electron-transport chain.
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PMID:Haem oxygenase 1 gene induction by glucose deprivation is mediated by reactive oxygen species via the mitochondrial electron-transport chain. 1258 63

Ischemic preconditioning confers cardiac protection during subsequent ischemia-reperfusion, in which protein kinase C (PKC) is believed to play an essential role, but controversial data exist concerning the PKC-delta isoform. In an accompanying study (26), we described metabolic changes in PKC-delta knockout mice. We now wanted to explore their effect on early preconditioning. Both PKC-delta(-/-) and PKC-delta(+/+) mice underwent three cycles of 5-min left descending artery occlusion/5-min reperfusion, followed by 30-min occlusion and 2-h reperfusion. Unexpectedly, preconditioning exaggerated ischemia-reperfusion injury in PKC-delta(-/-) mice. Whereas ischemic preconditioning increased superoxide anion production in PKC-delta(+/+) hearts, no increase in reactive oxygen species was observed in PKC-delta(-/-) hearts. Proteomic analysis of preconditioned PKC-delta(+/+) hearts revealed profound changes in enzymes related to energy metabolism, e.g., NADH dehydrogenase and ATP synthase, with partial fragmentation of these mitochondrial enzymes and of the E(2) component of the pyruvate dehydrogenase complex. Interestingly, fragmentation of mitochondrial enzymes was not observed in PKC-delta(-/-) hearts. High-resolution NMR analysis of cardiac metabolites demonstrated a similar rise of phosphocreatine in PKC-delta(+/+) and PKC-delta(-/-) hearts, but the preconditioning-induced increase in phosphocholine, alanine, carnitine, and glycine was restricted to PKC-delta(+/+) hearts, whereas lactate concentrations were higher in PKC-delta(-/-) hearts. Taken together, our results suggest that reactive oxygen species generated during ischemic preconditioning might alter mitochondrial metabolism by oxidizing key mitochondrial enzymes and that metabolic adaptation to preconditioning is impaired in PKC-delta(-/-) hearts.
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PMID:Ischemic preconditioning exaggerates cardiac damage in PKC-delta null mice. 1527 9

The ketogenic diet (KD) is an effective therapy for medically intractable epilepsy, but its anticonvulsant mechanisms are unknown. Few studies to date have addressed the molecular changes following treatment with a KD. In the present study, we fed juvenile rats either a standard diet or a KD for 1 month, and then determined changes in hippocampal gene expression using cDNA microarray analysis (Clontech). To validate the microarray expression results, we also performed Northern blot and RT-PCR analysis on a small subset of affected genes. Among a total of 1176 cDNAs, 42 genes were strongly up- or down-regulated (>2-fold change over controls) by a KD. We found that the expression of mitochondrial ATP synthase beta subunit, mitochondrial ATP synthase D subunit (ATP5H) and mitochondrial ATP synthase beta subunit precursor (ATP5F) were especially increased in KD-treated group, whereas the KD down-regulated protein kinase C (PKC) beta and epsilon isoforms. Thus, the most prominent changes were seen in genes encoding proteins involved in mitochondrial metabolic and intracellular signal transduction pathways. Our data provide some insights into the complex cascade of cellular changes in the hippocampus induced by a KD, some of which may contribute to its anticonvulsant effects.
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PMID:A cDNA microarray analysis of gene expression profiles in rat hippocampus following a ketogenic diet. 1546 84

Elevated plasma homocysteine has been reported in individuals with diseases of the metabolic syndrome including vascular disease and insulin resistance. As homocysteine exerts detrimental effects on endothelial and neuronal cells, this study investigated effects of acute homocysteine exposure on beta-cell function and insulin secretion using clonal BRIN-BD11 beta-cells. Acute insulin release studies in the presence of various test reagents were performed using monolayers of BRIN-BD11 cells and samples assayed by insulin radioimmunoassay. Cellular glucose metabolism was assessed by nuclear magnetic resonance (NMR) analysis following 60-min exposure of BRIN-BD11 cell monolayers to glucose in either the absence or presence of homocysteine. Homocysteine dose-dependently inhibited insulin release at moderate and stimulatory glucose concentrations. This inhibitory effect was reversible at all but the highest concentration of homocysteine. 13C-glucose NMR demonstrated decreased labelling of glutamate from glucose at positions C2, C3 and C4, indicating that the tricarboxylic acid (TCA) cycle-dependent glucose metabolism was reduced in the presence of homocysteine. Homocysteine also dose-dependently inhibited insulinotropic responses to a range of glucose-dependent secretagogues including nutrients (alanine, arginine, 2-ketoisocaproate), hormones (glucagon-like peptide-1 (7-36)amide, gastric inhibitory polypeptide and cholecystokinin-8), neurotransmitter (carbachol), drug (tolbutamide) as well as a depolarising concentration of KCl or elevated Ca2+. Insulin secretion induced by activation of adenylate cyclase and protein kinase C pathways with forskolin and phorbol 12-myristate 13-acetate were also inhibited by homocysteine. These effects were not associated with any adverse action on cellular insulin content or cell viability, and there was no increase in apoptosis/necrosis following exposure to homocysteine. These data indicate that homocysteine impairs insulin secretion through alterations in beta-cell glucose metabolism and generation of key stimulus-secretion coupling factors. The participation of homocysteine in possible beta-cell demise merits further investigation.
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PMID:Detrimental actions of metabolic syndrome risk factor, homocysteine, on pancreatic beta-cell glucose metabolism and insulin secretion. 1664 97

Heroin use is postulated to act as a cofactor in the neuropathogenesis of human immunodeficiency virus (HIV-1) infection. Astrocytes, integral components of the CNS, are reported to be susceptible to HIV-1 infection. Upon activation, astrocytes release a number of immunoregulatory products or modulate the expression of a number of proteins that foster the immunopathogenesis of HIV-1 infection. However, the role of heroin on HIV-1 infectivity and the expression of the proteome of normal human astrocytes (NHA) have not been elucidated. We hypothesize that heroin modulates the expression of a number of proteins by NHA that foster the neuoropathogenesis of HIV-1 infection. We utilized LTR amplification and the p24 antigen assay to quantitate the effect of heroin on HIV-1 infectivity while difference gel electrophoresis (DIGE) combined with protein identification through high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) to analyze the effects of heroin on the proteomic profile of NHA. Results demonstrate that heroin potentiates HIV-1 replication in NHA. Furthermore, heroin significantly increased protein expression levels for protein kinase C (PKC), reticulocalbin 1 precursor, reticulocalbin 1, tyrosine 3-monooxgenase/tryptophan 5-monooxgenase activation protein, chloride intracellular channel 1, cathepsin D preproprotein, galectin 1 and myosin light chain alkali. Heroin also significantly decreased protein expression for proliferating cell nuclear antigen, proteasome beta 6 subunit, tropomyosin 3, laminin receptor 1, tubulin alpha 6, vimentin, EF hand domain family member D2, Tumor protein D54 (hD54), ATP synthase, H+ transporting, mitochondrial F1 complex and ribosomal protein S14. Identification of unique, heroin-induced proteins may help to develop novel markers for diagnostic, preventative and therapeutic targeting in heroin using subjects.
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PMID:Heroin-Induces Differential Protein Expression by Normal Human Astrocytes (NHA). 1723 76

Mitochondrial ATP synthase (F1Fo-ATPase) is regulated by an intrinsic ATPase inhibitor protein. In the present study, using RT-PCR combined with in silico cloning, we isolated and sequenced the cDNA encoding the inhibitor protein of the giant panda (Ailuropoda melanoleuca). The deduced protein sequence showed that the protein is composed of 106 amino acids and the estimated molecular weight of the ATPIF(1) protein is 12.32 kDa with an isoelectric point (pI) of 10.17. Alignment analysis revealed that the deduced protein sequence shares 66%, 78.3%, 66%, 72.6%, 77.4%, and 78.3% homology with that of Mus musculus, Pan troglodytes, Rattus norvegicus, Bos taurus, Macaca mulatta, and Homo sapiens, respectively. Topology prediction showed that there are three protein kinase C phosphorylation sites, one amidation site, three N-myristoylation sites, one casein kinase II phosphorylation site, and one tyrosine kinase phosphorylation site in the ATPase inhibitor. In particular, amino acids in the region between 39 and 72, which is the minimum sequence showing ATPase inhibitory activity, were highly conserved in the protein.
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PMID:Nucleotide sequence of cDNA encoding the mitochondrial precursor protein of the ATPase inhibitor from the giant panda (Ailuropoda melanoleuca). 1782 58


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