Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.6.1.3 (ATPase)
 65,361 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The calcium pump of human red cells can be irreversibly activated by preincubation of the membranes in the presence of calcium ions, with a pattern reminiscent of that produced by controlled trypsin attack. With 1 mM Ca2+, the activity of the basal enzyme increases three to fourfold over 30 to 60 min, to levels about half those obtained in the presence of calmodulin. On the whole, the effect occurs slowly, with a very low Ca2+ affinity at 37 degrees C and is unaffected by serine-protease inhibitors. The activation caused by 1 mM Ca2+ is little affected by leupeptin (a thiol-protease inhibitor) and that obtained at 10 microM Ca2+ is not inhibited. Preincubations at 0 degrees C also lead to activation, to a level up to half that seen at 37 degrees C, and the effect is not affected by leupeptin or antipain. No activation is observed by preincubating soluble purified Ca,Mg-ATPase in Ca(2+)-containing solutions at 37 degrees C. Instead, calcium ions protect the detergent-solubilized enzyme from thermal inactivation, the effect being half-maximal between 10 and 20 microM Ca2+. We conclude that the activation of the membrane-bound Ca,Mg-ATPase by Ca2+ should result from an irreversible conformational change in the enzyme and not from attack by a membrane-bound protease, and that this change presumably arises from the release of inhibitory particles existing in the original membrane preparations.
 ...
PMID:Irreversible effects of calcium ions on the plasma membrane calcium pump. 811 81

When expressed alone in fibroblasts, approximately 80% of newly made H2b subunits of the human asialoglycoprotein receptor are retained and degraded in the endoplasmic reticulum (ER), whereas about 20% reaches the plasma membrane (1). Thapsigargin, an inhibitor of the ER Ca2+ ATPase, blocks ER folding of the H1 (2) as well as of the H2b subunit, prevents maturation of H2b, and accelerates ER degradation of newly made H2b. The secretory pathway is normal in thapsigargin-treated cells, as monitored by maturation of the vesicular stomatitis virus G protein. The protease inhibitors TLCK and TPCK block the first step in ER degradation of H2, an endoproteolytic cleavage just exoplasmic to the membrane-spanning domain. In protease inhibitor-treated cells, the approximately 80% of H2b that would normally be degraded remains in the ER; as judged by migration on nonreducing SDS-polyacrylamide gel electrophoresis this H2b is improperly folded. Thus, incorrectly folded H2b is normally subjected to ER degradation. In the presence of thapsigargin H2b cannot fold properly and is degraded within the ER. The preferential ER degradation of misfolded or unfolded membrane proteins demonstrated here, functions as a step in ER quality control.
 ...
PMID:Unfolded H2b asialoglycoprotein receptor subunit polypeptides are selectively degraded within the endoplasmic reticulum. 831 99

The tumor suppressor wild-type p53 can induce apoptosis. M1-t-p53 myeloid leukemic cells have a temperature-sensitive p53 protein that changes its conformation to wild-type p53 after transfer from 37 degrees C to 32 degrees C. We have now found that these cells showed an early lysosomal rupture after transfer to 32 degrees C. Mitochondrial damage, including decreased membrane potential and release of cytochrome c, and the appearance of apoptotic cells occurred later. Lysosomal rupture, mitochondrial damage, and apoptosis were all inhibited by the cytokine IL-6. Some other compounds can also inhibit apoptosis induced by p53. The protease inhibitor N-tosyl-l-phenylalanine chloromethyl ketone inhibited the decrease in mitochondrial membrane potential and cytochrome c release, the Ca(2+)-ATPase inhibitor thapsigargin inhibited only cytochrome c release, and the antioxidant butylated hydroxyanisole inhibited only the decrease in mitochondrial membrane potential. In contrast to IL-6, these other compounds that inhibited some of the later occurring mitochondrial damage did not inhibit the earlier p53-induced lysosomal damage. The results indicate that apoptosis is induced by p53 through a lysosomal-mitochondrial pathway that is initiated by lysosomal destabilization, and that this pathway can be dissected by using different apoptosis inhibitors. These findings on the induction of p53-induced lysosomal destabilization can also help to formulate new therapies for diseases with apoptotic disorders.
 ...
PMID:Lysosomal destabilization in p53-induced apoptosis. 1195 17

Oxidative stress plays an important role in many neurodegenerative conditions including Alzheimer's disease and Parkinson's disease. 4-Hydroxynonenal (HNE), a lipid-soluble aldehydic product of membrane peroxidation, has been known to decrease neuronal survival by impairing Na+, K+, and -ATPase activity. HNE also increases neuronal vulnerability to excitotoxic injury and disrupts homeostasis by activating proteases which mediate the destruction of cellular protein and structure. The present study demonstrated that the hydrophobic HIV protease inhibitor, ritonavir inhibited HNE-mediated apoptosis in hippocampal primary neurons. In neurons exposed to oxidative stress induced by HNE (1 microM), ritonavir at 100 pM increased cell survival and completely abolished the apoptotic effects of HNE (P < 0.01). Ritonavir and its analogues might have useful cytoprotective effects for use in limiting the natural course of tissue injury after conditions where oxidative stress plays a role.
 ...
PMID:Ritonavir protects hippocampal neurons against oxidative stress-induced apoptosis. 1238 58

The presence of the normal cellular prion-protein (PrPc) is a prerequisite for the development of fatal, neurodegenerative diseases called transmissible spongiform encephalopathies (TSEs). We discovered a new biological activity of the well-known coumarin antibiotic novobiocin; the treatment of eukaryotic cells with novobiocin induces the rapid depletion of PrPc. This activity is shared by coumermycin A1, another coumarin with a related molecular structure. Novobiocin's effects on the prion-protein are time- and dose-dependent. No permanent damage to the treated cells was observed, which continue to proliferate after cessation of drug exposure. Most of the cellular proteins are unaffected by novobiocin treatment. Pretreatment with geldanamycin, an inhibitor of the aminoterminal ATPase of heat-shock protein 90 (Hsp90) partially antagonizes novobiocin's depletory activity. Concurrent treatment with the protease inhibitor chymostatin completely prevents PrPc loss. Here we show that the stability of the normal cellular prion-protein may be targeted pharmacologically. These findings open up a hitherto unknown avenue to the study of TSEs in general and may have therapeutic implications.
 ...
PMID:Destabilization of the non-pathogenic, cellular prion-protein by a small molecular drug. 1525 7

Horse flies feed from superficial haematomas and probably rely heavily on the pharmacological properties of their saliva to find blood. Here we describe the first evidence of vasodilators in horse fly Hybomitra bimaculata (Diptera, Tabanidae) salivary gland extract and clone and express one of the active peptides (termed vasotab). Physiological tests using crude salivary gland extracts and reverse-phase HPLC fractions demonstrated positive inotropism in isolated rat hearts, vasodilatation of coronary and peripheral vessels, and Na, K-ATPase inhibition. One of the vasoactive fractions was analysed by N-terminal Edman degradation and a 47-amino-acid sequence obtained. A full-length cDNA encoding the peptide was cloned from a phage library using degenerate primer PCR and the peptide expressed in insect cells. A 20-amino-acid signal sequence precedes the mature 56-amino-acid vasotab peptide, which is a member of the Kazal-type protease inhibitor family. The peptide has a unique 7-amino-acid insertion between the third and fourth cysteine residues. The recombinant peptide prolonged the action potential and caused positive inotropism of isolated rat heart myocytes, and may be an ion channel modulator.
 ...
PMID:Vasotab, a vasoactive peptide from horse fly Hybomitra bimaculata (Diptera, Tabanidae) salivary glands. 1639 56

5-[5-(2-Nitrophenyl) furfuryliodine]-1,3-diphenyl-2-thiobarbituric acid (UCF-101) is a protease inhibitor which was reported to protect against ischaemic heart damage and apoptosis. This study evaluated the impact of UCF-101 on steptozotocin (STZ)-induced diabetic cardiomyocyte dysfunction. Adult FVB mice were made diabetic with a single injection of STZ (200 mg kg(1)). Two weeks after STZ injection, cardiomyocytes from control and STZ-treated mice were isolated and treated with UCF-101 (20 mum for 1 h). Cardiomyocyte contractile properties were analysed, including peak shortening (PS), maximal velocity of shortening/relengthening (+/-dL/dt), time to PS (TPS) and time to 90% relengthening (TR(90)). Steptozotocin-induced diabetes depressed PS and +/-dL/dt and prolonged TPS and TR(90) in cardiomyocytes, all of which were significantly alleviated by UCF-101. Immunoblotting analysis showed that UCF-101 significantly alleviated STZ-induced loss of phospholamban phosphorylation without affecting sarco(endo)plasmic reticulum Ca(2+)-ATPase (SERCA2a) and phospholamban. Steptozotocin reduced AMP-activated protein kinase (AMPK) phosphorylation at Thr172 of the catalytic subunit without affecting total AMPK expression, which was restored by UCF-101. Short-term exposure to UCF-101 did not change the expression of X-linked inhibitor of apoptosis protein (XIAP) and Omi stress-regulated endoprotease, high temperature requirement protein A2 (Omi/HtrA2), favouring an apoptosis-independent mechanism. Both the AMPK activator resveratrol and the antioxidant N-acetylcysteine mimicked the UCF-101-induced beneficial effect in STZ-induced diabetic cardiomyocytes. In addition, UCF-101 promoted the phosphorylation of p38 mitogen-activated protein kinases and c-Jun N-terminal kinase (JNK) after 15 min of incubation, while it failed to affect the phosphorylation of extracellular signal-regulated kinase (ERK) and glycogen synthase kinase-3beta (GSK-3beta) within 120 min in H9C2 myoblasts. Taken together, these results indicate that UCF-101 protects against STZ-induced cardiomyocyte contractile dysfunction, possibly via an AMPK-associated mechanism.
 ...
PMID:The protease inhibitor UCF-101 ameliorates streptozotocin-induced mouse cardiomyocyte contractile dysfunction in vitro: role of AMP-activated protein kinase. 2751 Jun 42

Ammopiptanthus mongolicus is the only evergreen broadleaf shrub endemic to the Alashan desert, northwest sand area of China, and can survive -30 degrees C or an even lower temperature in winter. A modified solid-phase subtraction hybridization technique was developed to isolate and screen cDNAs whose transcripts increased in cold-treated A. mongolicus seedlings. Sequence analysis of the screened clones indicated that 11 clones had coding regions, with four of them containing a complete open reading frame. Nine of the 11 clones shared various degrees of homology with the genes found in the GenBank database and the other two were unidentified sequences. Sequence data further revealed that these accumulated transcripts encoded: three low molecular weight proteins (a late-embryogenesis protein and two cold acclimation responsive proteins); two photosynthesis-related proteins, (photosystem I subunit II precursor (PsaD) and photosystem II oxygen-evolving complex 33kDa subunit OEC33); a protease inhibitor; an adenosine triphosphatase and a 14-3-3 related protein. Analysis of the function of these proteins indicated that the low molecular weight proteins were associated with water holding ability of cytoplasm, photosynthesis-related proteins participated in the adjustments of photosynthetic apparatus to resist photoinhibition; 14-3-3 related protein could interact with adenosine triphosphatase to enhance ATPase activity and energy metabolism, and protease inhibitor is involved in the prevention of unwanted cell death caused by reactive oxygen species. We suggest that cold acclimation with low light intensity in A. mongolicus is a more complex interaction of low temperature, light, energy and signal than that assumed previously.
 ...
PMID:Functional analysis of cold-inducible cDNA clones in the legume Ammopiptanthus mongolicus. 1982 50

S5, a hepatitis C virus protease inhibitor, displays partially saturable efflux in the Caco-2 system. In addition, the efflux can be reversed by cyclosporine, indicating that S5 may be a human P-glycoprotein (P-gp) substrate. S5 can also activate the ATPase activity in vesicle membranes containing mouse P-gp 1a and 1b, suggesting that S5 may be a substrate for mouse P-gp. The pharmacokinetics and tissue distribution of S5 were evaluated after intravenous and oral administration to wild-type and 1a/1b knockout mice. Plasma and kidney levels of this compound in knockout mice were transiently higher than those in wild-type mice only after oral dosing, indicating effective P-gp efflux occurs in wild-type mice. The levels of S5 in brain samples from knockout mice were higher than those from wild-type mice after both intravenous and oral administration, but much more significantly after intravenous administration. The levels in liver were four time higher in knockout mice than in wild-type mice after oral administration, but were not different between knockout and wild-type mice after intravenous administration. These results suggest that P-gp efflux limits exposure to S5 in the brain and liver, and that the effect is dependent on the route of administration.
 ...
PMID:The role of P-glycoprotein in the pharmacokinetics and tissue distribution of a hepatitis C virus protease inhibitor. 1999 30

We report a case of hyperkalemia in a recipient of living-related liver transplantation. The patient received a continuous infusion of gabexate mesilate at 60 mg x hr(-1) starting about 1 hr after the induction of anesthesia. The serum potassium concentration (K+) was increased from 4.53 mEq x l-(1) to 5.08 mEq x l(-1) within about 1 hr. Thereafter, a massive blood loss caused by an accidental damage of the portal vein necessitated rapid fluid therapy to maintain blood pressure. We observed an abnormal ECG recording including a wide QRS complex and a high T wave when about 30 units of leukocytes-reduced red cell concentrates had been transfused. Blood gas analysis showed high K+ (7.52 mEq x l(-1)) and metabolic acidosis (pH 7.167, base excess-12.5 mmol x l(-1)). We successfully controlled K+ with combination of therapies before causing any cardiac events to the patient. Gabexate mesilate is one possible cause of hyperkalemia in the present case because an increase in K+ was observed before transfusion, and transfusion might have augmented the effect. Gabexate mesilate is one of the protease inhibitors. Naphamostat mesilate, another protease inhibitor, is known to cause hyperkalemia by limiting potassium excretion from the kidney through an inhibition of Na/K-ATPase at the cortical collecting ducts. Although the mechanism by which gabexate mesilate causes hyperkalemia is unclear, it would be of benefit to use this drug cautiously, as it may cause hyperkalemia.
 ...
PMID:[Case of hyperkalemia possibly caused by gabexate mesilate]. 2016 71


<< Previous 1 2 3 Next >>