Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.6.3.1 (Mg2+-ATPase)
 1,484 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A hypothesis of the flippase nature of the glutathione S-conjugate transport is presented. Experimental premises for this hypothesis include interaction of glutathione S-conjugates with the membrane, as demonstrated by their effects on membrane fluidity, quenching of 1-(4-trimethylammoniumphenyl)-6-phenyl-1,3,5-hexatriene fluorescence and induction of echinocytosis by 2,4-dinitrophenyl-S-glutathione (DNP-SG). This hypothesis can rationalize, i. a., observations of the enhancement of DNP-SG transport by butanol and stimulation of erythrocyte membrane Mg(2+)-ATPase activity by albumin-coupled DNP-SG.
Biochem Mol Biol Int 1998 Jan
PMID:Is the glutathione S-conjugate pump a flippase? 950 52

We studied the effect of cyclosporine A on hepatic Ca2+, Mg2+-ATPase and F-actin on bile canalicular and basolateral membranes in rats fed either soyabean lecithin, or triacylglycerol enriched diet, or low fat diet. Ca2+, Mg2+-ATPase histochemical activity was not modified in lecithin-cyclosporine A group, whereas the activity was decreased in the other groups. The triacylglycerol-cyclosporine A group had the lower activity. The histochemical staining of F-actin was quite normal in lecithin-cyclosporine group but decreased in the other cyclosporine A treated groups. The lower staining was observed in the triacylglycerol-cyclosporine group. The alteration of Ca2+, Mg2+-ATPase and F-actin by cyclosporine A, related to cholestasis evidenced by a decrease in bile salt secretion, were prevented by dietary soyabean lecithin and amplified by dietary soyabean triacylglycerol.
Cell Mol Biol (Noisy-le-grand) 1998 Dec
PMID:Modification of Ca2+, Mg2+-ATPase and F-actin distribution in hepatocytes of cyclosporine A treated rats. Effect of soyabean lecithin and triacylglycerol. 987 9

B16 murine melanoma melanosomes were purified using sucrose density gradient centrifugation. ATPase activity was evaluated in presence of specific ATPase inhibitors, and compared with melanosome ATP-driven proton translocating activity in the melanosome. Mg2+ dependent ATPase activity was greatly inhibited (82%) by the specific inhibitors of vaculor proton translocating ATPase; Cis-didimethylsulfoxide dichloroplatinum (II) at approximately 90 microM and bafilomycin AI at two fold higher concentrations. Less inhibition, about 30 and 45% was obtained with N, N1-dicyclohexylcarbodiimide and N-ethylmaleimide, and the maximal effect occurred in the 50-100 microM and 0.1-1.5 mM ranges, respectively. These drugs at similar concentrations also inhibited the proton pumping activity to the same extent as observed for ATPase activity and half-maximal inhibition of each activity was found at nearly similar concentrations. Carbonylcyanide p-trifluoromethoxyphenyl hydra zone (FCCP) prevented ATP from setting up a pH gradient across the melanosomal membrane but stimulated Mg2+ ATPase activity significantly. Replacement of 5 mM Mg2+ with equimolar Ca2+ brought about a 60% inhibition in divalent cation-dependent ATPase- activity, and an 85% inactivation of ATP-linked melanosomal H+ pump activity. In the presence of optimal concentrations of Ca2+ and Mg2+ ATPase activity was similar to that seen in a Mg2+ medium. In Ca2+ medium ATPase activity was inhibited by CDDP and stimulated by FCCP, however these effects were two to three fold less than those observed in Mg2+ medium. FCCP failed to stimulate ATPase activity in CDDP- supplemented medium, thus suggesting that the same ATPase activity fraction was sensitive to both CDDP and FCCP. Mg2+-ATPase activity, like the proton-pump was anion dependent. The lowest activity was recorded in F medium, and increased in the order of F < So4(2-) < CL- = Br-. These results show that the ATPase activity may be related to the melanosomal proton pump.
Mol Cell Biochem 1998 Dec
PMID:Characterization of Mg2+-ATPase activity in isolated B16 murine melanoma melanosomes. 987 59

P-glycoprotein (P-gp), encoded by the MDR1 gene, is a plasma membrane transporter which effluxes a large number of structurally nonrelated hydrophobic compounds. The molecular basis of the broad substrate recognition of P-gp is not well understood. Despite the 78% amino acid sequence identity of the MDR1 and MDR2 transporter, MDR2, which has been identified as a phosphatidylcholine transporter, does not transport most MDR1 substrates. The structural and functional differences between MDR1 and MDR2 provide an opportunity to identify the residues essential for the broad substrate spectrum of MDR1. Using an approach involving exchanging homologous segments of MDR1 and MDR2 and site-directed mutagenesis, we have demonstrated that MDR1 residues Q330, V331, and L332 in transmembrane domain 6 are sufficient to allow an MDR2 backbone in the N-terminal half of P-gp to transport several MDR1 substrates, including bisantrene, colchicine, vinblastine, and rhodamine-123. These studies help define some residues important for multidrug transport and indicate the close functional relationship between the multidrug transporter (MDR1) and phosphatidylcholine flippase (MDR2).
Mol Cell Biol 1999 Feb
PMID:Studies of human MDR1-MDR2 chimeras demonstrate the functional exchangeability of a major transmembrane segment of the multidrug transporter and phosphatidylcholine flippase. 989 Oct 78

Multidrug resistance (MDR) mediated by P-glycoprotein (MDR1) is clinically significant. Understanding how MDR1 substrate specificity is determined will help to overcome MDR to improve cancer treatment. One potential approach to achieve this goal is to study chimeras of MDR1 and its homolog MDR2 (also called MDR3), which has been identified as a phosphatidylcholine flippase. With an approach involving exchanging homologous segments of MDR1 and MDR2 and site-directed mutagenesis, we previously demonstrated MDR1 residues Q330, V331, and L332 in transmembrane domain 6 (TM6) are essential for multidrug transport activity; substituting these residues allows the N-terminal transmembrane region of MDR2 to support MDR1 activity. To further determine the exchangeability between MDR1 and MDR2, we constructed additional MDR1/MDR2 chimeras. We found that the N-terminal half of MDR1 and MDR2 was mostly exchangeable except for a few residues in TM6. However, this degree of exchangeability was not found in the C-terminal half of MDR1 and MDR2. In addition, with substitution of MDR1 residues 318-332 (TM6) and 937-994 (TM11-12), MDR2 had relatively normal affinity for MDR1 substrates, but it did not have multidrug transporter activity. These results suggest that the inability of MDR2 to transport most MDR1 drugs efficiently may be due to failure of those drugs to stimulate ATPase and activate transport as well as to decreased drug binding.
Mol Pharmacol 1999 Nov
PMID:Domain exchangeability between the multidrug transporter (MDR1) and phosphatidylcholine flippase (MDR2). 1053 6

This study examined the status of sarcolemmal Na+/K+-ATPase activity in rat heart under conditions of Ca2+-paradox to explore the existence of a relationship between changes in Na+/K+-pump function and myocardial Na+ as well as K+ content. One min of reperfusion with Ca2+ after 5 min of Ca2+-free perfusion reduced Na+/K+-ATPase activity in the isolated heart by 53% while Mg2+-ATPase, another sarcolemmal bound enzyme, retained 74% of its control activity. These changes in sarcolemmal ATPase activities were dependent on the duration and Ca2+ concentration of the initial perfusion and subsequent reperfusion periods; however, the Na+/K+-ATPase activity was consistently more depressed than Mg2+-ATPase activity under all conditions. The depression in both enzyme activities was associated with a reduction in Vmax without any changes in Km values. Low Na+ perfusion and hypothermia, which protect the isolated heart from the Ca2+-paradox, also prevented reperfusion-induced enzyme alterations. A significant relationship emerged upon comparison of the changes in myocardial Na+ and K+ content to Na+/K+-ATPase activity under identical conditions. At least 60% of the control enzyme activity was necessary to maintain normal cation gradients. Depression of the Na+/K+-ATPase activity by 60-65% resulted in a marked increase and decrease in intracellular Na+ and K+ content, respectively. These results suggest that changes in myocardial Na+ and K+ content during Ca2+-paradox are related to activity of the Na+/K+-pump; the impaired Na+/K+-ATPase activity may lead to augmentation of Ca2+-overload via an enhancement of the Na+/Ca2+-exchange system.
Mol Cell Biochem 2000 Apr
PMID:Modification of heart sarcolemmal Na+/K+-ATPase activity during development of the calcium paradox. 1088 31

To investigate the mechanism underlying postischemic contractile dysfunction (myocardial stunning) we examined myocardial sulflhydryl group content, myofibrillar Ca2+-dependent Mg2+-ATPase activity and protein profile after global ischemia and reperfusion. The Langerdorff-perfused rabbit hearts were subjected to 15 min normothermic ischemia followed by 10 min reperfusion and myofibrils were isolated from homogenates of left ventricular tissues. Depressed contractile function during reperfusion was accompanied by a decrease in total sulfhydryl group content. However, myofibrillar protein profile was unchanged and Western immunoblotting analysis showed no significant differences in troponin I immunoreactive bands between control and stunned hearts. Likewise, myofibrillar Mg2+-ATPase activity was unaltered after ischemia and reperfusion. We conclude that myocardial stunning is not caused by altered myofibrillar function and protein degradation but may be partly due to the oxidative modification of as yet undefined proteins.
Mol Cell Biochem 2002 Apr
PMID:Effect of myocardial stunning on thiol status, myofibrillar ATPase and troponin I proteolysis. 1208 69

A numerical model of the LmrA multi-drug transport system of Lactococcus lactis is used to explore the possibility of distinguishing experimentally between two putative transport mechanisms, i.e., the vacuum-cleaner and the flippase mechanisms. This comparative model also serves as an example of numerical simulation with the scripting language Python and its scientific add-on Scipy.
Mol Biol Rep 2002
PMID:How to distinguish between the vacuum cleaner and flippase mechanisms of the lmrA multi-drug transporter in Lactococcus lactis. 1224 Oct 38

The spread of multidrug resistance (MDR) is a world health crisis that presents a significant challenge to the treatment of cancer and infection. MDR can be caused by a group of ABC (MDR-ABC) transporters that move hydrophobic drug molecules and lipids across the cell membrane. To gain insight into the conformational changes these transporters undergo when flipping hydrophobic substrates across the lipid bilayer, we have determined the structure of the lipid flippase MsbA from Vibrio cholera (VC-MsbA) to 3.8A. Structural comparison of VC-MsbA to MsbA from Escherichia coli reveals that the transporters share a structurally conserved core of transmembrane alpha-helices, but differ in the relative orientations of their nucleotide-binding domains (NBD). The transmembrane domain of VC-MsbA is captured in a closed conformation and the structure supports a "power stroke" model of transporter dynamics where opposing NBDs associate upon ATP binding. The separation of the alpha and beta domains of the NBD suggests the possibility that their association could make them competent to bind ATP and gives further insight into the structural basis for catalytic regulation.
J Mol Biol 2003 Jul 04
PMID:Structure of MsbA from Vibrio cholera: a multidrug resistance ABC transporter homolog in a closed conformation. 1758 Mar 80

Adriamycin, which is widely used in the treatment of various neoplastic conditions, exerts toxic effects in several organs. Adriamycin nephrotoxicity has been recently documented in a variety of animal species. The present study was designed to investigate the effect of lipoic acid on the nephrotoxic potential of adriamycin. The study was carried out with adult male albino rats of Wistar strain. Test animals were divided into four groups of six rats each as follows: Group I (control) received only normal saline throughout the course of the experiment. Group II (ADR) received intravenous injections of adriamycin through the tail vein (1 mg kg(-1) body wt day(-1)) once a week for a period of 12 weeks. Group III (LA) received lipoic acid (35 mg kg(-1) body wt day(-1)) intraperitoneally once a week for a period of 12 weeks. Group IV (ADR + LA) received a single injection of lipoic acid intraperitoneally 24 h prior to the administration of adriamycin through the tail vein once a week for a period of 12 weeks. Intravenous injections of adriamycin resulted in decreased activities of the glycolytic enzymes; hexokinase, phosphoglucoisomerase, aldolase and lactate dehydrogenase in the rat renal tissue. The gluconeogenic enzymes, glucose-6-phosphatase and fructose-1,6-diphosphatase, showed a decline in their activities on adriamycin administration. The transmembrane enzymes namely the Na+,K+-ATPase, Ca2+-ATPase, Mg2+-ATPase and the brush-border enzyme alkaline phosphatase also showed a decrease in their activities. This decrease in the activities of ATPases and alkaline phosphatase suggests basolateral and brush-border membrane damage. Decreased activities of the TCA cycle enzymes isocitrate dehydrogenase, succinate dehydrogenase and malate dehydrogenase, suggest a loss in mitochondrial function and integrity. Nephrotoxicity was evident from the increased excretions of N-acetyl-beta-D-glucosaminidase and gamma-glutamyl transferase in the urine of adriamycin administered rats. These biochemical disturbances were effectively counteracted on pre-treatment with lipoic acid, which brought about an increase in the activities of glycolytic enzymes, ATPases and the TCA cycle enzymes. On the other hand, the gluconeogenic enzymes showed a further decrease in their activities on lipoic acid pretreatment. LA pretreatment also restored the activities of the urinary enzymes to normal. These observations shed light on the nephroprotective action of lipoic acid rendered against experimental aminoglycoside toxicity.
Mol Cell Biochem 2003 May
PMID:The influence of lipoic acid on adriamycin induced nephrotoxicity in rats. 1284 26


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