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)

Mutations in the FIC1 gene constitute the molecular defect in familial intrahepatic cholestasis I (Fic1 [Byler's disease]) and benign recurrent intrahepatic cholestasis. This report describes the localization of Fic1 in rat liver and intestine, as well as biochemical and transfection studies that support its function as an energy-dependent aminophospholipid translocase. Immunocytochemistry of rat liver and immunoblotting of membrane fractions localized Fic1 to the canalicular, but not basolateral, plasma membrane domain. In the small intestine, Fic1 was localized to the apical membrane of epithelial cells. The distribution of Fic1 in liver plasma membrane fractions from control and taurocholate-treated rats correlated positively with adenosine triphosphate (ATP)-dependent aminophospholipid (phosphatidyl-serine) translocase activity. In canalicular membrane vesicles, translocase activity had an initial velocity of 3.3 nmol phosphatidylserine (PS) translocated per milligram of protein per minute and a K(m) (ATP) = 1.2 mmol/L; was inhibited by vanadate, N-ethylmaleimide, sodium azide, and calcium; and was unidirectional (i.e., from the outer to the inner canalicular plasma membrane leaflet). Transient transfection of CHOK1 cells with FIC1 cDNA resulted in appearance of FIC1 in membrane preparations and energy-dependent PS translocation in cells. These studies indicate that FIC1 is a canalicular P-type ATPase that participates in maintaining the distribution of aminophospholipids between the inner and outer leaflets of the plasma membrane. How this process produces cholestasis is under study.
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PMID:Familial intrahepatic cholestasis 1: studies of localization and function. 1158 74

The iridovirus isolate termed cricket iridovirus (CrIV) was isolated in 1996 from Gryllus campestris L. and Acheta domesticus L. (both Orthoptera, Gryllidae). CrIV DNA shows distinct DNA restriction patterns different from those known for Insect iridescent virus type 6 (IIV-6). This observation led to the assumption that CrIV might be a new species within the family Iridoviridae. CrIV can be transmitted perorally to orthopteran species, resulting in specific, fatal diseases. These species include Gryllus bimaculatus L. and the African migratory locust Locusta migratoria migratorioides (Orthoptera, Acrididae). Analysis of genomic and host range properties of this isolate was carried out in comparison to those known for IIV-6. Host range studies of CrIV and IIV-6 revealed no differences in the peroral susceptibility in all insect species and developmental stages tested to date. Different gene loci of the IIV-6 genome were analyzed, including the major capsid protein (274L), thymidylate synthase (225R), an exonuclease (012L), DNA polymerase (037L), ATPase (075L), DNA ligase (205R) and the open reading frame 339L, which is homologous to the immediate-early protein ICP-46 of frog virus 3. The average identity of the selected viral genes and their gene products was found to be 95.98 and 95.18% at the nucleotide and amino acid level, respectively. These data led to the conclusion that CrIV and IIV-6 are not different species within the Iridoviridae family and that CrIV must be considered to be a variant and/or a novel strain of IIV-6.
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PMID:Comparative analysis of the genome and host range characteristics of two insect iridoviruses: Chilo iridescent virus and a cricket iridovirus isolate. 1180 40

Ischaemic brain oedema appears to involve two distinct processes, the relative contribution and time course of which depend on the duration and severity of ischaemia, and the presence of reperfusion. The first process involves an increase in tissue Na+ and water content accompanying increased pinocytosis and Na+, K+ ATPase activity across the endothelium. This is apparent during the early phase of infarction and before any structural damage is evident. This phenomenon is augmented by reperfusion. A second process results from a more indiscriminate and delayed BBB breakdown that is associated with infarction of both the parenchyma and the vasculature itself. Although, tissue Na+ level still seems to be the major osmotic force for oedema formation at this second stage, the extravasation of serum proteases is an additional potentially deleterious factor. The relative importance of protease action is not yet clear, however, degradation of the extracellular matrix conceivably leads to further BBB disruption and softening of the tissue, setting the stage for the most pronounced forms of brain swelling. A number of factors mediate or modulate ischaemic oedema formation, however, most current information comes from experimental models, and clinical data on this microcosmic level is lacking. Clinically significant brain oedema develops in a delayed fashion after large hemispheric strokes and is a cause of substantial mortality. Neurological signs appear to be at least as good as direct ICP measurement and neuroimaging in detecting and gauging the secondary damage produced by stroke oedema. The neuroimaging characteristics of the stroke, specifically the early involvement of greater than half of the MCA territory, are, however, highly predictive of the development of severe oedema over the subsequent hours and days. None of the available medical therapies provide substantial relief from the oedema and raised ICP, or at best, they are temporizing in most cases. Hemicraniectomy appears most promising as a method of avoiding death from brain compression, but the optimum timing and manner of patient selection are currently being investigated. All approaches to massive ischaemic brain swelling are clouded by the potential for survival with poor functional outcome. It is possible to manage blood pressure, serum osmolarity by way of selective fluid administration, and a number of other systemic factors that exaggerate brain oedema. Broad guidelines for treatment of stroke oedema can therefore be given at this time.
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PMID:Ischaemic brain oedema. 1192 96

ATP8B1/FIC1 is a member of the Type IV P-type ATPase family, which function as ATP dependent aminophospholipid translocases (APLT). We identified two familial intrahepatic cholestasis type 1 (FIC1) homologues, ATP8B2 and ATP8B3, with 53% and 45% amino acid identity, respectively. The expression profile for each gene was determined using a 73-tissue human RNA expression array. The subfamily of FIC1-like proteins is expressed in a wide range of tissues. Given that mutations in FIC1 result in liver disease, these proteins may have important roles in other organs in which they are candidates for genetic and acquired diseases.
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PMID:FIC1, a P-type ATPase linked to cholestatic liver disease, has homologues (ATP8B2 and ATP8B3) expressed throughout the body. 1288 Aug 72

Mutations in ATP8B1, a broadly expressed P-type ATPase, result, through unknown mechanisms, in disorders of bile secretion. These disorders vary in severity from mild and episodic to progressive with liver failure. We generated Atp8b1G308V/G308V mutant mice, which carry a mutation orthologous to that present in homozygous form in patients from the Amish index kindred for severe ATP8B1 disease. In contrast to human patients, Atp8b1(G308V/G308V) mice had unimpaired bile secretion and no liver damage, but showed mild abnormalities including depressed weight at weaning and elevated serum bile salt levels. We challenged the hepatobiliary metabolism of Atp8b1G308V/G308V mice by administering exogenous bile salts. Upon bile salt feeding, Atp8b1G308V/G308V mice, but not wild-types, demonstrated serum bile salt accumulation, hepatic injury and expansion of the systemic bile salt pool. Unexpectedly, this failure of bile salt homeostasis occurred in the absence of any defect in hepatic bile secretion. Upon infusion of a hydrophobic bile salt, wild-type mice developed cholestasis while Atp8b1G308V/G308V mice maintained high biliary output and more extensively rehydroxylated the infused bile salt. Increased bile salt hydroxylation, which reduces bile salt toxicity, may explain the milder phenotype in Atp8b1G308V/G308V mice compared with humans with the equivalent mutation. These results demonstrate the key role of Atp8b1 in bile salt homeostasis and highlight the importance of bile salt hydroxylation in the prevention of cholestasis. The mouse phenotype reveals that loss of Atp8b1 disrupts bile salt homeostasis without impairment of canalicular bile secretion; in humans this process is likely to be obscured by early onset of severe liver disease.
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PMID:A mouse genetic model for familial cholestasis caused by ATP8B1 mutations reveals perturbed bile salt homeostasis but no impairment in bile secretion. 1497 63

Benign recurrent intrahepatic cholestasis (BRIC) is a rare inherited liver disease characterized by recurrent attacks of severe cholestasis with no progression to end stage liver disease. Patients have jaundice, however, serum gamma-glutamyltransferase and cholesterol levels remain within the normal range during the attacks. Three mutations in the familial intrahepatic cholestasis 1 (ATP8B1) gene encoding a P-type ATPase have been reported so far in patients with the autosomal recessive form of BRIC. A novel rare type insertion-deletion mutation, also called indel, was found in exon 24 of ATP8B1 in our patient together with a known missense mutation 1982T>C in exon 17. The mechanism of the indel formation is proposed and impact of the indel mutation on the function of ATP8B1 protein is discussed.
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PMID:Indel in the FIC1/ATP8B1 gene-a novel rare type of mutation associated with benign recurrent intrahepatic cholestasis. 1534 67

ZntA from Escherichia coli, a P1-type ATPase, specifically transports Pb(II), Zn(II), and Cd(II). Most P1-type ATPases have an N-terminal domain that contains one or more copies of the conserved metal-binding motif, GXXCXXC. In ZntA, the N-terminal domain has approximately 120 residues with a single GXXCXXC motif, as well as four additional cysteine residues as part of the CCCDGAC motif. The metal-binding specificity and affinity of this domain in ZntA was investigated. Isolated proteins, N1-ZntA and N2-ZntA, containing residues 1-111 and 47-111 of ZntA, respectively, were characterized. N1-ZntA has both the CCCDGAC and GXXCXXC motifs, while N2-ZntA has only the GXXCXXC motif. ICP-MS measurements showed that N1-ZntA can bind both divalent metal ions such as Cd(II), Pb(II), and Zn(II) and monovalent metal ions such as Ag(I), with a stoichiometry of 1. N2-ZntA can bind Zn(II) and Cd(II) with a stoichiometry of 1 but not Pb(II). The affinity of N1-ZntA for Zn(II), Pb(II), and Cd(II) was measured by competition titration with metallochromic indicators. Association constants of approximately 10(8) M(-)(1) were obtained for Zn(II), Pb(II), and Cd(II) binding to N1-ZntA. To investigate whether the CCCDGAC sequence has an important role in binding specifically Pb(II), a mutant of ZntA, which lacked the first 46 residues, was constructed. This mutant, Delta46-ZntA, had the same activity as wtZntA with respect to Cd(II) and Zn(II). However, its activity with Pb(II) was similar to the mutant DeltaN-ZntA, which lacks the entire N-terminal domain (Mitra, B., and Sharma, R. (2001) Biochemistry 40, 7694-7699). Thus, binding of Pb(II) appears to involve different ligands, and possibly geometry, compared to Cd(II) and Zn(II).
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PMID:Metal-binding characteristics of the amino-terminal domain of ZntA: binding of lead is different compared to cadmium and zinc. 1579 53

Human Wilson protein functions in the secretory pathway to insert copper ultimately into the multicopper oxidase ceruloplasmin and also plays a role in the excretion of excess copper to the bile. This copper-transporting P-type ATPase possesses six N-terminal cytosolic copper-binding domains contained within an approximately 72 amino acid consensus motif and the first four of these domains, denoted WLN1-4, are implicated in copper acquisition from the metallochaperone HAH1, whereas the domains closest to the membrane portion of the enzyme, WLN5-6, are essential for copper transport across the membrane. In order to test our hypothesis that copper transfer occurs between domains in the N-terminus of Wilson protein, we expressed and purified to homogeneity copper-binding domains 1, 3, 4, 5-6, and 6, denoted by WLN1, WLN3, WLN4, WLN5-6, and WLN6, respectively. Since we determined WLN1 and WLN4 to have the highest and lowest isoelectric points (6.77 and 3.85, respectively) and thus are readily separated via ion exchange chromatography, we developed a copper transfer assay between these domains. We anaerobically incubated either Cu(I)-WLN1 with apo-WLN4 or apo-WLN1 with Cu(I)-WLN4, then separated these domains and quantified the amount of copper that migrates from one domain to another by ICP-MS. Regardless of whether we start with Cu(I)-WLN1 or Cu(I)-WLN4 as the initial copper donor, we demonstrate facile copper transfer between WLN1 and WLN4, thereby demonstrating the feasibility of copper transfer between these domains in vivo.
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PMID:Copper transfer studies between the N-terminal copper binding domains one and four of human Wilson protein. 1663 4

Bile acids are the major determinant and driving force for the generation of bile flow. Bile acid transport across the canalicular membrane is primarily an ATP-dependent process. The predominant transporter is the bile salt excretory pump (BSEP, ABCB11), a member of the adenosine triphosphate-binding cassette (ABC) family of transporters. Regulatory mechanisms that can coordinate the genes encoding bile acid transport proteins are critically important to avoid hepatocyte damage from intracellar accumulation of bile acids. Bile salts are natural ligands for several nuclear hormone receptors expressed in liver and intestine. Nuclear receptors are transcription factors that bind specific ligands such as bile acids and regulate gene expression according to the metabolic requirements of the cell. In cloning of the BSEP gene, we found a binding site in the promoter for the farnesoid X receptor (FXR), a nuclear receptor for bile acids. FXR activity requires heterodimerization with the 9-cis retinoid receptor (RXR alpha), and when bound by bile acids and retinoic acid, the complex effectively activates the transcription of BSEP. There is a growing body of evidence for the activation of nuclear hormone receptors through the remodeling of chromatin by histone modification involving acetylation, in concert with methylation of H3 and H4 histones. We have recently demonstrated a role for the coactivator-associated arginine methyltransferase 1 (CARM1), as a coactivator of the FXR/RXR receptor and regulator of FXR responsive genes such as BSEP. Chromatin immunoprecipitation showed that the bile acid-dependent activation of the human BSEP is associated with a simultaneous increase of FXR and CARM1 occupation of the BSEP promoter. The increased occupation of the BSEP locus by CARM1 also corresponds with the increased deposition of Arg-17 methylation and Lys-9 acetylation of histone H3 within the FXR DNA-binding element of BSEP. Our work on the role of nuclear receptors in regulation of bile acid homeostasis has led to an increased understanding of the pathogenesis of the disorder, progressive familial intrahepatic cholestasis, type 1 (PFIC1) or Byler disease. The gene mutated in PFIC1 is called FIC1 and codes for a type IV P-type ATPase whose function is unknown. Increased ileal apical sodium-dependent bile acid transporter messenger RNA (mRNA) expression was detected in 3 patients with PFIC1. Ileal FXR and short heterodimer partner (an inhibitory nuclear receptor) messenger RNA levels were reduced in the same 3 patients. In studies of cells after antisense-mediated knock-down of endogenous FIC1, the activity of the ileal apical bile acid transporter promoter was enhanced, whereas the activities of the human FXR and BSEP promoters were reduced. Nuclear but not cytoplasmic localization of FXR is markedly decreased in FIC1-negative cells, indicating that FIC1 is necessary for posttranslational modifications necessary for the nuclear translocation of FXR. This defect leads to enhanced ileal bile salt uptake and impaired canalicular bile salt secretion by BSEP. In PFIC1, an increased load of bile acids is retained in the liver leading to cholestasis and progressive liver injury.
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PMID:Bile salt excretory pump: biology and pathobiology. 1681 95

A method for speciation of vanadium in soil is presented in this work. The sequential extraction analysis procedure of Tessier et al. for heavy metals was used for the vanadium separation. The method consists of sequential leaching of the soil samples to separate five fractions of metals: (1) exchangeable, (2) bound to carbonates, (3) bound to Fe-Mn oxides, (4) bound to organic matter and (5) residual. The leaching solutions of Tessier were used for the vanadium extraction, only for the residual fraction the HClO(4) was replaced with H(2)SO(4). The optimum conditions for leaching of vanadium from soil (weight of sample, concentration and volume of extractants, time of extraction) were chosen for each fraction. A sensitive, spectrophotometric method based on the ternary complex V(IV) with Chrome Azurol S and benzyldodecyldimethylammonium bromide (epsilon=7.1x10(4) l mol(-1) cm(-1)) was applied for the vanadium determination after separation of V(V) by solvent extraction using mesityl oxide and reduction of V(V) using ascorbic acid. This method was applied for vanadium speciation in soil from two different regions of Poland: Upper Silesia (industrial region) and Podlasie (agricultural region). The content of vanadium in the fractions of Upper Silesia soil was respectively (in 10(-3)%): I, 3.39; III, 4.53; IV, 10.70; V, 8.70 and it was the highest in the organic fraction, indicating input by anthropogenic activities. The content of vanadium in Podlasie soil was clearly lower and it was (in 10(-3)%): I, 2.07; III, 0.92; IV, 0.69; V, 1.23. The concentration of vanadium in fraction 2 of both soils was less than detection limit of applied method. The total content of vanadium in the five soil fractions was in good correlation with the total content of this element in both soils found after HF-H(2)SO(4) digestion. Analysis using the ICP-AES method gave comparable results.
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PMID:Speciation of vanadium in soil. 1896 78


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