Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.3.1 (alkaline phosphatase)
 47,916 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Certain phosphonocarboxylate analogues of phosphate are known to inhibit Na(+)-phosphate (Pi) cotransport in renal brush border membrane (BBM), but previously tested potential inhibitors incorporating structurally versatile aryl functionality were inactive. In this work, a series of novel alpha-halogenated [(phenylphosphinyl)methyl]phosphonates [PhpXYMP: X, Y = H, F (2); F, F (3); H, Cl (6); Cl, Cl (4); H, Br (7); Br, Br (5); and Cl, Br (8)] were prepared via synthesis of the corresponding triethyl esters, acid hydrolysis, and isolation as pyridine salts. The compounds were evaluated as inhibitors of Na(+)-gradient-dependent 32Pi uptake by rat renal cortex BBM vesicles (BBMV) in vitro. The PhpFMP racemate 2 had higher activity (-49% delta inhibition) than other members of the series (-22 to -39% delta inhibition). pKa values of 1.5-2.0, 2.7, and 7.1 were estimated for 2 using a 31P delta vs pH plot, indicating that in the activity assays it exists as both dianion and trianion, with the latter form predominant. PhpFMP had no significant inhibitory effect on Na(+)-gradient-dependent uptake of D-glucose or L-proline in the same BBMV, and did not inhibit BBM alkaline phosphatase. Kinetic analysis showed that PhpFMP acts as a strictly competitive inhibitor of Na(+)-Pi cotransport with Ki = 0.358 +/- 0.021 mM (n = 3). The racemate 2 was resolved as its (-)-quinine salt into enantiopure (+)-2 [Na+ salt, [alpha]25D = +6 degrees (aqueous MeOH)] and a Na+ salt of 2 enriched in (-)-2. The two compounds did not differ significantly as inhibitors of Na(+)-gradient dependent 32Pi uptake by rat renal cortex BBM vesicles (BBMV) in vitro. The results are discussed in terms of structural requirements for inhibition.
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PMID:Alpha-halo [(phenylphosphinyl)methyl]phosphonates as specific inhibitors of Na(+)-gradient-dependent Na(+)-phosphate cotransport across renal brush border membrane. 147 88

Mice fed on an 8% protein (low-protein; LP) diet for 21 days exhibited a significant (p less than 0.001) decrease in their body weights compared with the pair-fed controls (18% protein). Brush border enzyme analysis revealed a 56% increase in sucrase activity and a significant decrease in alkaline phosphatase (p less than 0.05), beta-D-glucosidase (p less than 0.001) and beta-D-galactosidase (p less than 0.05) activities in protein-deficient mice. Lactase activity was unaltered in these conditions. Hexose and hexosamine contents of the brush border membranes (BBM) decreased considerably as a result of the LP diet. Protein deprivation significantly enhanced (p less than 0.01) brush border sialic acid and reduced (p less than 0.05) fucose content compared to the controls. The binding of 125I-labelled wheat germ agglutinin and Ulex europaeus agglutinin I to BBM was in agreement with the data on sialic acid and fucose levels of the membranes. The binding of peanut agglutinin to BBM was 38% higher in LP-diet-fed animals. The incorporation of [14C]mannose and [14C]glucosamine into BBM was markedly reduced (25%), while that of [3H]fucose was apparently unaffected. These results suggest that the feeding of an LP diet to mice results in marked alterations in the intestinal epithelial cell surface glycosylation.
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PMID:Intestinal epithelial cell surface glycosylation in mice. 1. Effect of low-protein diet. 151 Mar 49

The controlled Smith degradation of ukonan A, a phagocytosis-activating polysaccharide isolated from the rhizome of Curcuma longa L., was performed. The reticuloendothelial system-potentiating, anti-complementary and alkaline phosphatase-inducing activities of ukonan A and its degradation products were investigated. Methylation analyses of both the primary and the secondary Smith degradation products indicated that the core structural features of ukonan A include a backbone chain mainly composed of beta-1,3-linked D-galactose, beta-1,4-linked D-xylose and alpha-1,2-linked L-rhamnose residues. All of the galactose units in the backbone carry side chains composed of alpha-L-arabino-beta-D-galactosyl or beta-D-galactosyl residues at position 6. Ukonan A has a remarkable effect on each of the three kinds of immunological activities. Periodate oxidation caused pronounced decrease or disappearance of the activities, but the controlled Smith degradation product having the core structure of polysaccharide showed considerable restoration of these activities.
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PMID:The core structure of ukonan A, a phagocytosis-activating polysaccharide from the rhizome of Curcuma longa, and immunological activities of degradation products. 152 57

Alkaline phosphatase is anchored to the membrane via glycosylphosphatidylinositol (GPI). Mannose residues of the GPI glycan are suggested to be derived from dolichol-P-mannose. In the present study we examined the effect of 2-fluoro-2-deoxy-D-glucose (F-Glc), an inhibitor of dolichol-P-mannose synthesis, on the biosynthesis and processing of alkaline phosphatase in JEG-3 cells. In control cells, a proform precursor (64.5 kDa) with a hydrophobic peptide domain at the COOH terminus was immediately processed into an intermediate form (63 kDa) by proteolytic removal of the COOH-terminal extension and replacement with the GPI anchor, and then to a mature form (66 kDa) by terminal glycosylation of its N-linked oligosaccharides. In contrast, when cells were treated with F-Glc (1 mM), the protein was synthesized as a proform of 61 kDa. The reduction in its molecular mass was mostly due to the inhibition in maturation of N-linked oligosaccharides by F-Glc. The 61-kDa proform identified by antibodies to the COOH-terminal peptide was detectable even at 3 h after the synthesis, and was gradually processed to doublet forms of 58-59 kDa which were finally secreted into the medium. None of these forms were labeled with [3H]ethanolamine and [3H]stearic acid, components of the GPI anchor, and expressed on the cell surface as a membrane-bound form. Taken together, these results suggest that the inhibition of the GPI synthesis causes a prolonged accumulation of the proform, which is then gradually processed into secretory forms by proteolytic removal of the COOH-terminal hydrophobic peptide.
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PMID:Aberrant processing of alkaline phosphatase precursor caused by blocking the synthesis of glycosylphosphatidylinositol. 153 Sep 33

A ceramide-anchored glycophosphosphingolipid antigen was isolated from the lipid extract of Leishmania donovani promastigotes. The affinity-purified glycolipid antigen contained galactose, mannose, myo-inositol, phosphate, ceramide, and hexosamine but no sialic acid. The phosphate group was present internally at the core of the structure: inositol (1-O)-phosphorylceramide. The phosphate group became susceptible to alkaline phosphatase only after alkali-catalyzed hydrolysis of the glycolipid.
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PMID:Leishmania donovani: purification and partial characterization of a glycophosphosphingolipid antigen expressed on promastigote surface. 153 40

A colorimetric microassay for the simultaneous quantitative determination of galactose (Gal) and galactose-1-phosphate (Gal-1-P) in dried blood spots is described. An enzymatic reaction involving alkaline phosphatase (EC 3.1.3.1) and galactose dehydrogenase (EC 1.1.1.48) produces NADH, which is coupled with diaphorase (EC 1.8.1.4) and iodonitrotetrazolium violet (INT). The colourless INT is converted to a formazan of red colour the intensity of which is quantitated either photometrically by a microplate reader or determined visually with sufficient sensitivity for screening purposes. We evaluated the assay on 200,000 blood samples in a newborn screening program, and were able to distinguish between classical and milder forms of galactosemia with ease.
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PMID:Colorimetric determination of galactose and galactose-1-phosphate from dried blood. 155 Dec 39

Na-coupled D-glucose transport in rabbits with cis-diamminedichloride platinum (CDDP; cisplatin) induced acute renal failure (ARF) has been studied. ARF occurred at 3 days after injection of CDDP (3 mg/kg i.v.). Na-coupled D-glucose transport into brush-border membrane vesicles (BBMV) from both outer cortex (OC) and outer medulla (OM) of ARF rabbits under zero-trans condition was decreased. Increased Km (i.e., decreased affinity of transport carrier for D-glucose) in OC and decreased Vmax (i.e., decreased number of glucose carrier) in OM were observed in CDDP-induced ARF rabbits. Decrease glucose transport was also observed under equilibrium exchange condition. Intravesicular volume of BBMV from OC and OM of ARF rabbits was decreased. In homogenate and BBMV from OC and OM of ARF rabbits, activities of gamma-glutamyl transpeptidase and alkaline phosphatase (marker enzymes of brush-border membrane) were decreased. Activities of succinate dehydrogenase, glucose-6-phosphatase, and Na-K ATPase (marker enzymes of mitochondria, endoplasmic reticulum, and basal lateral membrane, respectively) were not affected by CDDP administration. These results suggested that one of the main target sites of CDDP in kidney is brush-border membrane (BBM) along the proximal tubule, that is, not only Na-coupled D-glucose transport carrier protein but also other proteins in BBM.
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PMID:Decreased sodium dependent D-glucose transport across renal brush-border membranes in cis-diamminedichloride platinum induced acute renal failure. 156 86

Prorenin was isolated by immunoprecipitation from the culture medium of Chinese hamster ovary cells transfected with a human prorenin cDNA. The N-linked oligosaccharide structures on the in vivo [3H]mannose-labeled, purified protein were characterized using a combination of serial lectin affinity chromatography, high-pressure liquid chromatography, ion-exchange chromatography, and size-exclusion chromatography and treatment with specific glycosidases and methylation analysis. Approximately 61% of the oligosaccharides on the molecule are complex type, in the form of tetraantennary (2%), 2,6-branched triantennary (13%), 2,4-branched triantennary (3%), and biantennary (43%) structures. The majority of all complex type structures are core-fucosylated. Sialic acids are linked at the C-3 position of terminal galactose, and the degree of sialylation of the bi- and triantennary structures varies between nonsialylated and fully sialylated; no tetraatennary structure contains more than three sialic acid residues. Recombinant prorenin contains 4% hybrid-type structures, all of which carry a terminal sialic acid residue. The remaining 35% of the structures on the molecule are high mannose type, composed of 5, 6, or 7 mannose residues. Approximately 6% of the high mannose type structures and 10% of the hybrid structures are phosphorylated, as judged by their susceptibility to treatment with alkaline phosphatase. Compositional analysis of an unlabeled preparation of the protein suggested the presence of approximately 1.4 oligosaccharide units per molecule.
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PMID:Characterization of the oligosaccharide structures on recombinant human prorenin expressed in Chinese hamster ovary cells. 163 29

Liver test abnormalities are a well-recognized complication in the parenterally fed population. Numerous etiologies for the development of elevated liver tests have been suggested. However, the etiology and clinical significance remain unclear. The aim of this retrospective study was to determine the extent of liver-associated test (LAT) abnormalities in patients receiving total parenteral nutrition (TPN) and to investigate whether the composition of TPN solutions and the magnitude of malnutrition could be used to predict subsequent LAT abnormalities. Medical records of 78 adult patients who received TPN for at least 2 weeks were reviewed. All subjects had normal LAT results before TPN, were not receiving hepatotoxic drugs, and had no underlying liver disease. Aspartate aminotransferase peaked transiently during week 2 and returned to normal during week 4. Alkaline phosphatase and total bilirubin peaked during weeks 4 and 3, respectively. The average nonprotein kilocalorie distribution was approximately 80% dextrose and 20% lipid. Caloric intake ranged from 7% to 23% above estimated needs. The mean nutritional status score was 22 +/- 15, with a possible range of 0 to 75 (0 indicates no malnutrition). The composition of TPN solutions was not significantly associated with the changes in the three LATs during any week of the 4-week study. The nutritional status score was significantly associated (p less than .05) with the change in alkaline phosphatase during week 1. This study confirms that LAT abnormalities occur during TPN, but the composition of the solution has no significant ability to predict subsequent LAT abnormalities.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Liver test alterations with total parenteral nutrition and nutritional status. 164 Jun 33

N-(2-Hydroxypropyl)methacrylamide (HPMA) copolymers containing doxorubicin (DOX) and galactosamine can be targeted to the hepatocyte galactose receptor for organ-specific chemotherapy of primary and metastatic liver cancer. Here we report the dose-dependent pharmacokinetics of this macromolecular conjugate. Following intravenous administration to mice most efficient liver targeting was seen at low dose (0.05 mg DOX kg-1), with receptor saturation observed using higher bolus doses. Repeated low dose bolus injections did not cause down-regulation of the galactose receptor and targeted drug delivery rates of greater than or equal to 2 micrograms DOX g-1 liver h-1 were achieved. DOX is released from such conjugates intracellularly via action of lysosomal proteinases. It was shown that isolated rat liver lysosomal enzymes (Tritosomes) can release unmodified DOX from the peptidyl side chain Gly-Phe-Leu-Gly at a rate greater than or equal to 3 micrograms DOX g-1 liver h-1 i.e. the hydrolytic capacity is greater than the observed rate of drug delivery to the liver lysosomes in vivo. Although most conjugate would be captured by normal hepatocytes following intravenous administration, it was shown that the human hepatoma cell line HepG2 retains the galactose receptor, accumulating and processing the conjugate efficiently. Potential dose limiting toxicities of such drug conjugates could include cardio- or hepatotoxicity. Administration of conjugate reduced the 15 min heart level of DOX approximately 100-fold compared with that observed for an equivalent dose of free drug. Preliminary experiments showed that plasma levels of alkaline phosphatase, alanine transaminase and asparate transaminase did not change following administration of HPMA copolymer-daunorubicin (DNR) (10 mg DNR kg-1) indicating no significant heptatoxicity.
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PMID:N-(2-hydroxypropyl)methacrylamide copolymers targeted to the hepatocyte galactose-receptor: pharmacokinetics in DBA2 mice. 164 46


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