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:3.1.3.1 (alkaline phosphatase)
47,916 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Most of the alkaline phosphatase activity in the mouse uterus during early pregnancy was found to be membrane-bound and was associated with particulate material when homogenates were centrifuged at 105 000 g. The activity of the enzyme increased in both the particulate and cytosol fractions of uterine homogenates during early pregnancy to reach maximum values on day 7 of pregnancy. Studies of the enzyme in its membrane-bound and cytosolic forms before and after solubilization with Triton X-100, and n-butanol failed to detect any evidence that the membrane microenvironment or membrane are deeply buried within the membranes of uterine cells. Thus, the properties of the enzyme in response to amino acids, inhibitors, and Mg2+ and Zn2+, and changes in pH, substrate concentration and temperature were essentially unaltered when the phosphatase was present in a membrane-bound or cytosolic form, or when fractions were treated with Triton X-100 and n-butanol. Solubilized preparations of the enzyme from particulate and cytosol fractions of uterine homogenates displayed zones of activity with similar anodal migration rates during electrophoresis on cellulose acetate membranes suggesting that the cytosolic activity may arise from particulate material during homogenization of the tissue. Several amino acids stimulated the activity of the phosphatase while cysteine, histidine, homoarginine, Na2HPO4 and 4-(p-aminophenylazo)phenylarsonic acid were inhibitory. In addition, Km values for the enzyme from all uterine fractions hydrolysing p-nitrophenyl phosphate were temperature-dependent.
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PMID:Behaviour and properties of membrane-bound mouse uterine alkaline phosphatase during early pregnancy. 721 59

Pseudohypoparathyroidism (PHP) is a condition characterized by hypocalcemia, hyperphosphatemia, and an impaired phosphaturic response to exogenous parathormone (PTH). A minority of patients with PHP have associated bone disease, and in some the radiological appearances have been suggestive of rickets. We report a patient with PHP who had epiphyseal enlargement and bowing of the long bones similar to that seen in rickets. Radiology showed generalized osteomalacia with failure of epiphyseal calcification and several pseudofractures. Bone biopsy showed increased osteoid seams. The phalanges of both hands showed subperiosteal erosions consistent with hyperparathyroidism. Biochemically, he had persistent hypocalcemia, hyperphosphatemia, and an elevated alkaline phosphatase. Plasma calcitonin, magnesium, and 25-hydroxycholecalciferol levels were normal. The 1,25-dihydroxycholecalciferol level was within the normal adult range but was probably inappropriately low for an adolescent. Plasma parathormone was elevated (1.3--1.7 microgram/liter; normal, < 0.73). His diet was not deficient in vitamin D. Gastrointestinal function was normal. Renal function was normal, apart from an increase in the maximum tubular reabsorption of phosphate (46--52.6 mg/liter glomerular filtration rate; normal, 38 +/- 5). Intravenous PTH infusion tests were performed on the patient and a control subject before and 6 months after serum calcium levels had returned to normal. The maximum increases in cAMP excretion in the patient were 0.03 and 0.05 mmol/g creatinine before and after treatment, respectively (control, 0.53 and 0.24); the maximum increases in phosphate excretion in the patient were 0.14 and 0.04 mmol/g creatinine before and after treatment, respectively (control, 0.32 and 0.07). He responded to initial treatment with a high dose of calciferol and later to 1,25-dihydroxycholecalciferol in a dose of 1 microgram/day. It is considered that renal resistance to PTH is his primary abnormality, with the bone disease representing a secondary phenomenon.
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PMID:Pseudohypoparathyroidism presenting with rickets. 741 91

In this paper we have studied copper (Cu) uptake by microvillar vesicles isolated from human term placenta. We have characterised Cu uptake from CuHis2 complexes and shown that ceruloplasmin (Cp) inhibits uptake. Inhibition is complex and variable; in one series of experiments, the Vmax for uptake drops from 31.3 +/- 1.2 nmol/min per mg vesicle protein without added Cp to 11.3 +/- 1 nmol/min per mg vesicle protein at 91 micrograms/ml Cp. Similarly, the K0.5 increases from 0.35 +/- 0.08 microM to 1.35 +/- 0.25 microM, while the n value (the Hill coefficient) falls from 1.9 +/- 0.23 in the absence of Cp to 1.1 +/- 0.13 In another series, Cp had no effect below concentrations of about 100 micrograms/ml and in a third series only increased K0.5. The variability in effect seems to be related to the specific activity of the ceruloplasmin, which in turn is related to the copper complexes of the protein. The effect is specific for Cp; apotransferrin and a2-macroglobulin have no effect. 67Cu-labelled ceruloplasmin binds specifically to vesicles of term placenta with an affinity of 2.8 microU/mg vesicle protein and a Bmax of 79 microU/mg vesicle protein. CuHis2, but not histidine alone, can block the uptake. The data can be reconciled by proposing that the binding site of the transporter is relatively small and recognises a Cu-dihistidine structure common to the low-molecular-weight complex and to the Type I and Type II coppers of ceruloplasmin. We have used these observations to develop an isolation method for the transporter and have identified it as a protein of M(r) 90,000 which is closely associated with alkaline phosphatase. There are also two proteins of M(r) 45,000 and 40,000 which may be breakdown products of the larger complex. Antibodies to the 45,000 protein block Cu binding and uptake from CuHis2 complexes, strongly implicating it as the copper transporter/ceruloplasmin receptor of human term placenta.
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PMID:Characterisation of the copper uptake mechanism and isolation of the ceruloplasmin receptor/copper transporter in human placental vesicles. 749 71

We examined neutrophil functions in seven elderly patients with non-Hodgkin's lymphoma before and during treatment with granulocyte colony-stimulating factor (G-CSF) at the neutropenic stage after combination chemotherapy. Subcutaneous injection of 75 micrograms/d of G-CSF produced by E. coli was started when the neutrophil count decreased less than 1,500/microliter, and continued until the neutrophil count increased to about 10,000/microliter. The phagocytic activity of neutrophils from the elderly on day 3 of G-CSF treatment was markedly enhanced; 1,129.9 +/- 403 ps/100 PMNs, which was 185.7 +/- 31.4% (p < 0.001) as compared with that before G-CSF treatment. The neutrophil alkaline phosphatase (NAP) activity was also enhanced on day 3; 398.3 +/- 48 score, which was 135.2 +/- 5.1% (p < 0.001) as compared with that before G-CSF treatment. Two patients developed interstitial pneumonitis during or shortly after the treatment with G-CSF. Interstitial pneumonitis suddenly developed when their neutrophil count was increased, and the phagocytic activity and NAP activity recovered. The phagocytic activity of neutrophils from them was enhanced to 1,090 +/- 26 ps/100 PMNs and 772 ps/100 PMNs during the treatment with G-CSF, as compared with that before G-CSF treatment of 644 +/- 29 ps/100 PMNs and 465 +/- 69 ps/100 PMNs, respectively. The NAP activity was also enhanced to 372 from 264. One patient suffered from transient pulmonary dysfunction during the treatment with G-CSF. His neutrophil count was more than 13,000/microliter, and the phagocytic activity enhanced to 949 +/- 105 ps/100 PMNs. Dyspnea with suppressed PaO2 recovered reversibly after cessation of G-CSF.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Neutrophil functions during treatment with granulocyte colony-stimulating factor (G-CSF) in the elderly with non-Hodgkin's lymphoma: including two patients accompanied with interstitial pneumonitis during the treatment with G-CSF]. 750 33

The effect of the N-terminal amino acid substitution on E. coli alkaline phosphatase biogenesis has been studied. The substitutions of Ser, Gln, Tyr, Leu, Gly, Ala, Glu, Phe, His, Cys, Lys and Pro for Arg(+1) were obtained by creating amber mutation at the corresponding position within phoA gene and expressing this mutated gene in E. coli strains that produce the amber-suppressor tRNAs. All mutant proteins were shown to translocate across the cytoplasmic membrane and possess enzyme activity. The introduction of Pro in +1 position disturbs the cleavage of signal peptide whereas the insertion of the other amino acids does not change the rates of processing in comparison with wild-type protein. All amino acid substitutions affect alkaline phosphatase isoenzyme composition. Some experimental evidence were also obtained on the specificity of protease, which split off N-terminal Arg during alkaline phosphatase maturation.
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PMID:[Biogenesis and secretion of alkaline phosphatase and its mutants in Escherichia coli. III. Substitution of N-terminal amino acids of alkaline phosphatase affect its biogenesis]. 751 65

The membrane-anchoring subunit of Bacillus subtilis succinate:menaquinone reductase is a protein of 202 residues containing two protoheme IX groups with bis-histidine axial ligation. Residues His13, His28, His70, His113, and His155 are the possible heme ligands. The transmembrane topology of this cytochrome was analyzed using fusions to alkaline phosphatase. The results support a proposed model with five transmembrane polypeptide segments and the N-terminus exposed to the cytoplasm. Mutant B. subtilis cytochromes containing a His13-->Tyr, a His28-->Tyr, and a His113-->Tyr mutation, respectively, were produced in Escherichia coli, partially purified, and analyzed. In addition, succinate: menaquinone reductase containing the His13-->Tyr mutation in the anchor subunit was overproduced in B. subtilis, purified, and characterized. The data demonstrate that His13 is not an axial heme ligand. Thermodynamic and spectroscopic properties of the cytochrome are, however, affected by the His13-->Tyr mutation; compared to wild type, the redox potentials of both hemes are negatively shifted and the gmax signal in the EPR spectrum of the high-potential heme is shifted from 3.68 to 3.50. From the combined results we conclude that His28 and His113 function as axial ligands to the low-potential heme, which is located in the membrane near the outer surface of the cytoplasmic membrane. Residues His70 and His155 ligate the high-potential heme, which is positioned close to His13 in the protein, near the inner surface of the membrane.
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PMID:Transmembrane topology and axial ligands to hemes in the cytochrome b subunit of Bacillus subtilis succinate:menaquinone reductase. 766 65

Using site-directed mutagenesis, an aspartate side chain involved in binding metal ions in the active site of Escherichia coli alkaline phosphatase (Asp-369) was replaced, alternately, by asparagine (D369N) and by alanine (D369A). The purified mutant enzymes showed reduced turnover rates (kcat) and increased Michaelis constants (Km). The kcat for the D369A enzyme was 5,000-fold lower than the value for the wild-type enzyme. The D369N enzyme required Zn2+ in millimolar concentrations to become fully active; even under these conditions the kcat measured for hydrolysis of p-nitrophenol phosphate was 2 orders of magnitude lower than for the wild-type enzyme. Thus the kcat/Km ratios showed that catalysis is 50 times less efficient when the carboxylate side chain of Asp-369 is replaced by the corresponding amide; and activity is reduced to near nonenzymic levels when the carboxylate is replaced by a methyl group. The crystal structure of D369N, solved to 2.5 A resolution with an R-factor of 0.189, showed vacancies at 2 of the 3 metal binding sites. On the basis of the kinetic results and the refined X-ray coordinates, a reaction mechanism is proposed for phosphate ester hydrolysis by the D369N enzyme involving only 1 metal with the possible assistance of a histidine side chain.
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PMID:Kinetics and crystal structure of a mutant Escherichia coli alkaline phosphatase (Asp-369-->Asn): a mechanism involving one zinc per active site. 770 48

Infantile type hypophosphatasia, an autosomal recessive disease with severe clinical manifestations, is characterized biochemically by subnormal activities of circulating alkaline phosphatase. In this report, we presented a five-day-old male with this rare disorder. His parents were first cousins, and he was first seen for jaundice. He had soft calvaria, large fontanel, extremely wide cranial sutures, low-set ears, a depressed nasal bridge, funnel chest, and short and bowed distal limbs. Roentgenographic studies showed widened sutures and poor ossification of the skull, bowing of the femora and slight modeling defects in the long bones. A low serum alkaline phosphatase activity led us to measure excretion of phosphoethanolamine and found it to be increased.
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PMID:Hypophosphatasia in a newborn infant. 773 10

The L/B/K type of mammalian alkaline phosphatase (ALP) is inhibited uncompetitively by nucleotides. A combination of adenosine and nicotinamide is more effective than either adenosine or nicotinamide alone, probably because a dinucleotide structure is necessary to trigger a conformational change accompanying binding of structures such as NADH. It has been suggested that a loop region containing residue 429 in the ALP polypeptide is important in the interaction of uncompetitive inhibitors with the enzyme. In the L/B/K isoenzyme, residue 429 is a histidine and is a potential target for modification. In an attempt to learn more about the molecular events accompanying inhibition of ALP by uncompetitive inhibitors, bovine kidney ALP was reacted with oxidized adenosine in the presence of nicotinamide to see if site-directed modification occurs. Kidney ALP was irreversibly inactivated by oxidized adenosine but the reaction was slow. The site modified is likely to be close to the region of binding. Sequence data for the kidney enzyme shows that in the region of residue 429 there are no residues except His429 itself that is likely to react with oxidized adenosine.
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PMID:Time-dependent irreversible inhibition of bovine kidney alkaline phosphatase by oxidized adenosine. Use of this compound as a site-directed inhibitor for studying uncompetitive inhibition. 783 15

A rare case of gastric carcinoma associated with increased serum variant alkaline phosphatase activities is presented. A 54 year old man had extremely high serum alkaline phosphatase activity (18,607 U/l) with normal calcium and phosphate concentrations. His bone scintigram showed abnormal findings, 'super bone scan'. He was diagnosed as having Borrmann type 4 gastric carcinoma with diffuse bone metastases by examinations of the upper gastrointestinal tract and iliac bone biopsy. The alkaline phosphatase isozyme of this patient was of the bone type as measured by cellulose acetate membrane electrophoresis and the placenta/bone type by agarose gel electrophoresis, respectively. Immunoelectrophoresis and the immunoprecipitation method using monoclonal antibodies against various alkaline phosphatase isozymes, however, showed that his serum alkaline phosphatase had the liver type antigenicity. Furthermore, it had a larger molecular size and different sugar chains compared with the common liver type alkaline phosphatase. These findings suggest that a unique variant alkaline phosphatase was produced by gastric cancer cells, which is possibly an explanation for the high serum alkaline phosphatase activities in this patient.
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PMID:A variant alkaline phosphatase found in a case of gastric carcinoma with super bone scan. 788 33


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