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PubMed1990

Muscle glycogenosis.

This review describes clinical, biochemical and genetic features of the four inborn errors affecting muscle glycogen breakdown, namely deficiencies of phosphorylase, phosphorylase kinase, amylo-1,6-glucosidase and acid alpha-glucosidase. They are characterized by a wide spectrum of clinical manifestation, affecting age of onset, clinical features, progress of disease and tissue involvement. Biochemically, variability of all four enzyme deficiencies is evident in terms of differences in residual enzyme present in tissues, and in the presence or absence of enzyme protein. Genetic heterogeneity, which has been documented in each of the enzyme deficiencies, manifests itself in terms of the presence, absence, quantity or size of mRNA. In phosphorylase deficiency heterogeneity has also been documented at the DNA level. In acid maltase deficiency nine mutant phenotypes have been described affecting various stages of lysosomal enzyme processing.

DNA↗

PubMedDate not supplied

Regulation of the sarcoplasmic reticular Ca2+ transport ATPase by phosphorylation and dephosphorylation.

At 0.1 mg/ml protein and 0.45 micrometers free Ca2+ l mol trichloroacetic acid precipitable phosphate is incorporated into 100,000 g SR protein as hydroxylamine sensitive acylphosphate. At nearly physiological protein concentration (ca. 7 mg/ml) a total of ca. 0.8 mol phosphate/100,000 g protein is incorporated, from which a fraction of 0.3 mol/100,000 g protein is insensitive to the hydroxylamine treatment, i.e. it is alkylphosphate. Phosphorylase kinase accelerates the alkylphosphate incorporation ca. 3-fold and enhances its final level to 0.7 mol/100,000 g protein. At 1.6 nm free Ca2+ alkylphosphate incorporation occurs at high SR concentration to a maximal extent of 0.5 mol/ 100,000 g protein. The incorporated alkylphosphate is present in comparable amounts in the 100,000 Mr Ca2+-transport ATP-ase and a polypeptide of Mr 9,000.

Animals↗

PubMed1982

A new variant of glycogen storage disease. Type IXc.

Three siblings, a body and two girls, had clinical, laboratory, and morphologic findings that were suggestive of glycogen storage disease (GSD) type IXa. Patients of both sexes with phosphorylase kinase (PK) deficiency usually have an excessive glycogen content only in the liver and normal glycogen content and PK activity in muscle. The siblings in this study had an increased glycogen content in the liver but also in muscle and reduced PK activity in liver, muscle, erythrocytes, and leukocytes. This condition should be labeled as GSD type IXc.

Child, Preschool↗

PubMed1979

Regulatory functions of protein multisite phosphorylation.

In recent years it has become apparent that an increasing number of proteins can be phosphorylated at several different sites. In this article protein multisite phosphorylation is discussed with reference to the enzymes glycogen synthase, pyruvate dehydrogenase, and phosphorylase kinase. Each of these enzymes contains three or more different phosphorylation sites on one or more subunits. Activation and inactivation of the enzymes appear to correlate quite well with phosphorylation of a few key sites on the protein. The other phosphorylation sites may influence other kinetic properties of the enzymes or regulate the rates of dephosphorylation of the key sites by the appropriate phosphatase. Thus, multisite phosphorylation may represent an important mechanism for regulating several functions of complex proteins.

Animals↗

PubMed1981

Platelet and leucocyte calmodulins: isolation and characterisation.

The calcium-dependent regulatory proteins, calmodulins, have been isolated from human blood platelets and guinea pig peritoneal polymorphonuclear leucocytes using the urea methanol procedure of Grand et al. [Biochem. J. 177, 521-529 (1978)]. The calmodulins were purified to homogeneity as indicated by polyacrylamide gel electrophoresis and both proteins comigrated with bovine brain calmodulin with mobilities corresponding to molecular weights of 16 000-17 000. The yield of calmodulin from platelets was higher on a wet weight basis than the yield from leucocytes but the former compared favourably with yields reported for brain and other tissues. Both calmodulin preparations significantly stimulated brain cyclic nucleotide phosphodiesterase, erythrocyte ghost Ca2+ ATPase and platelet phosphorylase kinase activities at the microgram level. Stimulation of Lubrol-solubilised brain adenylate cyclase was only marginally significant with platelet calmodulin and rarely demonstrable with the leucocyte preparations. Although biological activities of both proteins were retained during storage at -20 degrees C, higher-molecular-weight aggregates slowly formed which could not be dissociated during dodecylsulphate/mercaptoethanol denaturation.

2',3'-Cyclic-Nucleotide Phosphodiesterases↗

PubMed1986

Urinary proteinase activity in patients with multiple traumatic injuries, sepsis, or acute renal failure.

Urinary proteinase activity was measured and partly characterized in 29 patients, most of whom had multiple traumatic injuries and 14 of whom had sepsis. Seven of these 29 patients also had acute renal failure. When they were compared with healthy controls, a significant increase of urinary proteinase activity measured with azocasein as a substrate could be found 1 day after admission (15.3 +/- 4.8 vs. 4.8 +/- 1.0 U/ml; P less than 0.05). In urine fractions of patients with sepsis, significantly higher proteolytic activities were measured than in patients without septicemia (20.5 +/- 4.2 vs. 12.3 +/- 2.2 U/ml; P less than 0.05). Patients with sepsis and acute renal failure showed higher urinary proteinase activity than patients with sepsis and normal kidney function (37.7 +/- 4.9 vs. 20.5 +/- 4.2 U/ml; P less than 0.05). During recovery from sepsis urinary proteinase activity decreased to normal values. Phosphorylase kinase was used to characterize the type of urinary proteinase(s). A predominant splitting of the alpha and gamma subunits of the enzyme was observed after trauma and sepsis. However all three subunits, alpha, beta, and gamma, were rapidly digested in the case of posttraumatic acute renal failure and sepsis, indicating the presence of different urinary proteinases. We conclude that proteolytic enzymes are present in urine fractions after traumatic injuries. Sepsis, acute renal failure, or both induce a further increase in urinary proteolytic activity caused by different proteinases.

Acute Kidney Injury↗

PubMed1989

Effects of polymyxin B on the sarcoplasmic reticulum membrane.

Polymyxin B, a cyclic peptide antibiotic, inhibits Ca2+-ATPase, p-nitrophenyl phosphatase and phosphorylase kinase activities associated with rabbit skeletal muscle sarcoplasmic reticulum membranes; 50% inhibition is induced by 100 microM, 130 microM and 550 microM of polymyxin respectively. The fluorescence intensity of fluorescein isothiocyanate-labeled Ca2+-ATPase, decreases in the presence of polymyxin (50% of the total decrease at 70 microM polymyxin). On the other hand, the polypeptide inhibits calmodulin-dependent endogenous phosphorylation of 60 kDa, 20 kDa and 14 kDa membrane proteins, while an increase of calmodulin-dependent phosphorylation is observed in 132 kDa and 86 kDa proteins.

4-Nitrophenylphosphatase↗

PubMed1984

Proteolytic activity in patients with hypercatabolic renal failure.

Proteolytic enzymes exist in ultrafiltrated plasma, concentrated dialysates and urine fractions of patients with posttraumatic renal failure. Differences in digestion pattern of phosphorylase kinase suggest the existence of different proteases in patients with hypercatabolic renal failure. Trypsin binding capacity is reduced in RDT patients and markedly lower in patients with posttraumatic ARF. Protein catabolism is inhibited in vitro by alpha 2-macroglobulin. From our in vitro studies we favour the application of fresh frozen plasma instead of the available plasma protein solutions to hypercatabolic patients. Hemodialysis may enhance proteinase inhibitory capacity of the plasma. Hemodialysis therapy induces the increase of plasma E-X1 PI. The continuous release of granulocyte elastase during hemodialysis therapy may enhance the risk for the development of destructive lung disease.

Acute Kidney Injury↗

PubMed1984

Sequential phosphorylation of skeletal muscle troponin.

Phosphorylation of the isolated rabbit skeletal muscle holotroponin complex at troponin-T by phosphorylase kinase is unusual in that it shows maxima and minima. These oscillations are due to protein phosphatase activity present in the preparations. Following tryptic digestion two phosphorylated peptides, I and II, can be isolated. Their amino-acid compositions are identical and correspond to that of the tryptic peptide which contains the two known phosphorylatable sites 149/150 and 156/7 of troponin-T. Peptide I is phosphorylated on both sites and peptide II only on one site. During phosphorylation the doubly phosphorylated peptide I appears first; after a short lag phase peptide II is formed containing only one phosphate. These phenomena probably cause the observed oscillations in the degree of the holotroponin phosphorylation.

Animals↗

PubMed1988

Partial correction of an inherited biochemical defect of skeletal muscle by grafts of normal muscle precursor cells.

We have attempted to use allografts of normal muscle precursor cells (mpc) to insert donor nuclei, containing a normal genome, into growing or regenerating skeletal muscle fibres of mice with an inherited deficiency of the enzyme phosphorylase kinase (PhK). Analysis of the glucose-6-phosphate isomerase (GPI) isoenzymes of treated muscles showed that myonuclei of donor origin became incorporated into host muscle fibres in 8 of 9 regenerating autografts, but PhK activity was found only in the 3 grafts into which the largest numbers (1-3 x 10(6)) of mpc had been implanted. Following injection of normal mpc into growing PhK-deficient skeletal muscle, mosaic fibres containing myonuclei of donor origin were detected in only 11 of 192 muscles examined from 64 mice, but, of these 11 muscles, 5 contained PhK activity detectable by two separate assays in a further 4 muscles activity was detected by one or other assay.

Animals↗

PubMed1992

Ca(2+)-dependent ubiquitination of calmodulin in yeast.

Recently we were able to show that calmodulin from vertebrates, plants (spinach) and the mold Neurospora crassa can be covalently conjugated to ubiquitin in a Ca(2+)-dependent manner by ubiquityl-calmodulin synthetase (uCaM-synthetase) from mammalian sources [R. Ziegenhagen and H.P. Jennissen (1990) FEBS Lett. 273, 253-256]. It was therefore of high interest to investigate whether this covalent modification of calmodulin also occurs in one of the simplest eukaryotes, the unicellular Saccharomyces cerevisiae. Yeast calmodulin was therefore purified from bakers yeast. In contrast to calmodulin from spinach and N. crassa it does not activate phosphorylase kinase. Crude yeast uCaM-synthetase conjugated ubiquitin Ca(2+)-dependently to yeast and mammalian (bovine) calmodulin. Yeast calmodulin was also a substrate for mammalian (reticulocyte) uCaM-synthetase. As estimated from autoradiograms the monoubiquitination product (first-order conjugate) of yeast calmodulin has an apparent molecular mass of ca. 23-26 kDa and the second-order conjugate an apparent molecular mass of ca. 28-32 kDa. Two to three ubiquitin molecules can be incorporated per yeast calmodulin. Experiments with methylated ubiquitin in the heterologous reticulocyte system indicate that, as with vertebrate calmodulins, only one lysine residue of yeast calmodulin reacts with ubiquitin so that the incorporation of multiple ubiquitin molecules will lead to a polyubiquitin chain. These results also indicate that the ability of coupling ubiquitin to calmodulin was acquired at a very early stage in evolution.

Animals↗

PubMed1996

Inhibition of protein phosphatase-2B (calcineurin) activity towards Alzheimer abnormally phosphorylated tau by neuroleptics.

Abnormally hyperphosphorylated tau is the major protein component of neurofibrillary tangles, the characteristic lesion of Alzheimer's disease (AD). Protein phosphatases (PP) type 1 (PP-1), type 2A (PP-2A) and type 2B (PP-2B) appear to be involved in the regulation of tau phosphorylation. The incidence of neurofibrillary tangles is higher in brains of schizophrenic patients treated with neuroleptics than in those without this treatment. We have found that the commonly used neuroleptics chlorpromazine, trifluoperazine and clozapine inhibit PP-2B but not PP-1 or PP-2A activity towards [32P]phosphorylase kinase as a substrate. When AD abnormally hyperphosphorylated tau is used as a substrate, PP-2B activity is inhibited by trifluoperazine > chlorpromazine > clozapine. Using phosphorylation-dependent monoclonal antibodies, tau-1, AT8 and PHF-1, we have found that the dephosphorylation of the abnormal tau by PP-2B is inhibited at all the sites recognized by these antibodies. The IC50 of the inhibition of dephosphorylation at tau-1 site is approximately 20 microM for trifluoperazine and approximately 120 microM for chlorpromazine. These two neuroleptics inhibit tau dephosphorylation by PP-2B through antagonizing calmodulin as well as directly interacting with PP-2B. The inhibition of the dephosphorylation of abnormally hyperphosphorylated tau by neuroleptics raises an intriguing possibility that the chronic use of these drugs might contribute to neurofibrillary degeneration in schizophrenic and AD patients.

Alzheimer Disease↗

PubMed1984

Patterns of growth in the hepatic glycogenoses.

Longitudinal growth data from 31 patients with hepatic glycogen storage disease (type I (8 patients), type Ib (three patients), type III (13 patients), and type IX (phosphorylase kinase deficiency) (7 patients) ) have been reviewed. All patients were below the mean for height at presentation; the mean height standard deviation scores were -2.13 (type I), -2.0 (type Ib), -2.4 (type III), and -1.6 (type IX). Untreated, most patients with type I and Ib grew slowly with no catch up growth but three patients with mild disease grew normally. Most children with type III disease grew at a normal velocity throughout childhood. Puberty was delayed and final height normal. Some of the children with type III and all of those with type IX had catch up growth throughout childhood. Intensive treatment of patients with severe forms of type I and Ib disease resulted in catch up growth, but this was not complete if the treatment was started late.

Body Weight↗

PubMed1993

Nutrition therapy for hepatic glycogen storage diseases.

Hepatic glycogen storage diseases (GSD) are a group of rare genetic disorders in which glycogen cannot be metabolized to glucose in the liver because of one of a number of possible enzyme deficiencies along the glycogenolytic pathway. Patients with GSD are usually diagnosed in infancy or early childhood with hypoglycemia, hepatomegaly, poor physical growth, and a deranged biochemical profile. Dietary therapies have been devised to use the available alternative metabolic pathways to compensate for disturbed glycogenolysis in GSD I (glucose-6-phosphatase deficiency), GSD III (debrancher enzyme deficiency), GSD VI (phosphorylase deficiency, which is less common), GSD IX (phosphorylase kinase deficiency), and GSD IV (brancher enzyme deficiency). In GSD I, glucose-6-phosphate cannot be dephosphorylated to free glucose. Managing this condition entails overnight continuous gastric high-carbohydrate feedings; frequent daytime feedings with energy distributed as 65% carbohydrate, 10% to 15% protein, and 25% fat; and supplements of uncooked cornstarch. In GSD III, though glycogenolysis is impeded, gluconeogenesis is enhanced to help maintain endogenous glucose production. In contrast to treatment for GSD I, advocated treatment for GSD III comprises frequent high-protein feedings during the day and a high-protein snack at night; energy is distributed as 45% carbohydrate, 25% protein, and 30% fat. Patients with GSD IV, VI, and IX have benefited from high-protein diets similar to that recommended for patients with GSD III.

Adolescent↗

PubMed1993

Phosphoprotein phosphatase activities in Alzheimer disease brain.

Microtubule-associated protein tau is known to be hyperphosphorylated in Alzheimer disease brain and this abnormal hyperphosphorylation is associated with an inability of tau to promote the assembly of microtubule in the affected neurons. Our previous studies demonstrated that abnormally phosphorylated tau could be dephosphorylated after treatment with alkaline phosphatase, thereby suggesting that the abnormal phosphorylation of tau might in part be the result of a deficiency of the phosphoprotein phosphatase system in patients with Alzheimer disease. In the present study we used 32P-labeled phosphorylase kinase and poly(Glu, Tyr) 4:1 as substrates to measure phosphoprotein phosphatase activities in Alzheimer disease and control brains. The activities of phosphoseryl/phosphothreonyl-protein phosphatase types 1, 2A, 2B, and 2C and of phosphotyrosyl-protein phosphatase in frontal gray and white matters from 13 Alzheimer brains were determined and compared with those from 12 age-matched control brains. The activities of type 1 phosphatase and phosphotyrosyl phosphatase in gray matter and of type 2A phosphatase in both gray and white matters were significantly lower in Alzheimer disease brains than in controls. These findings suggest that the hyperphosphorylation of tau in Alzheimer disease brain could result from a protein dephosphorylation defect in vivo. The decrease in the phosphatase activities in Alzheimer disease might also be involved in the formation of beta-amyloid by augmenting the amyloidogenic pathway processing of beta-amyloid precursor protein.

Adult↗

PubMed1984

Micropreparative protein purification by reversed-phase high-performance liquid chromatography.

Micropreparative purification of the four subunits of phosphorylase kinase (molecular weights 16,680, 43,000, 113,000 and 132,000) by reversed-phase high-performance liquid chromatography has provided quantities sufficient for some of the first structural studies of these proteins. The best yield from a 25 X 0.46 cm I.D. column was obtained on a packing material (5-microns C18) bonded under conditions resulting in a relatively low ligand density; of a total 250 micrograms of protein applied, 76% was recovered. Low recoveries from 5-30-micrograms sample loads suggest partial irreversible adsorption. Retention of protein by the column after an initial micropreparative separation adversely affects resolution and recovery on subsequent separations. Incorporation of gradient wash steps between sample injections was necessary to maintain column performance and to prolong usable column lifetime. The use of a short column with a large diameter (6 X 1 cm) gave increased loading capacity above 400 micrograms protein and enhanced recovery while maintaining good resolution. A less expensive reversed-phase support (17-micron C18) provided adequate resolution for this separation.

Amino Acid Sequence↗

PubMed1998

Clinical, biochemical and molecular findings in a patient with X-linked liver glycogenosis followed for 40 years.

UNLABELLED: Phosphorylase kinase (PHK) is a regulatory enzyme in glycogen metabolism. Mutations in the gene encoding the alpha subunit of PHK (PHKA2) have been shown to be responsible for X-linked liver glycogenosis (XLG). XLG, a frequent type of glycogen storage disease, is characterised by hepatomegaly and growth retardation. Two subtypes of XLG have been described: XLG type I patients have a clear-cut PHK deficiency in liver and blood cells, whereas XLG type II patients have a normal or residual activity. Here, we present clinical, biochemical and molecular findings on a liver glycogenosis patient in whom the diagnosis XLG II only became clear after enzyme assays in the liver and identification of the disease-causing mutation. A missense mutation replacing arginine at amino acid position 186 by histidine (R186H) was identified in the PHKA2 gene. Mutations of the same arginine residue have been previously found in at least four other unrelated XLG II patients. CONCLUSION: Arginine at position 186 of the alpha subunit seems to play an important role in the structure or the regulation of PHK. In patients with XLG having normal or residual PHK activity where XLG II is suspected, the identification of mutations in PHKA2 leads to the final classification.

Adult↗

PubMed1999

Complete genomic structure and mutational spectrum of PHKA2 in patients with x-linked liver glycogenosis type I and II.

X-linked liver glycogenosis (XLG) is probably the most frequent glycogen-storage disease. XLG can be divided into two subtypes: XLG I, with a deficiency in phosphorylase kinase (PHK) activity in peripheral blood cells and liver; and XLG II, with normal in vitro PHK activity in peripheral blood cells and with variable activity in liver. Both types of XLG are caused by mutations in the same gene, PHKA2, that encodes the regulatory alpha subunit of PHK. To facilitate mutation analysis in PHKA2, we determined its genomic structure. The gene consists of 33 exons, spanning >/=65 kb. By SSCP analysis of the different PHKA2 exons, we identified five new XLG I mutations, one new XLG II mutation, and one mutation present in both a patient with XLG I and a patient with XLG II, bringing the total to 19 XLG I and 12 XLG II mutations. Most XLG I mutations probably lead to truncation or disruption of the PHKA2 protein. In contrast, all XLG II mutations are missense mutations or small in-frame deletions and insertions. These results suggest that the biochemical differences between XLG I and XLG II might be due to the different nature of the disease-causing mutations in PHKA2. XLG I mutations may lead to absence of the alpha subunit, which causes an unstable PHK holoenzyme and deficient enzyme activity, whereas XLG II mutations may lead to in vivo deregulation of PHK, which might be difficult to demonstrate in vitro.

Base Sequence↗