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PubMed1989

Sequence and expression of chicken and mouse rsk: homologs of Xenopus laevis ribosomal S6 kinase.

We have previously reported the isolation of cDNAs encoding two closely related Xenopus ribosomal S6 kinases, S6KII alpha and -beta (S. W. Jones, E. Erikson, J. Blenis, J. L. Maller, and R. L. Erikson, Proc. Natl. Acad. Sci. USA 85:3377-3381, 1988). We report here the molecular cloning of one chicken and two mouse homologs of the Xenopus laevis cDNAs. As described for the Xenopus proteins, these cDNAs were found to predict polypeptides that contain two distinct kinase domains, of which one is most closely related to the catalytic subunit of cyclic AMP-dependent protein kinase and the other is most closely related to the catalytic subunit of phosphorylase b kinase. The three predicted proteins were more than 79% identical to the Xenopus S6KII alpha protein. The chicken and one of the mouse cDNAs were, respectively, 3.7 and 3.1 kilobase pairs in length, predicted proteins of 752 and 724 amino acids with molecular weights of 84.4 and 81.6 kilodaltons, and hybridized to mRNAs in fibroblasts and tissues of approximately 3.6 and 3.4 kilobases (kb). The second mouse cDNA was approximately 6.1 kilobase pairs and was not full length but predicted the C-terminal 633 amino acids of a protein that is similar to the C-terminal portion of Xenopus S6KII alpha. This clone hybridized to mRNA transcripts of 7.6 and 3.4 kb. In vitro transcription and translation of the chicken and the mouse cDNAs that predict complete proteins produced major products with apparent molecular weights of 96 and 84 kilodaltons. Analysis of mRNA levels in chicken tissues showed significant quantities of the 3.6-kb transcript in small and large intestine, spleen, and bursa. Both mouse cDNA were similarly expressed at significant levels in intestine, thymus, and lung; however, the 7.6-kb mRNA was differentially and more highly expressed in heart and brain. The two mouse cDNAs represent two different S6 kinase genes, as shown by comparison of their protein sequences, mRNA transcript sizes, genomic organizations, and nucleic acid sequences. We propose that this family of genes be named rsk, for ribosomal S6 kinase.

Amino Acid Sequence↗
PubMed1986

A comparative study of the purine- and pyrimidine-metabolising enzymes of a range of trypanosomatids.

A range of trypanosomatids (amastigotes and cultured promastigotes of Leishmania mexicana mexicana, cultured promastigotes of L. m. amazonensis, L. donovani and L. tarentolae, culture forms of Crithidia fasciculata, Herpetomonas muscarum muscarum and H. m. ingenoplastis and procyclic trypomastigotes of Trypanosoma brucei brucei) have been surveyed for the presence of purine- and pyrimidine-metabolising enzymes. Several common features were observed, including the presence of nucleosidases, catabolic phosphorylases, phosphoribosyltransferases, kinases and cytidine deaminase and the apparent absence of AMP deaminase, anabolic purine phosphorylase and cytosine deaminase. Significant differences between species were discovered, notably in adenine and adenosine metabolism. Nucleoside phosphotransferase active on inosine was detected in insect trypanosomatids but not in L. m. mexicana.

Aminohydrolases↗
PubMed1990

[Use of enzyme test in chemotherapy of patients with cancer of the breast].

The activity of thymidine kinase, thymidine phosphorylase, adenosine deaminase, AMP 5'-nucleotidase was assessed in the serum of healthy females, patients with mastopathia cystica and those with stage IIIB breast cancer. The females age ranged from 23 to 70 years. The activity of the enzymes had significant differences in cancer patients. Minimal thymidine phosphorylase activity was found to suggest fibrous cancer. Changes in the enzymes levels in cancer patients on combined treatment may serve a biochemical test indicating the efficacy of the chemotherapy conducted.

5'-Nucleotidase↗
PubMed2002

Identification of protein degradation during post-mortem storage of pig meat.

Eighteen proteins and peptides that were found to change post-mortem in Longissimus dorsi from pig muscle were identified by the use of matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. The 18 peptides originate from 9 different proteins including the 3 structural proteins (actin, myosin heavy chain, and troponin T) and the 6 metabolic proteins glycogen phosphorylase, creatine kinase, phosphopyruvate hydratase, myokinase, pyruvate kinase, and dihydrolipoamide succinyltransferase. The molecular weight and estimated sequence length of the identified spots show that these fragments result from proteolytic activity in meat. Identification of the parent proteins and the enhanced post-mortem appearance of the degradation products make these specific peptides good candidates for meat quality markers, and further studies of these specific fragments will lead to a better understanding of the proteolytic activities involved in the post-mortem conversion of muscle to meat.

Animals↗
PubMed1994

Purine and pyrimidine metabolism in human gliomas: relation to chromosomal aberrations.

Chromosomal aberrations in human gliomas are principally numerical. In tumours of low malignancy, karyotypes are frequently normal, but occasionally an excess of chromosome 7 and a loss of sex chromosome are observed. In highly malignant tumours, the most frequent aberrations are gain of chromosome 7, loss of chromosome 10 and less frequently losses or deletions of chromosomes 9, 22, 6, 13 and 14 or gains of chromosomes 19 and 20. To understand the meaning of these chromosome imbalances, the relationships between chromosome abnormalities and metabolic disturbances were studied. The losses or deletions observed affected principally chromosomes carrying genes encoding enzymes involved in purine metabolism. The activities of ten enzymes were measured: adenosine kinase, adenine phosphoribosyltransferase, adenylate kinase, methylthioadenosine phosphorylase, hypoxanthine phosphoribosyltransferase, adenylosuccinate lyase, inosine monophosphate dehydrogenase, adenosine deaminase, nucleoside phosphorylase and adenosine monophosphate deaminase. In parallel, two enzymes involved in pyrimidine metabolism, thymidine kinase and thymidylate synthase (TS), were studied. The activities of all these enzymes were measured on samples from 30 human primary glial tumours with low or high malignancy, six xenografted tumours at different passages, four portions of normal brain tissue and four non-glial brain neoplasms. As suggested by cytogenetic data, the enzymatic results showed a relatively low activity of purine metabolism in glial tumours when compared with normal brain and non-glial brain neoplasms. Considering the two enzymes involved in pyrimidine metabolism, only TS had higher activity in glial tumours of high malignancy than in normal brain. In comparison with normal brain, the balance between salvage and de novo pathways changes in gliomas, and even more in grafted tumours, in favour of de novo synthesis. The relation between chromosomes and metabolic imbalances does not correspond to a simple gene dosage effect in these tumours. These data suggest that the decrease of adenosine metabolism occurs before chromosomal aberrations appear, since it is observed in tumours of low malignancy when most karyotypes are still normal, and that the de novo pathway increases with tumour progression.

Adolescent↗
PubMed1989

Development of inhibitors of pyrimidine metabolism.

Benzylacyclouridines were developed as specific and potent competitive inhibitors of uridine phosphorylase with Ki values in the nanomolar range. These compounds have no activity against thymidine phosphorylase, uridine kinase, thymidine kinase and orotate phosphoribosyltransferase. Benzylacyclouridines potentiate the chemotherapeutic effect of FdUrd. Coadministration of uridine phosphorylase inhibitor with FdUrd caused selective toxicity against tumors with low or no thymidine phosphorylase, but not against the host tissues which have thymidine phosphorylase, and thus retain the capacity to cleave FdUrd, and hence overcome its toxicity. There are distinct differences between uridine phosphorylase and thymidine phosphorylase. Benzylacyclouridines competitively inhibit the nucleoside transport of mammalian cells. The structure-activity relationship of inhibitors of uridine phosphorylase showed that a large hydrophobic pocket exists where C-5 of uracil binds, and that it is necessary to have the 3'-hydroxyl group and syn-configuration around the N-glycosidic bond for the nucleosides or their analogs to bind. Dihydrouracil dehydrogenase was found to be widely distributed among mammalian cells, where it was previously believed to be present only in the liver and the kidney. The structure-activity relationship of its inhibitors revealed benzyloxybenzyluracil and 2,6-pyridinediol as most potent. Also identified for orotate phosphoribosyltransferase was 2,4-pyridinediol.

Humans↗
PubMed1968

2-deoxyribose gene-enzyme complex in Salmonella typhimurium. I. Isolation and enzymatic characterization of 2-deoxyribose-negative mutants.

Salmonella typhimurium was found to utilize 2-deoxyribose as a sole carbon and energy source. Cells grown in the presence of deoxyribose contained increased levels of deoxyribose kinase, thymidine phosphorylase, and two forms of deoxyribose-5-phosphate aldolase (DR5P aldolase). One form of DR5P aldolase was induced by deoxyribose and coordinately regulated with deoxyribose kinase. The second form of DR5P aldolase was induced by deoxyribose-5-phosphate and coordinately regulated with thymidine phosphorylase. Mutants unable to ferment deoxyribose have been isolated and shown to be lacking either deoxyribose kinase or deoxyribose permease, but none has been found from which DR5P aldolase is missing. Thymine-requiring mutants which are able to grow on low levels of thymine have been isolated and shown, in some cases, to be lacking one or both DR5P aldolases.

Aldehyde-Lyases↗
PubMed1991

[Use of the study of DNA metabolism enzyme activities as a test system in the treatment of breast cancer].

Blood serum activities of thymidine kinase, thymidine phosphorylase, adenosine deaminase, and 5'-nucleotidase were measured in normal women, women suffering from mastopathies and mammary carcinomas, aged 36 to 70. Blood serum activities of the studied enzymes in mammary carcinoma patients differed from these values in healthy women and those suffering from mastopathies; these differences were age-associated. Measurements of the time course of enzymic activities before and in the course of chemotherapy may be employed as a biochemical test to monitor therapy efficacy.

5'-Nucleotidase↗
PubMed1981

Scaling of oxidative and glycolytic enzymes in mammals.

The catalytic activities of several oxidative and glycolytic enzymes were determined in the gastrocnemius muscle of 10 mammalian species differing in body weight by nearly 6 orders of magnitude. When expressed in terms of units gm-1, the activities of enzymes functioning in oxidative metabolism (citrate synthase, beta-hydroxybutyrylCoA dehydrogenase, and malate dehydrogenase) decrease as body weight increases. Log-log plots (activity gm-1 vs body mass) yield straight lines with negative slopes that are less than the allometric exponent (-0.25) typically observed for basal metabolic rates. Since the amount of power a muscle can generate depends upon the catalytic potential of its enzyme machinery (the higher the catalytic potential the higher the maximum rate of energy generation), these data predict that the scope for aerobic activity in large mammals should be greater than in small mammals if nothing else becomes limiting, a result in fact recently obtained by Taylor et al. (Respir. Physiol., 1981). In contrast to the scaling of oxidative enzymes, the activities of enzymes functioning in anaerobic glycogenolysis (glycogen phosphorylase, pyruvate kinase, and lactate dehydrogenase) increase as body size increases. Log-log plots (activity gm-1 vs body mass) display a positive slope indicating that the larger the animal the higher the glycolytic potential of its skeletal muscles. This unexpected result may indicate higher relative power costs for burst type locomotion in larger mammals, which is in fact observed in within-species studies of man. However, the scaling of anaerobic muscle power has not been closely assessed in between-species comparisons of mammals varying greatly in body size.

Animals↗
PubMed1985

Mapping increased glycogen phosphorylase activity in dorsal root ganglia and in the spinal cord following peripheral stimuli.

A histochemical technique has been used to map the distribution and the relative proportion of the active and inactive form of the enzyme glycogen phosphorylase in the primary afferent cell bodies of lumbar dorsal root ganglia and within the lumbar spinal cord of the rat. The glycogen phosphorylase was found to be present in large and small diameter primary afferent cell bodies and in the grey matter of the spinal cord, except in lamina 2. Most of the glycogen phosphorylase in control rats was in the inactive form. Peripheral innocuous mechanical and thermal stimuli failed to alter the activity of glycogen phosphorylase in the lumbar spinal cord, but noxious mechanical, chemical, and thermal stimuli when applied to the hindlimb of decerebrate rats increased the enzyme activity in the ipsilateral dorsal horn within 10 minutes. The number of primary afferent cell bodies with active glycogen phosphorylase also increased. These changes are likely to be due to the conversion of the inactive "b" form of the enzyme to the active "a" form under the influence of a calcium or cyclic AMP activated phosphorylase b kinase. Pentobarbitone anaesthesia diminished but did not completely suppress the noxious stimulus-evoked glycogen phosphorylase activity changes. Graded electrical stimulation of the sciatic nerve was performed to simulate the effects of the peripheral noxious stimuli in a controlled fashion. Stimulation at a strength that activated only large myelinated afferents produced no greater effect on the distribution of the active form of the enzyme in the dorsal horn than that produced by exposure of the nerve, but stimulation of the thin myelinated A-delta afferents and unmyelinated C-fibres produced a widespread increase in glycogen phosphorylase activity in the spinal cord and in the L4 dorsal root ganglion. The increased activity could be detected after stimulation for as short a period of time as 5 minutes. The mechanisms underlying the stimulus-evoked increase in glycogen phosphorylase activity in the spinal cord and dorsal root ganglia are not yet known, nor have we positively established which elements in the spinal cord, neurones, or glia are responsible for the changes in the glycogen phosphorylase activity. Nevertheless, it is clear that the neural activity generated by certain types of high threshold input is associated with the activation of glycogen phosphorylase, and this may be a useful tool for studying the spatial distribution of some activity-related changes in the nervous system.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed2005

Proteomic analysis of protein nitration in aging skeletal muscle and identification of nitrotyrosine-containing sequences in vivo by nanoelectrospray ionization tandem mass spectrometry.

The nitration of protein tyrosine residues represents an important post-translational modification during development, oxidative stress, and biological aging. To rationalize any physiological changes with such modifications, the actual protein targets of nitration must be identified by proteomic methods. While several studies have used proteomics to screen for 3-nitrotyrosine-containing proteins in vivo, most of these studies have failed to prove nitration unambiguously through the actual localization of 3-nitrotyrosine to specific sequences by mass spectrometry. In this paper we have applied sequential solution isoelectric focusing and SDS-PAGE for the proteomic characterization of specific 3-nitrotyrosine-containing sequences of nitrated target proteins in vivo using nanoelectrospray ionization-tandem mass spectrometry. Specifically, we analyzed proteins from the skeletal muscle of 34-month-old Fisher 344/Brown Norway F1 hybrid rats, a well accepted animal model for biological aging. We identified the 3-nitrotyrosine-containing sequences of 11 proteins, including cytosolic creatine kinase, tropomyosin 1, glyceraldehyde-3-phosphate dehydrogenase, myosin light chain, aldolase A, pyruvate kinase, glycogen phosphorylase, actinin, gamma-actin, ryanodine receptor 3, and neurogenic locus notch homolog. For creatine kinase and neurogenic locus notch homolog, two 3-nitrotyrosine-containing sequences were identified, i.e. at positions 14 and 20 for creatine kinase and at positions 1175 and 1205 for the neurogenic locus notch homolog. The selectivity of the in vivo nitration of creatine kinase at Tyr14 and Tyr20 does not correspond to the product selectivity in vitro, where exclusively Tyr82 was nitrated when creatine kinase was exposed to peroxynitrite. The latter experiments demonstrate that the in vitro exposure of an isolated protein to peroxynitrite may not always be a good model to mimic protein nitration in vivo.

Aging↗
PubMedDate not supplied

[Age-related changes in metabolism of DNA precursors in patients with mastopathy].

The activity of thymidine kinase, thymidine phosphorylase, adenosine deaminase and 5'-nucleotedase of AMP was studied in tissues, blood serum and lymphocytes of 60 healthy females and 50 females with fibrocavernous mastopathy aged 23-70. It was revealed that age-related changes in the activity of thymidine kinase in blood serum reflect the analogous changes in enzyme activity in tissues of healthy women. A direct correlation was established between thymidine kinase activity and age both in healthy females and those with mastopathy. A significant decrease in activity of thymidine phosphorylase was demonstrated in blood serum of patients with mastopathy aged 46-60. Determined 4-fold increase in activity of adenosine deaminase in serum was accompanied by decreased enzyme activity in lymphocytes and decreased Lymphocyte Blast Transformation Index in the same age range. The revealed metabolic changes in DNA-precursors' metabolism in patients with mastopathy aged 46-60 might be one of the reasons of increased risk of oncological diseases in this age group.

5'-Nucleotidase↗
PubMed1977

On the role of calcium as second messenger in liver for the hormonally induced activation of glycogen phosphorylase.

We have studied the mode of action of three hormones (angiotensin, vasopressin and phenylephrine, an alpha-adrenergic agent) which promote liver glycogenolysis in a cyclic AMP-independent way, in comparison with that of glucagon, which is known to act essentially via cyclic AMP. The following observations were made using isolated rat hepatocytes: (a) In the normal Krebs-Henseleit bicarbonate medium, the hormones activated glycogen phosphorylase (EC 2.4.1.1) to about the same degree. In contrast to glucagon, the cyclic AMP-independent hormones did not activate either protein kinase (EC 2.7.1.37) or phosphorylase b kinase (EC 2.7.1.38). (b) The absence of Ca2+ from the incubation medium prevented the activation of glycogen phosphorylase by the cyclic AMP-independent agents and slowed down that induced by glucagon. (c) The ionophore A 23187 produced the same degree of activation of glycogen phosphorylase, provided that Ca2+ was present in the incubation medium. (d) Glucagon, cyclic AMP and three cyclic AMP-dependent hormones caused an enhanced uptake of 45Ca; it was verified that concentrations of angiotensin and of vasopressin known to occur in haemorrhagic conditions were able to produce phosphorylase activation and stimulate 45Ca uptake. (e) Appropriate antagonists (i.e. phentolamine against phenylephrine and an angiotensin analogue against angiotensin) prevented both the enhanced 45Ca uptake and the phosphorylase activation. We interpret our data in favour of a role of calcium (1) as the second messenger in liver for the three cyclic AMP-independent glycogenolytic hormones and (2) as an additional messenger for glucagon which, via cyclic AMP, will make calcium available to the cytoplasm either from extracellular or from intracellular pools. The target enzyme for Ca2+ is most probably phosphorylase b kinase.

Angiotensin II↗
PubMed1983

Mechanism of adenosine inhibition of catecholamine-induced responses in heart.

The properties of adenosine inhibition of catecholamine-induced responses were investigated, using an isolated rat heart preparation. Perfusion of hearts with 0.1 microM isoproterenol increased myocardial cAMP content 2.8-fold, activation of cAMP-dependent protein kinase 4.4-fold, phosphorylase a formation 3.4-fold, left ventricular pressure 1.8-fold, rate of ventricular pressure development 2.1-fold, and rate of ventricular relaxation 2.2-fold within 1 minute. When perfused with the isoproterenol, 10 microM adenosine reduced the catecholamine-produced increase in cAMP, cAMP-dependent protein kinase, and phosphorylase by 30-40%, and the elevation in left ventricular pressure and rate of ventricular pressure development by 40-70% within 40 seconds. More than 2 minutes were required for the nucleoside to significantly reduce the isoproterenol-elicited increase in the rate of ventricular relaxation. Perfusion of adenosine alone at concentrations from 0.1 to 10 microM were without effect on the above parameters. Theophylline at 50 microM had no effect alone on the above parameters but blocked the inhibitory actions of adenosine on the isoproterenol-induced responses. In the presence of 15 mM Mg++ adenosine reduced by approximately 56% the 2-fold increase in myocardial membrane adenylate cyclase activity produced by 1 microM isoproterenol without affecting basal or fluoride-stimulated activity. Adenosine also reduced the isoproterenol-induced increase in enzyme activity assayed at 1-2 mM Mg++, a level that more closely approximates the intracellular activity of the ion. The results suggest that physiological concentrations of adenosine attenuate the catecholamine-induced increase in cAMP content, cAMP-dependent protein kinase activation, phosphorylase a formation, and contractile parameters in the working heart, via reducing the beta-adrenergic activation of adenylate cyclase.

2-Chloroadenosine↗
PubMed1998

Ser-262 in human recombinant tau protein is a markedly more favorable site for phosphorylation by CaMKII than PKA or PhK.

Several kinases have been shown to phosphorylate tau protein at Ser-262, an important site involved in the regulation of the binding of tau to microtubules. In this study we compared the phosphorylation of tau at Ser-262 by CaMKII, PhK and PKA in vitro as determined by radioimmunoblots developed by the monoclonal antibody 12E8 which recognizes P-Ser-262 and P-Ser-356; and Ab-262, a polyclonal antibody which is specific to unphosphorylated Ser-262 in tau. We found that the phosphorylation at Ser-262 was several times more effective by CaMKII than PKA or PhK. Employing rat brain extract as a source of all brain kinases and KN-62, a specific inhibitor of CaMKII, we found that CaMKII accounts for approximately 45% of phosphorylation at Ser-262. Furthermore, in rat brain slices kept metabolically active in oxygenated artificial CSF, phosphorylation of tau at Ser-262 was (i) increased up to 120% in the presence of bradykinin, a CaMKII activator, and (ii) inhibited by approximately 35% in the presence of KN-62. Thus, CaMKII is a major tau Ser-262 kinase in mammalian brain.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed2002

Amorphin is phosphorylase; phosphorylase is an alpha-actinin-binding protein.

In a study of myofibrillar proteins, Chowrashi and Pepe [1982: J. Cell Biol. 94:565-573] reported the isolation of a new, 85-kD Z-band protein that they named amorphin. We report that partial sequences of purified amorphin protein indicate that amorphin is identical to phosphorylase, an enzyme important in the metabolism of glycogen. Anti-amorphin antibodies also reacted with purified chicken and rabbit phosphorylase. To explore the basis for phosphorylase's (amorphin's) localization in the Z-bands of skeletal muscles, we reacted biotinylated alpha-actinin with purified amorphin and with purified phosphorylase and found that alpha-actinin bound to each. Radioimmune assays also indicated that phosphorylase (amorphin) bound to alpha-actinin, and, with lower affinity, to F-actin. Negative staining of actin filaments demonstrated that alpha-actinin mediates the binding of phosphorylase to actin filaments. There are several glycolytic enzymes that bind actin (e.g., aldolase, phosphofructokinase, and pyruvate kinase), but phosphorylase is the first one demonstrated to bind alpha-actinin. Localization of phosphorylase in live cells was assessed by transfecting cultures of quail embryonic myotubes with plasmids expressing phosphorylase fused to Green Fluorescent Protein (GFP). This resulted in targeting of the fusion protein to Z-bands accompanied by a diffuse pattern in the cytoplasm.

Actinin↗