Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Rat brain glycogen branching enzyme was partially purified in order to elucidate its mechanism of action. The alpha1,4-alpha1,6-glucan polysaccharide was synthesized using rat brain branching enzyme under two different elongation conditions: Glc-1-P and phosphorylase or UDP-Glc and glycogen synthase. The products obtained demonstrated that the cpolysaccharides synthesized (pattern of the spectra obtained in the presence of Krisman's reagent, lambda max, parameter A and R, % beta-amylolysis and degree of branching) under different incubation times are nearly constant. These results imply that the degree of branching of a polysaccharide depends only on the enzyme specificity.
Cell Mol Biol (Noisy-le-grand) 1998 May
PMID:Glycogen brain branching enzyme. 962 Apr 41

In obesity several mechanisms contribute to produce insulin resistance. Elevation of plasma FFA increases the concentration of cytoplasmic long-chain-CoA (LC-CoA) and mitochondrial acetyl-CoA. The latter inhibits pyruvate dehydrogenase (PDH) and, therefore, glucose oxidation. LC-CoA exerts an array of effects, some mediated by peroxisome proliferator-activated receptors, including modulation of gene expression of enzymes of glycolipid metabolism, thus inhibiting glucose utilization and potentiating FFA oxidation. Enhanced availability of glucose plus insulin forces glucose utilization (activation of PDH and glycogen synthase) and leads to increased production of malonyl-CoA (via citrate), which inhibits carnitine palmitoyl transferase 1 and therefore FFA beta-oxidation. In obesity there is often enhanced availability of both FFA and glucose plus insulin. The latter, by increasing malonyl-CoA, may limit FFA beta-oxidation. This, however, leads to further increases in LC-CoA, which worsens insulin resistance. All these mechanisms occur through both short-term and long-term effects. Therefore, when insulin sensitivity is measured with the hyperinsulinemic clamp, which artificially suppresses FFA levels, the FFA short-term effects are lost. More physiological methods are those utilizing OGTT data, allowing calculation of an Insulin Sensitivity Index for glycemia, or ISI(gly), through the formula: 2/((INSp x GLYp)+1), where INSp and GLYp are the measured insulin and glycemic areas expressed by taking mean normal value as 1. The corresponding Insulin Resistance Index, or IRI(gly), can be obtained through the formula: 2/((1/(INSp x GLYp))+1). Substitution of glycemic (GLYp) with FFA (FFAp) values allows the calculation of indices of insulin sensitivity and resistance for FFA, i.e., ISI(ffa) and IRI(ffa).
Mol Genet Metab 1998 Oct
PMID:Insulin resistance in obesity: metabolic mechanisms and measurement methods. 978 4

This study was designed to assess the effects of chronic estrogen replacement therapy on mechanical function and glucose utilization in aerobic and post-ischemic hearts. Ovariectomized female rats were either untreated or were treated subcutaneously with 17 beta -estradiol (0.25 mg 21-day slow release pellets). After 14 days, when serum concentrations of 17 beta -estradiol were 3.8+/-0.8 and 148+/-15 pg/ml, respectively, hearts were isolated and perfused in working mode with Krebs-Henseleit solution containing 1.2 m m palmitate and 11 m m[5-(3)H/U-(14)C]glucose. Hearts were perfused aerobically (60 min) and then subjected to low-flow ischemia (0.5 ml/min, 60 min) followed by reperfusion (30 min). During reperfusion, hearts from rats treated chronically with 17 beta -estradiol had an improved (two-fold) recovery of mechanical function. 17 beta -estradiol (400 p m, 109 pg/ml), when present acutely in heart perfusate during ischemia and reperfusion, did not improve recovery. Chronic 17 beta -estradiol increased glucose oxidation during reperfusion as well as during aerobic perfusion but had no effect on glycolysis. Chronic 17 beta -estradiol also altered post-ischemic glycogen metabolism and increased glycogen content and glycogen synthase activity at the end of reperfusion. As stimulation of glucose oxidation has been shown previously to be cardioprotective, and as the enhanced rate of glucose oxidation was not simply a consequence of enhanced recovery of mechanical function, alterations in glycogen and glucose utilization may contribute to the direct cardioprotective effects of chronic estrogen treatment.
J Mol Cell Cardiol 1999 Aug
PMID:Enhancement of post-ischemic myocardial function by chronic 17 beta -estradiol treatment: role of alterations in glucose metabolism. 1042 51

In Saccharomyces cerevisiae, PHO85 encodes a cyclin-dependent protein kinase (Cdk) catalytic subunit with multiple regulatory roles thought to be specified by association with different cyclin partners (Pcls). Pcl10p is one of four Pcls with little sequence similarity to cyclins involved in cell cycle control. It has been implicated in specifying the phosphorylation of glycogen synthase (Gsy2p). We report that recombinant Pho85p and Pcl10p produced in Escherichia coli reconstitute an active Gsy2p kinase in vitro. Gsy2p phosphorylation required Pcl10p, occurred at physiologically relevant sites, and resulted in inactivation of Gsy2p. The activity of the reconstituted enzyme was even greater than Pho85p-Pcl10p isolated from yeast, and we conclude that, unlike many Cdks, Pho85p does not require phosphorylation for activity. Pcl10p formed complexes with Gsy2p, as judged by (i) gel filtration of recombinant Pcl10p and Gsy2p, (ii) coimmunoprecipitation from yeast cell lysates, and (iii) enzyme kinetic behavior consistent with Pcl10p binding the substrate. Synthetic peptides modeled on the sequences of known Pho85p sites were poor substrates with high K(m) values, and we propose that Pcl10p-Gsy2p interaction is important for substrate selection. Gel filtration of yeast cell lysates demonstrated that most Pho85p was present as a monomer, although a portion coeluted in high-molecular-weight fractions with Pcl10p and Gsy2p. Overexpression of Pcl10p sequestered most of the Pho85p into association with Pcl10p. We suggest a model for Pho85p function in the cell whereby cyclins like Pcl10p recruit Pho85p from a pool of monomers, both activating the kinase and targeting it to substrate.
Mol Cell Biol 1999 Oct
PMID:Substrate targeting of the yeast cyclin-dependent kinase Pho85p by the cyclin Pcl10p. 1049 Jun 39

The glycogen-associated regulatory subunit of protein phosphatase-1 (PP-1G) plays a major role in insulin-stimulated glycogen synthesis and thus the regulation of nonoxidative glucose disposal in skeletal muscle. In a general population of Caucasians a polymorphism at codon 905 of PP-1G from an aspartate to tyrosine has been reported to be associated with insulin resistance and hypersecretion. In this report functional studies were performed on rat skeletal muscle L6 cells stably transfected with an Asp905Tyr mutant PP-1G to evaluate the impact of this mutation on cellular responsiveness to insulin and cAMP. Although transfection resulted in a 3-fold increase in mutant PP-1G subunit expression, basal and insulin-stimulated PP-1 catalytic activities were decreased when compared with L6 cells transfected with wild-type PP-1G. The Asp905Tyr mutation resulted in an increase in cellular sensitivity to cAMP agonist, resulting in an inhibition of insulin's stimulatory effect on glycogen synthesis. More importantly, low concentrations of (Bu)2cAMP completely reversed insulin's stimulatory effects on glycogen synthesis when added to insulin-treated cells expressing mutant PP-1G. This was due to a rapid activation of glycogen phosphorylase a and a simultaneous inactivation of glycogen synthase via cAMP-mediated reductions in insulin-stimulated PP-1 catalytic activities. We conclude that an Asp905Tyr mutation of PP-1G is accompanied by a relative increase in sensitivity to cAMP agonists as well as a diminished capacity of the mutant PP-1G to effectively mediate the inhibitory effects of insulin on glycogen breakdown via PP-1 activation.
Mol Endocrinol 1999 Oct
PMID:Effect of an Asp905Tyr mutation of the glycogen-associated regulatory subunit of protein phosphatase-1 on the regulation of glycogen synthesis by insulin and cyclic adenosine 3',5'-monophosphate agonists. 1051 78

The glycogen content in fresh raw dog spermatozoa was 0.22+/-0.03 micromol/mg protein. This matched with the presence of a glycogen-like staining in the head and midpiece. Glycogen levels lowered to 0.05 micromol/mg protein after incubation for 60 min without sugars. Addition of either 10 mM fructose or 10 mM glucose increased glycogen content to 0.70 micromol/mg protein. On the other hand, glycogen synthase activity ratio of fresh dog sperm (0.35+/-0.07, measured in the absence and the presence of glucose 6-P) increased to 0.55 with 10 mM fructose for 20 min, whereas glucose had a smaller effect. Spermatozoa extracts had also a protein of about 100 Kd, which reacted against a rat liver glycogen synthase antibody. This was located in sperm head and midpiece. Furthermore, glycogen phosphorylase activity ratio measured in presence and absence of AMP (0.25+/-0.03 in fresh samples) decreased to 0.15 by 10 mM glucose for 20 min, whereas fructose was less potent in this regard. The maximal effect of glucose and fructose were observed from 10-20 mM onwards. This work is the first indication for a functional glycogen metabolism in mammal spermatozoa, which could play an important role in regulating sperm survival in vivo.
Mol Reprod Dev 2000 Jun
PMID:Evidence for a functional glycogen metabolism in mature mammalian spermatozoa. 1081 53

The PPP1R3 gene encoding the G-subunit of protein phosphatase-1 has three polymorphisms in linkage disequilibrium in the Pima Indians: an mRNA-destabilizing element in the 3'-untranslated region (ARE1/ARE2 alleles), Arg883Ser, and Asp905Tyr substitutions. The ARE2 allele, Arg883, and Asp905 variants are associated with insulin resistance and higher prevalence of type 2 diabetes in the Pima Indians. The ARE2 allele is associated with lower PPP1R3 transcript and protein levels in muscle tissue. Here we determined the functional contribution of the amino acid substitutions independent of the ARE alleles to insulin-stimulated glycogen synthesis by adenoviral-mediated gene expression in L6 myotubes. Similar overexpression levels of the G-subunit variants increased glycogen synthase fractional activity in the presence ( approximately 1. 5-fold) of insulin compared to control myotubes transduced with adenovirus encoding beta-galactosidase. The glycogen synthesis rate of myotubes overexpressing the G-subunit variants also increased by approximately 1.7-fold over the control with and without insulin. However, these measures were not significantly different among the variants. This study does not support a role for Arg883 and Asp905 variants independent of the ARE2 allele in the impaired insulin-stimulated glycogen synthesis in the muscle of Pima Indians.
Mol Genet Metab 2000 Jun
PMID:Functional analyses of amino acid substitutions Arg883Ser and Asp905Tyr of protein phosphatase-1 G-subunit. 1087 97

The effects of alpha-D-glucose pentaacetate (1.7 mM) upon glycogen synthase a activity and lactate output were examined in rat hepatocytes incubated at increasing concentrations of D-glucose. The ester enhanced the activity of glycogen synthase a at all concentrations (2.8, 4.0 and 8.0 mM) of D-glucose, which itself provoked a concentration-related increase in enzymatic activity. Likewise, the output of lactate augmented at increasing concentrations of D-glucose. However, alpha-D-glucose pentaacetate failed to cause a further increase in lactate output, the trend being even towards a lower production of lactate in the presence than absence of the ester. These findings suggest that the activation of glycogen synthase a by alpha-D-glucose pentaacetate and the subsequent increase in glycogen synthesis are sufficiently pronounced to prevent the increase in glycolysis otherwise expected from the generation of unesterified D-glucose from the same ester. Such a situation, which differs from that previously documented in pancreatic islet cells, could be favourable in the perspective of using alpha-D-glucose pentaacetate as a novel insulinotropic, and hence hypoglycaemic, tool in the treatment of non-insulin-dependent diabetes mellitus.
Int J Mol Med 2000 Aug
PMID:Activation of glycogen synthase a in hepatocytes exposed to alpha-D-glucose pentaacetate. 1089 66

Leakage of mitochondrial oxidants contributes to a variety of harmful conditions ranging from neurodegenerative diseases to cellular senescence. We describe here, however, a physiological and heretofore unrecognized role for mitochondrial oxidant release. Mitochondrial metabolism of pyruvate is demonstrated to activate the c-Jun N-terminal kinase (JNK). This metabolite-induced rise in cytosolic JNK1 activity is shown to be triggered by increased release of mitochondrial H(2)O(2). We further demonstrate that in turn, the redox-dependent activation of JNK1 feeds back and inhibits the activity of the metabolic enzymes glycogen synthase kinase 3beta and glycogen synthase. As such, these results demonstrate a novel metabolic regulatory pathway activated by mitochondrial oxidants. In addition, they suggest that although chronic oxidant production may have deleterious effects, mitochondrial oxidants can also function acutely as signaling molecules to provide communication between the mitochondria and the cytosol.
Mol Cell Biol 2000 Oct
PMID:Role for mitochondrial oxidants as regulators of cellular metabolism. 1098 48

Phosphoinositide (PI) 3-kinase is a key mediator of insulin-dependent metabolic actions, including stimulation of glucose transport and glycogen synthesis. The gene for the p85alpha regulatory subunit yields three splicing variants, p85alpha, AS53/p55alpha, and p50alpha. All three have (i) a C-terminal structure consisting of two Src homology 2 domains flanking the p110 catalytic subunit-binding domain and (ii) a unique N-terminal region of 304, 34, and 6 amino acids, respectively. To determine if these regulatory subunits differ in their effects on enzyme activity and signal transduction from insulin receptor substrate (IRS) proteins under physiological conditions, we expressed each regulatory subunit in fully differentiated L6 myotubes using adenovirus-mediated gene transfer with or without coexpression of the p110alpha catalytic subunit. PI 3-kinase activity associated with p50alpha was greater than that associated with p85alpha or AS53. Increasing the level of p85alpha or AS53, but not p50alpha, inhibited both phosphotyrosine-associated and p110-associated PI 3-kinase activities. Expression of a p85alpha mutant lacking the p110-binding site (Deltap85) also inhibited phosphotyrosine-associated PI 3-kinase activity but not p110-associated activity. Insulin stimulation of two kinases downstream from PI-3 kinase, Akt and p70 S6 kinase (p70(S6K)), was decreased in cells expressing p85alpha or AS53 but not in cells expressing p50alpha. Similar inhibition of PI 3-kinase, Akt, and p70(S6K) was observed, even when p110alpha was coexpressed with p85alpha or AS53. Expression of p110alpha alone dramatically increased glucose transport but decreased glycogen synthase activity. This effect was reduced when p110alpha was coexpressed with any of the three regulatory subunits. Thus, the three different isoforms of regulatory subunit can relay the signal from IRS proteins to the p110 catalytic subunit with different efficiencies. They also negatively modulate the PI 3-kinase catalytic activity but to different extents, dependent on the unique N-terminal structure of each isoform. These data also suggest the existence of a mechanism by which regulatory subunits modulate the PI 3-kinase-mediated signals, independent of the kinase activity, possibly through subcellular localization of the catalytic subunit or interaction with additional signaling molecules.
Mol Cell Biol 2000 Nov
PMID:Positive and negative regulation of phosphoinositide 3-kinase-dependent signaling pathways by three different gene products of the p85alpha regulatory subunit. 1102 74


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