Mechanism of glycogen synthase inactivation and interaction with glycogenin

The macromolecule glycogen is the major glucose reserve in eukaryotes and defects of glycogen metabolism and structure lead to glycogen storage diseases and neurodegeneration. Glycogenesis begins with self-glucosylation of glycogenin (GN), which recruits glycogen synthase (GS). GS is activated by glucose-6-phosphate (G6P) and inactivated by phosphorylation, but how these opposing processes are coupled is unclear. We provide the first structure of phosphorylated human GS-GN complex revealing an autoinhibited GS tetramer flanked by two GN dimers. Phosphorylated N- and C-terminal tails from two GS protomers converge to form dynamic "spike" regions, which are buttressed against GS regulatory helices. This keeps GS in a constrained "tense" conformation that is inactive and more resistant to G6P activation. Mutagenesis that weaken the interaction between the regulatory helix and phosphorylated tails leads to a moderate increase in basal/unstimulated GS activity, supporting the idea that phosphorylation contributes to GS inactivation by constraining GS inter-subunit movement. We propose that multivalent phosphorylation supports GS autoinhibition through interactions from a dynamic "spike" region, thus allowing a "tuneable rheostat" for regulating GS activity. Our structures of human GS-GN provide new insights into the regulation of glycogen synthesis, facilitating future studies of glycogen storage diseases.

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Transgenic overexpression of protein targeting to glycogen markedly increases adipocytic glycogen storage in mice

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00559.2006 ◽

2007 ◽

Vol 292 (3) ◽

pp. E952-E963 ◽

Cited By ~ 28

Author(s):

Michael J. Jurczak ◽

Arpad M. Danos ◽

Victoria R. Rehrmann ◽

Margaret B. Allison ◽

Cynthia C. Greenberg ◽

...

Keyword(s):

Adipose Tissue ◽

Fatty Acid ◽

Glycogen Synthase ◽

Glycogen Synthesis ◽

Transgenic Animals ◽

Glycogen Metabolism ◽

Glycogen Storage ◽

Fatty Acid Binding ◽

Fat Depots

Adipocytes express the rate-limiting enzymes required for glycogen metabolism and increase glycogen synthesis in response to insulin. However, the physiological function of adipocytic glycogen in vivo is unclear, due in part to the low absolute levels and the apparent biophysical constraints of adipocyte morphology on glycogen accumulation. To further study the regulation of glycogen metabolism in adipose tissue, transgenic mice were generated that overexpressed the protein phosphatase-1 (PP1) glycogen-targeting subunit (PTG) driven by the adipocyte fatty acid binding protein (aP2) promoter. Exogenous PTG was detected in gonadal, perirenal, and brown fat depots, but it was not detected in any other tissue examined. PTG overexpression resulted in a modest redistribution of PP1 to glycogen particles, corresponding to a threefold increase in the glycogen synthase activity ratio. Glycogen synthase protein levels were also increased twofold, resulting in a combined greater than sixfold enhancement of basal glycogen synthase specific activity. Adipocytic glycogen levels were increased 200- to 400-fold in transgenic animals, and this increase was maintained to 1 yr of age. In contrast, lipid metabolism in transgenic adipose tissue was not significantly altered, as assessed by lipogenic rates, weight gain on normal or high-fat diets, or circulating free fatty acid levels after a fast. However, circulating and adipocytic leptin levels were doubled in transgenic animals, whereas adiponectin expression was unchanged. Cumulatively, these data indicate that murine adipocytes are capable of storing far higher levels of glycogen than previously reported. Furthermore, these results were obtained by overexpression of an endogenous adipocytic protein, suggesting that mechanisms may exist in vivo to maintain adipocytic glycogen storage at a physiological set point.

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146 GLYCOGEN METABOLISM IN CHORIONIC VILLOUS SAMPLINGS: POSSIBILITIES FOR PRENATAL DIAGNOSIS OF GLYCOGEN STORAGE DISEASES

Pediatric Research ◽

10.1203/00006450-198610000-00201 ◽

1986 ◽

Vol 20 (10) ◽

pp. 1058-1058 ◽

Cited By ~ 2

Author(s):

Y Shin ◽

J Friedel ◽

A Besser ◽

M Rieth ◽

J Gerg ◽

...

Keyword(s):

Prenatal Diagnosis ◽

Glycogen Metabolism ◽

Glycogen Storage ◽

Storage Diseases ◽

Glycogen Storage Diseases

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Biochemical and clinical aspects of glycogen storage diseases

Journal of Endocrinology ◽

10.1530/joe-18-0120 ◽

2018 ◽

Vol 238 (3) ◽

pp. R131-R141 ◽

Cited By ~ 18

Author(s):

Sara S Ellingwood ◽

Alan Cheng

Keyword(s):

Genetic Disorders ◽

Glycogen Metabolism ◽

Glycogen Storage ◽

Clinical Aspects ◽

Branch Points ◽

Storage Diseases ◽

Progressive Myoclonus Epilepsy ◽

Glycogen Storage Diseases ◽

Myoclonus Epilepsy ◽

Chain Lengths

The synthesis of glycogen represents a key pathway for the disposal of excess glucose while its degradation is crucial for providing energy during exercise and times of need. The importance of glycogen metabolism is also highlighted by human genetic disorders that are caused by mutations in the enzymes involved. In this review, we provide a basic summary on glycogen metabolism and some of the clinical aspects of the classical glycogen storage diseases. Disruptions in glycogen metabolism usually result in some level of dysfunction in the liver, muscle, heart, kidney and/or brain. Furthermore, the spectrum of symptoms observed is very broad, depending on the affected enzyme. Finally, we briefly discuss an aspect of glycogen metabolism related to the maintenance of its structure that seems to be gaining more recent attention. For example, in Lafora progressive myoclonus epilepsy, patients exhibit an accumulation of inclusion bodies in several tissues, containing glycogen with increased phosphorylation, longer chain lengths and irregular branch points. This abnormal structure is thought to make glycogen insoluble and resistant to degradation. Consequently, its accumulation becomes toxic to neurons, leading to cell death. Although the genes responsible have been identified, studies in the past two decades are only beginning to shed light into their molecular functions.

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Renal Calculi as Initial Presenting Symptom of Glycogen Storage Disease (Type 1 A) in Early Infancy

Journal of Child Science ◽

10.1055/s-0040-1713630 ◽

2020 ◽

Vol 10 (01) ◽

pp. e45-e47

Author(s):

Nida Mirza ◽

Smita Malhotra ◽

Anupam Sibal

Keyword(s):

Glycogen Storage Disease ◽

Storage Disease ◽

Case Reports ◽

Glycogen Synthesis ◽

Renal Stones ◽

Renal Calculi ◽

Glycogen Storage ◽

Storage Diseases ◽

Glycogen Storage Diseases

AbstractGlycogen storage diseases are a group of heterogeneous metabolic disorders that result from a defect in enzymatic pathway of either glycogen synthesis or glycogen degradation. Here we are reporting a case of glycogen storage diseases type 1 with renal stone as initial manifestation of disease at 2 months of age. There were case reports of recurrent renal calculi in older age group with this disease and considered to be arisen due to metabolic derangements. Although the exact mechanism of renal stones in glycogen storage disease is not clear, in this unique case occurrence of renal stones at 2 months of age suggests that the pathogenesis of renal calculi is probably multifactorial or a part of disease.

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Glycogen storage diseases-time to flip the outdated diagnostic approach centered on liver biopsy with the molecular testing

Pakistan Journal of Medical Sciences ◽

10.12669/pjms.36.2.1310 ◽

2019 ◽

Vol 36 (2) ◽

Author(s):

Sibtain Ahmed ◽

Bushra Afroze

Keyword(s):

Liver Biopsy ◽

Glycogen Synthesis ◽

Cost Effective ◽

Glycogen Storage ◽

Diagnostic Approach ◽

Molecular Testing ◽

Storage Diseases ◽

Creative Commons ◽

Gene Testing ◽

Glycogen Storage Diseases

The glycogen storage diseases (GSDs) are a group of inherited metabolic disorders that result from a defect in any one of several enzymes required for either glycogen synthesis or glycogen degradation. The traditional diagnostic approach is based on the invasive hepatic or muscle biopsies, which are neither cost effective nor convenient. Molecular (gene testing) has emerged over the course of past few years as a robust alternative diagnostic tool, which not only confirms the diagnosis of GSDs but also clearly differentiates the types of GSDs allowing the initiation of the type-specific appropriate treatment for the particular type of GSDs. The aim of this update is to highlight the limitations of undertaking a liver biopsy for the diagnosis of GSDs; and to further describe the pros of the molecular testing for better patient centered care. doi: https://doi.org/10.12669/pjms.36.2.1310 How to cite this:Ahmed S, Afroze B. Glycogen storage diseases-time to flip the outdated diagnostic approach centered on liver biopsy with the molecular testing. Pak J Med Sci. 2020;36(2):---------. doi: https://doi.org/10.12669/pjms.36.2.1310 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Glycogen Storage Diseases

10.1093/med/9780190685157.003.0048 ◽

2018 ◽

Author(s):

Tammy Wang ◽

Jocelyn Wong ◽

Anita Honkanen

Keyword(s):

Skeletal Muscles ◽

Autosomal Recessive ◽

Clinical Presentation ◽

Glycogen Metabolism ◽

Glycogen Storage ◽

Muscle Relaxants ◽

Storage Diseases ◽

Glycogen Storage Diseases ◽

Organ Systems ◽

Glucose Storage

Glycogen storage diseases result from deficiencies of various enzymes or proteins in the pathways of glycogen metabolism. The reduction in effective glucose storage and/or mobilization results in hypoglycemia and accumulation of glycogen in tissues. Diagnosis can occur at any age, from infancy to adulthood, depending on the pathway affected and the degree of enzyme deficiency. The clinical presentation varies, but the most commonly affected organ systems include the heart, liver, and skeletal muscles. In addition to the morbidity that can occur from dysfunction of these organs, important anesthetic implications include administration of glucose-containing fluids to avoid hypoglycemia, monitoring for acidosis, and caution with use of depolarizing muscle relaxants because of the potential risk of hyperkalemia and rhabdomyolysis. Inheritance is commonly autosomal recessive.

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Glycogen metabolism and glycogen-storage diseases

Physiological Reviews ◽

10.1152/physrev.1975.55.4.609 ◽

1975 ◽

Vol 55 (4) ◽

pp. 609-658 ◽

Cited By ~ 50

Author(s):

F. Huijing

Keyword(s):

Glycogen Metabolism ◽

Glycogen Storage ◽

Storage Diseases ◽

Glycogen Storage Diseases

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CARM1/PRMT4 is necessary for the glycogen gene expression programme in skeletal muscle cells

Biochemical Journal ◽

10.1042/bj20112033 ◽

2012 ◽

Vol 444 (2) ◽

pp. 323-331 ◽

Cited By ~ 25

Author(s):

Shu-Ching Mary Wang ◽

Dennis H. Dowhan ◽

Natalie A. Eriksson ◽

George E. O. Muscat

Keyword(s):

Gene Expression ◽

Skeletal Muscle ◽

Muscle Cells ◽

Glycogen Metabolism ◽

Glycogen Storage ◽

Skeletal Muscle Cells ◽

Arginine Methyltransferase ◽

Storage Diseases ◽

Sirna Expression ◽

Glycogen Storage Diseases

CARM1 (co-activator-associated arginine methyltransferase 1)/PRMT4 (protein arginine methyltransferase 4), functions as a co-activator for transcription factors that are regulators of muscle fibre type and oxidative metabolism, including PGC (peroxisome-proliferator-activated receptor γ co-activator)-1α and MEF2 (myocyte enhancer factor 2). We observed significantly higher Prmt4 mRNA expression in comparison with Prmt1–Prmt6 mRNA expression in mouse muscle (in vitro and in vivo). Transfection of Prmt4 siRNA (small interfering RNA) into mouse skeletal muscle C2C12 cells attenuated PRMT4 mRNA and protein expression. We subsequently performed additional qPCR (quantitative PCR) analysis (in the context of metabolism) to examine the effect of Prmt4 siRNA expression on >200 critical genes that control (and are involved in) lipid, glucose and energy homoeostasis, and circadian rhythm. This analysis revealed a strikingly specific metabolic expression footprint, and revealed that PRMT4 is necessary for the expression of genes involved in glycogen metabolism in skeletal muscle cells. Prmt4 siRNA expression selectively suppressed the mRNAs encoding Gys1 (glycogen synthase 1), Pgam2 (muscle phosphoglycerate mutase 2) and Pygm (muscle glycogen phosphorylase). Significantly, PGAM, PYGM and GYS1 deficiency in humans causes glycogen storage diseases type X, type V/McArdle's disease and type 0 respectively. Attenuation of PRMT4 was also associated with decreased expression of the mRNAs encoding AMPK (AMP-activated protein kinase) α2/γ3 (Prkaa2 and Prkag3) and p38 MAPK (mitogen-activated protein kinase), previously implicated in Wolff–Parkinson–White syndrome and Pompe Disease (glycogen storage disease type II). Furthermore, stable transfection of two PRMT4-site-specific (methyltransferase deficient) mutants (CARM1/PRMT4 VLD and CARM1E267Q) significantly repressed the expression of Gys1, Pgam2 and AMPKγ3. Finally, in concordance, we observed increased and decreased glycogen levels in PRMT4 (native)- and VLD (methylation deficient mutant)-transfected skeletal muscle cells respectively. This demonstrated that PRMT4 expression and the associated methyltransferase activity is necessary for the gene expression programme involved in glycogen metabolism and human glycogen storage diseases.

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