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1.
J Biol Chem ; 300(5): 107271, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38588813

RESUMEN

Lafora disease (LD) is an autosomal recessive myoclonus epilepsy with onset in the teenage years leading to death within a decade of onset. LD is characterized by the overaccumulation of hyperphosphorylated, poorly branched, insoluble, glycogen-like polymers called Lafora bodies. The disease is caused by mutations in either EPM2A, encoding laforin, a dual specificity phosphatase that dephosphorylates glycogen, or EMP2B, encoding malin, an E3-ubiquitin ligase. While glycogen is a widely accepted laforin substrate, substrates for malin have been difficult to identify partly due to the lack of malin antibodies able to detect malin in vivo. Here we describe a mouse model in which the malin gene is modified at the C-terminus to contain the c-myc tag sequence, making an expression of malin-myc readily detectable. Mass spectrometry analyses of immunoprecipitates using c-myc tag antibodies demonstrate that malin interacts with laforin and several glycogen-metabolizing enzymes. To investigate the role of laforin in these interactions we analyzed two additional mouse models: malin-myc/laforin knockout and malin-myc/LaforinCS, where laforin was either absent or the catalytic Cys was genomically mutated to Ser, respectively. The interaction of malin with partner proteins requires laforin but is not dependent on its catalytic activity or the presence of glycogen. Overall, the results demonstrate that laforin and malin form a complex in vivo, which stabilizes malin and enhances interaction with partner proteins to facilitate normal glycogen metabolism. They also provide insights into the development of LD and the rescue of the disease by the catalytically inactive phosphatase.


Asunto(s)
Enfermedad de Lafora , Proteínas Tirosina Fosfatasas no Receptoras , Ubiquitina-Proteína Ligasas , Enfermedad de Lafora/metabolismo , Enfermedad de Lafora/genética , Enfermedad de Lafora/patología , Animales , Ratones , Ubiquitina-Proteína Ligasas/metabolismo , Ubiquitina-Proteína Ligasas/genética , Proteínas Tirosina Fosfatasas no Receptoras/metabolismo , Proteínas Tirosina Fosfatasas no Receptoras/genética , Humanos , Fosfatasas de Especificidad Dual/metabolismo , Fosfatasas de Especificidad Dual/genética , Modelos Animales de Enfermedad , Glucógeno/metabolismo , Glucógeno/genética
2.
J Biol Chem ; 290(2): 841-50, 2015 Jan 09.
Artículo en Inglés | MEDLINE | ID: mdl-25416783

RESUMEN

Glycogen is a branched polymer of glucose that acts as an energy reserve in many cell types. Glycogen contains trace amounts of covalent phosphate, in the range of 1 phosphate per 500-2000 glucose residues depending on the source. The function, if any, is unknown, but in at least one genetic disease, the progressive myoclonic epilepsy Lafora disease, excessive phosphorylation of glycogen has been implicated in the pathology by disturbing glycogen structure. Some 90% of Lafora cases are attributed to mutations of the EPM2A or EPM2B genes, and mice with either gene disrupted accumulate hyperphosphorylated glycogen. It is, therefore, of importance to understand the chemistry of glycogen phosphorylation. Rabbit skeletal muscle glycogen contained covalent phosphate as monoesters of C2, C3, and C6 carbons of glucose residues based on analyses of phospho-oligosaccharides by NMR. Furthermore, using a sensitive assay for glucose 6-P in hydrolysates of glycogen coupled with measurement of total phosphate, we determined the proportion of C6 phosphorylation in rabbit muscle glycogen to be ∼20%. C6 phosphorylation also accounted for ∼20% of the covalent phosphate in wild type mouse muscle glycogen. Glycogen phosphorylation in Epm2a(-/-) and Epm2b(-/-) mice was increased 8- and 4-fold compared with wild type mice, but the proportion of C6 phosphorylation remained unchanged at ∼20%. Therefore, our results suggest that C2, C3, and/or C6 phosphate could all contribute to abnormal glycogen structure or to Lafora disease.


Asunto(s)
Glucógeno/genética , Glucógeno/metabolismo , Enfermedad de Lafora/genética , Enfermedad de Lafora/metabolismo , Animales , Modelos Animales de Enfermedad , Fosfatasas de Especificidad Dual/genética , Glucosa-6-Fosfato/metabolismo , Glucógeno/química , Humanos , Enfermedad de Lafora/patología , Ratones , Ratones Transgénicos , Mutación , Fosforilación , Proteínas Tirosina Fosfatasas no Receptoras , Conejos , Ubiquitina-Proteína Ligasas/genética
3.
Arch Biochem Biophys ; 597: 21-9, 2016 05 01.
Artículo en Inglés | MEDLINE | ID: mdl-27036853

RESUMEN

The storage polymer glycogen normally contains small amounts of covalently attached phosphate as phosphomonoesters at C2, C3 and C6 atoms of glucose residues. In the absence of the laforin phosphatase, as in the rare childhood epilepsy Lafora disease, the phosphorylation level is elevated and is associated with abnormal glycogen structure that contributes to the pathology. Laforin therefore likely functions in vivo as a glycogen phosphatase. The mechanism of glycogen phosphorylation is less well-understood. We have reported that glycogen synthase incorporates phosphate into glycogen via a rare side reaction in which glucose-phosphate rather than glucose is transferred to a growing polyglucose chain (Tagliabracci et al. (2011) Cell Metab13, 274-282). We proposed a mechanism to account for phosphorylation at C2 and possibly at C3. Our results have since been challenged (Nitschke et al. (2013) Cell Metab17, 756-767). Here we extend the evidence supporting our conclusion, validating the assay used for the detection of glycogen phosphorylation, measurement of the transfer of (32)P from [ß-(32)P]UDP-glucose to glycogen by glycogen synthase. The (32)P associated with the glycogen fraction was stable to ethanol precipitation, SDS-PAGE and gel filtration on Sephadex G50. The (32)P-signal was not affected by inclusion of excess unlabeled UDP before analysis or by treatment with a UDPase, arguing against the signal being due to contaminating [ß-(32)P]UDP generated in the reaction. Furthermore, [(32)P]UDP did not bind non-covalently to glycogen. The (32)P associated with glycogen was released by laforin treatment, suggesting that it was present as a phosphomonoester. The conclusion is that glycogen synthase can mediate the introduction of phosphate into glycogen, thereby providing a possible mechanism for C2, and perhaps C3, phosphorylation.


Asunto(s)
Glucógeno Sintasa/química , Glucógeno/química , Fosfatos/química , Proteínas de Saccharomyces cerevisiae/química , Saccharomyces cerevisiae/enzimología , Glucógeno/biosíntesis , Glucógeno Sintasa/metabolismo , Humanos , Fosfatos/metabolismo , Proteínas Tirosina Fosfatasas no Receptoras/química , Proteínas Tirosina Fosfatasas no Receptoras/metabolismo , Proteínas de Saccharomyces cerevisiae/metabolismo , Azúcares de Uridina Difosfato/química , Azúcares de Uridina Difosfato/metabolismo
4.
Proc Natl Acad Sci U S A ; 110(52): 20976-81, 2013 Dec 24.
Artículo en Inglés | MEDLINE | ID: mdl-24324135

RESUMEN

Glycogen is a glucose polymer that contains minor amounts of covalently attached phosphate. Hyperphosphorylation is deleterious to glycogen structure and can lead to Lafora disease. Recently, it was demonstrated that glycogen synthase catalyzes glucose-phosphate transfer in addition to its characteristic glucose transfer reaction. Glucose-1,2-cyclic-phosphate (GCP) was proposed to be formed from UDP-Glc breakdown and subsequently transferred, thus providing a source of phosphate found in glycogen. To gain further insight into the molecular basis for glucose-phosphate transfer, two structures of yeast glycogen synthase were determined; a 3.0-Å resolution structure of the complex with UMP/GCP and a 2.8-Å resolution structure of the complex with UDP/glucose. Structural superposition of the complexes revealed that the bound ligands and most active site residues are positioned similarly, consistent with the use of a common transfer mechanism for both reactions. The N-terminal domain of the UDP-glucose complex was found to be 13.3° more closed compared with a UDP complex. However, the UMP · GCP complex was 4.8° less closed than the glucose complex, which may explain the low efficiency of GCP transfer. Modeling of either α- or ß-glucose or a mixture of both anomers can account for the observed electron density of the UDP-glucose complex. NMR studies of UDP-Glc hydrolysis by yeast glycogen synthase were used to verify the stereochemistry of the product, and they also showed synchronous GCP accumulation. The similarities in the active sites of glycogen synthase and glycogen phosphorylase support the idea of a common catalytic mechanism in GT-B enzymes independent of the specific reaction catalyzed.


Asunto(s)
Glucógeno Sintasa/metabolismo , Glucógeno/química , Modelos Moleculares , Fosfatos/química , Cristalografía , Glucógeno/metabolismo , Glucógeno Sintasa/química , Espectroscopía de Resonancia Magnética , Espectrometría de Masas , Mutagénesis , Fosfatos/metabolismo
5.
J Endocrinol ; 262(2)2024 Aug 01.
Artículo en Inglés | MEDLINE | ID: mdl-38842911

RESUMEN

ß-Cell death contributes to ß-cell loss and insulin insufficiency in type 1 diabetes (T1D), and this ß-cell demise has been attributed to apoptosis and necrosis. Apoptosis has been viewed as the lone form of programmed ß-cell death, and evidence indicates that ß-cells also undergo necrosis, regarded as an unregulated or accidental form of cell demise. More recently, studies in non-islet cell types have identified and characterized novel forms of cell death that are biochemically and morphologically distinct from apoptosis and necrosis. Several of these mechanisms of cell death have been categorized as forms of regulated necrosis and linked to inflammation and disease pathogenesis. In this review, we revisit discoveries of ß-cell death in humans with diabetes and describe studies characterizing ß-cell apoptosis and necrosis. We explore literature on mechanisms of regulated necrosis including necroptosis, ferroptosis and pyroptosis, review emerging literature on the significance of these mechanisms in ß-cells, and discuss experimental approaches to differentiate between various mechanisms of ß-cell death. Our review of the literature leads us to conclude that more detailed experimental characterization of the mechanisms of ß-cell death is warranted, along with studies to better understand the impact of various forms of ß-cell demise on islet inflammation and ß-cell autoimmunity in pathophysiologically relevant models. Such studies will provide insight into the mechanisms of ß-cell loss in T1D and may shed light on new therapeutic approaches to protect ß-cells in this disease.


Asunto(s)
Apoptosis , Muerte Celular , Diabetes Mellitus Tipo 1 , Células Secretoras de Insulina , Necrosis , Humanos , Células Secretoras de Insulina/patología , Células Secretoras de Insulina/fisiología , Diabetes Mellitus Tipo 1/patología , Diabetes Mellitus Tipo 1/inmunología , Animales , Muerte Celular/fisiología , Apoptosis/fisiología , Necroptosis/fisiología , Piroptosis/fisiología , Ferroptosis/fisiología
6.
Mol Metab ; 80: 101877, 2024 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-38218538

RESUMEN

OBJECTIVE: Aggregation of human islet amyloid polypeptide (hIAPP), a ß-cell secretory product, leads to islet amyloid deposition, islet inflammation and ß-cell loss in type 2 diabetes (T2D), but the mechanisms that underlie this process are incompletely understood. Receptor interacting protein kinase 3 (RIPK3) is a pro-death signaling molecule that has recently been implicated in amyloid-associated brain pathology and ß-cell cytotoxicity. Here, we evaluated the role of RIPK3 in amyloid-induced ß-cell loss using a humanized mouse model of T2D that expresses hIAPP and is prone to islet amyloid formation. METHODS: We quantified amyloid deposition, cell death and caspase 3/7 activity in islets isolated from WT, Ripk3-/-, hIAPP and hIAPP; Ripk3-/- mice in real time, and evaluated hIAPP-stimulated inflammation in WT and Ripk3-/- bone marrow derived macrophages (BMDMs) in vitro. We also characterized the role of RIPK3 in glucose stimulated insulin secretion (GSIS) in vitro and in vivo. Finally, we examined the role of RIPK3 in high fat diet (HFD)-induced islet amyloid deposition, ß-cell loss and glucose homeostasis in vivo. RESULTS: We found that amyloid-prone hIAPP mouse islets exhibited increased cell death and caspase 3/7 activity compared to amyloid-free WT islets in vitro, and this was associated with increased RIPK3 expression. hIAPP; Ripk3-/- islets were protected from amyloid-induced cell death compared to hIAPP islets in vitro, although amyloid deposition and caspase 3/7 activity were not different between genotypes. We observed that macrophages are a source of Ripk3 expression in isolated islets, and that Ripk3-/- BMDMs were protected from hIAPP-stimulated inflammatory gene expression (Tnf, Il1b, Nos2). Following 52 weeks of HFD feeding, islet amyloid-prone hIAPP mice exhibited impaired glucose tolerance and decreased ß-cell area compared to WT mice in vivo, whereas hIAPP; Ripk3-/- mice were protected from these impairments. CONCLUSIONS: In conclusion, loss of RIPK3 protects from amyloid-induced inflammation and islet cell death in vitro and amyloid-induced ß-cell loss and glucose intolerance in vivo. We propose that therapies targeting RIPK3 may reduce islet inflammation and ß-cell loss and improve glucose homeostasis in the pathogenesis of T2D.


Asunto(s)
Diabetes Mellitus Tipo 2 , Intolerancia a la Glucosa , Proteína Serina-Treonina Quinasas de Interacción con Receptores , Animales , Humanos , Ratones , Amiloide/metabolismo , Péptidos beta-Amiloides/metabolismo , Caspasa 3/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Glucosa , Inflamación , Polipéptido Amiloide de los Islotes Pancreáticos/genética , Polipéptido Amiloide de los Islotes Pancreáticos/metabolismo , Proteína Serina-Treonina Quinasas de Interacción con Receptores/genética
7.
J Biol Chem ; 286(39): 33999-4006, 2011 Sep 30.
Artículo en Inglés | MEDLINE | ID: mdl-21835915

RESUMEN

Glycogen synthase is a rate-limiting enzyme in the biosynthesis of glycogen and has an essential role in glucose homeostasis. The three-dimensional structures of yeast glycogen synthase (Gsy2p) complexed with maltooctaose identified four conserved maltodextrin-binding sites distributed across the surface of the enzyme. Site-1 is positioned on the N-terminal domain, site-2 and site-3 are present on the C-terminal domain, and site-4 is located in an interdomain cleft adjacent to the active site. Mutation of these surface sites decreased glycogen binding and catalytic efficiency toward glycogen. Mutations within site-1 and site-2 reduced the V(max)/S(0.5) for glycogen by 40- and 70-fold, respectively. Combined mutation of site-1 and site-2 decreased the V(max)/S(0.5) for glycogen by >3000-fold. Consistent with the in vitro data, glycogen accumulation in glycogen synthase-deficient yeast cells (Δgsy1-gsy2) transformed with the site-1, site-2, combined site-1/site-2, or site-4 mutant form of Gsy2p was decreased by up to 40-fold. In contrast to the glycogen results, the ability to utilize maltooctaose as an in vitro substrate was unaffected in the site-2 mutant, moderately affected in the site-1 mutant, and almost completely abolished in the site-4 mutant. These data show that the ability to utilize maltooctaose as a substrate can be independent of the ability to utilize glycogen. Our data support the hypothesis that site-1 and site-2 provide a "toehold mechanism," keeping glycogen synthase tightly associated with the glycogen particle, whereas site-4 is more closely associated with positioning of the nonreducing end during catalysis.


Asunto(s)
Glucógeno Sintasa/química , Glucógeno/química , Oligosacáridos/química , Proteínas de Saccharomyces cerevisiae/química , Saccharomyces cerevisiae/enzimología , Sitios de Unión , Glucógeno/genética , Glucógeno/metabolismo , Glucógeno Sintasa/genética , Glucógeno Sintasa/metabolismo , Mutación , Oligosacáridos/genética , Oligosacáridos/metabolismo , Estructura Cuaternaria de Proteína , Estructura Terciaria de Proteína , Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/metabolismo
8.
Mol Metab ; 65: 101582, 2022 11.
Artículo en Inglés | MEDLINE | ID: mdl-36030035

RESUMEN

OBJECTIVE: Type 1 diabetes (T1D) is characterized by autoimmune-associated ß-cell loss, insulin insufficiency, and hyperglycemia. Although TNFα signaling is associated with ß-cell loss and hyperglycemia in non-obese diabetic mice and human T1D, the molecular mechanisms of ß-cell TNF receptor signaling have not been fully characterized. Based on work in other cell types, we hypothesized that receptor interacting protein kinase 1 (RIPK1) and receptor interacting protein kinase 3 (RIPK3) regulate TNFα-induced ß-cell death in concert with caspase activity. METHODS: We evaluated TNFα-induced cell death, caspase activity, and TNF receptor pathway molecule expression in immortalized NIT-1 and INS-1 ß-cell lines and primary mouse islet cells in vitro. Our studies utilized genetic and small molecule approaches to alter RIPK1 and RIPK3 expression and caspase activity to interrogate mechanisms of TNFα-induced ß-cell death. We used the ß-cell toxin streptozotocin (STZ) to determine the susceptibility of Ripk3+/+ and Ripk3-/- mice to hyperglycemia in vivo. RESULTS: Expression of TNF receptor signaling molecules including RIPK1 and RIPK3 was identified in NIT-1 and INS-1 ß cells and isolated mouse islets at the mRNA and protein levels. TNFα treatment increased NIT-1 and INS-1 cell death and caspase activity after 24-48 h, and BV6, a small molecule inhibitor of inhibitor of apoptosis proteins (IAPs) amplified this TNFα-induced cell death. RIPK1 deficient NIT-1 cells were protected from TNFα- and BV6-induced cell death and caspase activation. Interestingly, small molecule inhibition of caspases with zVAD-fmk (zVAD) did not prevent TNFα-induced cell death in either NIT-1 or INS-1 cells. This caspase-independent cell death was increased by BV6 treatment and decreased in RIPK1 deficient NIT-1 cells. RIPK3 deficient NIT-1 cells and RIPK3 kinase inhibitor treated INS-1 cells were protected from TNFα+zVAD-induced cell death, whereas RIPK3 overexpression increased INS-1 cell death and promoted RIPK3 and MLKL interaction under TNFα+zVAD treatment. In mouse islet cells, BV6 or zVAD treatment promoted TNFα-induced cell death, and TNFα+zVAD-induced cell death was blocked by RIPK3 inhibition and in Ripk3-/- islet cells in vitro. Ripk3-/- mice were also protected from STZ-induced hyperglycemia and glucose intolerance in vivo. CONCLUSIONS: RIPK1 and RIPK3 regulate TNFα-induced ß-cell death in concert with caspase activity in immortalized and primary islet ß cells. TNF receptor signaling molecules such as RIPK1 and RIPK3 may represent novel therapeutic targets to promote ß-cell survival and glucose homeostasis in T1D.


Asunto(s)
Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 1 , Hiperglucemia , Insulinas , Animales , Caspasas/metabolismo , Muerte Celular , Glucosa , Humanos , Proteínas Inhibidoras de la Apoptosis/metabolismo , Insulinas/metabolismo , Ratones , ARN Mensajero , Proteína Serina-Treonina Quinasas de Interacción con Receptores/genética , Estreptozocina , Factor de Necrosis Tumoral alfa/metabolismo
9.
Metabolites ; 11(11)2021 Nov 22.
Artículo en Inglés | MEDLINE | ID: mdl-34822454

RESUMEN

ß-cell death is regarded as a major event driving loss of insulin secretion and hyperglycemia in both type 1 and type 2 diabetes mellitus. In this review, we explore past, present, and potential future advances in our understanding of the mechanisms that promote ß-cell death in diabetes, with a focus on the primary literature. We first review discoveries of insulin insufficiency, ß-cell loss, and ß-cell death in human diabetes. We discuss findings in humans and mouse models of diabetes related to autoimmune-associated ß-cell loss and the roles of autoreactive T cells, B cells, and the ß cell itself in this process. We review discoveries of the molecular mechanisms that underlie ß-cell death-inducing stimuli, including proinflammatory cytokines, islet amyloid formation, ER stress, oxidative stress, glucotoxicity, and lipotoxicity. Finally, we explore recent perspectives on ß-cell death in diabetes, including: (1) the role of the ß cell in its own demise, (2) methods and terminology for identifying diverse mechanisms of ß-cell death, and (3) whether non-canonical forms of ß-cell death, such as regulated necrosis, contribute to islet inflammation and ß-cell loss in diabetes. We believe new perspectives on the mechanisms of ß-cell death in diabetes will provide a better understanding of this pathological process and may lead to new therapeutic strategies to protect ß cells in the setting of diabetes.

10.
Cell Metab ; 33(7): 1404-1417.e9, 2021 07 06.
Artículo en Inglés | MEDLINE | ID: mdl-34043942

RESUMEN

Glycosylation defects are a hallmark of many nervous system diseases. However, the molecular and metabolic basis for this pathology is not fully understood. In this study, we found that N-linked protein glycosylation in the brain is metabolically channeled to glucosamine metabolism through glycogenolysis. We discovered that glucosamine is an abundant constituent of brain glycogen, which functions as a glucosamine reservoir for multiple glycoconjugates. We demonstrated the enzymatic incorporation of glucosamine into glycogen by glycogen synthase, and the release by glycogen phosphorylase by biochemical and structural methodologies, in primary astrocytes, and in vivo by isotopic tracing and mass spectrometry. Using two mouse models of glycogen storage diseases, we showed that disruption of brain glycogen metabolism causes global decreases in free pools of UDP-N-acetylglucosamine and N-linked protein glycosylation. These findings revealed fundamental biological roles of brain glycogen in protein glycosylation with direct relevance to multiple human diseases of the central nervous system.


Asunto(s)
Encéfalo/metabolismo , Glucosamina/metabolismo , Glucógeno/fisiología , Procesamiento Proteico-Postraduccional , Animales , Células Cultivadas , Modelos Animales de Enfermedad , Femenino , Glucógeno/metabolismo , Glucógeno Sintasa/genética , Glucógeno Sintasa/metabolismo , Glucogenólisis/genética , Glicosilación , Enfermedad de Lafora/genética , Enfermedad de Lafora/metabolismo , Enfermedad de Lafora/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Procesamiento Proteico-Postraduccional/genética
11.
Carbohydr Polym ; 230: 115651, 2020 Feb 15.
Artículo en Inglés | MEDLINE | ID: mdl-31887930

RESUMEN

The addition of phosphate groups into glycogen modulates its branching pattern and solubility which all impact its accessibility to glycogen interacting enzymes. As glycogen architecture modulates its metabolism, it is essential to accurately evaluate and quantify its phosphate content. Simultaneous direct quantitation of glucose and its phosphate esters requires an assay with high sensitivity and a robust dynamic range. Herein, we describe a highly-sensitive method for the accurate detection of both glycogen-derived glucose and glucose-phosphate esters utilizing gas-chromatography coupled mass spectrometry. Using this method, we observed higher glycogen levels in the liver compared to skeletal muscle, but skeletal muscle contained many more phosphate esters. Importantly, this method can detect femtomole levels of glucose and glucose phosphate esters within an extremely robust dynamic range with excellent accuracy and reproducibility. The method can also be easily adapted for the quantification of plant starch, amylopectin or other biopolymers.

12.
Cell Metab ; 13(3): 274-82, 2011 Mar 02.
Artículo en Inglés | MEDLINE | ID: mdl-21356517

RESUMEN

Glycogen is a branched polymer of glucose that serves as an energy store. Phosphate, a trace constituent of glycogen, has profound effects on glycogen structure, and phosphate hyperaccumulation is linked to Lafora disease, a fatal progressive myoclonus epilepsy that can be caused by mutations of laforin, a glycogen phosphatase. However, little is known about the metabolism of glycogen phosphate. We demonstrate here that the biosynthetic enzyme glycogen synthase, which normally adds glucose residues to glycogen, is capable of incorporating the ß-phosphate of its substrate UDP-glucose at a rate of one phosphate per approximately 10,000 glucoses, in what may be considered a catalytic error. We show that the phosphate in glycogen is present as C2 and C3 phosphomonoesters. Since hyperphosphorylation of glycogen causes Lafora disease, phosphate removal by laforin may thus be considered a repair or damage control mechanism.


Asunto(s)
Glucógeno/biosíntesis , Fosfatos/metabolismo , Proteínas Tirosina Fosfatasas no Receptoras/metabolismo , Animales , Glucógeno Sintasa/metabolismo , Enfermedad de Lafora/enzimología , Fosforilación , Conejos , Uridina Difosfato Glucosa/metabolismo
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