bims-glecem 2023-05-28 papers

bims-glecem

Biomed News

on Glycogen metabolism in exercise, cancer and energy metabolism

Issue of 2023–05–28
eleven papers selected by
Dipsikha Biswas, Københavns Universitet

Astrocyte glycogen is a major source of hypothalamic lactate in rats with recurrent hypoglycemia.
Diagnosis and management of metabolic myopathies.
Treatment of the Neutropenia Associated with GSD1b and G6PC3 Deficiency with SGLT2 Inhibitors.
Discovery of 2-(Anilino)pyrimidine-4-carboxamides as Highly Potent, Selective, and Orally Active Glycogen Synthase Kinase-3 (GSK-3) Inhibitors.
In Silico-Motivated Discovery of Novel Potent Glycogen Synthase-3 Inhibitors: 1-(Alkyl/arylamino)-3H-naphtho[1,2,3-de]quinoline-2,7-dione Identified as a Scaffold for Kinase Inhibitor Development.
PROTAC-Induced Glycogen Synthase Kinase 3β Degradation as a Potential Therapeutic Strategy for Alzheimer's Disease.
Metabolic Myopathies in the Era of Next-Generation Sequencing.
An Insight into the Development of Potential Antidiabetic Agents along with their Therapeutic Targets.
Parallel proteomic comparison of mutants with altered carbon metabolism reveals Hik8 regulation of PII phosphorylation and glycogen accumulation in a cyanobacterium.
Metabolic Cardiomyopathies and Cardiac Defects in Inherited Disorders of Carbohydrate Metabolism: A Systematic Review.
[Analysis of lysosomal enzyme activity and genetic variants in a child with late-onset Pompe disease].

Diabetes. 2023 May 22. pii: db220902. [Epub ahead of print]

Astrocyte glycogen is a major source of hypothalamic lactate in rats with recurrent hypoglycemia.

Gong Su, Rawad Farhat, Anil K Laxman, Kimberly Chapman-Natewa, Irvane E Nelson, Owen Chan.

Lactate is an important metabolic substrate for sustaining brain energy requirements when glucose supplies are limited. Recurring exposure to hypoglycemia (RH) raises lactate levels in the ventromedial hypothalamus (VMH) which contributes to counter-regulatory failure. However, the source of this lactate remains unclear. The present study investigates whether astrocytic glycogen serves as the major source of lactate in the VMH of RH rats. By decreasing the expression of a key lactate transporter in VMH astrocytes of RH rats, we reduced extracellular lactate concentrations, suggesting excess lactate was locally produced from astrocytes. To determine whether astrocytic glycogen serves as the major source of lactate, we chronically delivered either artificial extracellular fluid or 1,4-dideoxy-1,4-imino-d-arabinitol (DAB) to inhibit glycogen turnover in the VMH of RH animals. Inhibiting glycogen turnover in RH animals prevented the rise in VMH lactate and the development of counter-regulatory failure. Lastly, we noted that RH led to an increase in glycogen shunt activity in response to hypoglycemia and elevated glycogen phosphorylase activity in the hours following a bout of hypoglycemia. Our data suggests that dysregulation of astrocytic glycogen metabolism following recurring exposure to hypoglycemia may be responsible, at least in part, for the rise in VMH lactate levels.

DOI: https://doi.org/10.2337/db22-0902
Muscle Nerve. 2023 May 25.

Diagnosis and management of metabolic myopathies.

Salman F Bhai, John Vissing.

  Metabolic myopathies are a set of rare inborn errors of metabolism leading to disruption in energy production. Relevant to skeletal muscle, glycogen storage disease and fatty acid oxidation defects can lead to exercise intolerance, rhabdomyolysis, and weakness in children and adults, distinct from the severe forms that involve multiple-organ systems. These nonspecific, dynamic symptoms along with conditions that mimic metabolic myopathies can make diagnosis challenging. Clinicians can shorten the time to diagnosis by recognizing the typical clinical phenotypes and performing next generation sequencing. With improved access and affordability of molecular testing, clinicians need to be well-versed in resolving variants of uncertain significance relevant to metabolic myopathies. Once identified, patients can improve quality of life, safely engage in exercise, and reduce episodes of rhabdomyolysis by modifying diet and lifestyle habits.

Keywords:  fatty acid oxidation defects; glycogen storage disease; lipid storage myopathy; metabolic myopathy; muscle metabolism; rhabdomyolysis

DOI:  https://doi.org/10.1002/mus.27840
Diagnostics (Basel). 2023 May 19. pii: 1803. [Epub ahead of print]13(10):

Treatment of the Neutropenia Associated with GSD1b and G6PC3 Deficiency with SGLT2 Inhibitors.

Maria Veiga-da-Cunha, Saskia B Wortmann, Sarah C Grünert, Emile Van Schaftingen.

  Glycogen storage disease type Ib (GSD1b) is due to a defect in the glucose-6-phosphate transporter (G6PT) of the endoplasmic reticulum, which is encoded by the SLC37A4 gene. This transporter allows the glucose-6-phosphate that is made in the cytosol to cross the endoplasmic reticulum (ER) membrane and be hydrolyzed by glucose-6-phosphatase (G6PC1), a membrane enzyme whose catalytic site faces the lumen of the ER. Logically, G6PT deficiency causes the same metabolic symptoms (hepatorenal glycogenosis, lactic acidosis, hypoglycemia) as deficiency in G6PC1 (GSD1a). Unlike GSD1a, GSD1b is accompanied by low neutrophil counts and impaired neutrophil function, which is also observed, independently of any metabolic problem, in G6PC3 deficiency. Neutrophil dysfunction is, in both diseases, due to the accumulation of 1,5-anhydroglucitol-6-phosphate (1,5-AG6P), a potent inhibitor of hexokinases, which is slowly formed in the cells from 1,5-anhydroglucitol (1,5-AG), a glucose analog that is normally present in blood. Healthy neutrophils prevent the accumulation of 1,5-AG6P due to its hydrolysis by G6PC3 following transport into the ER by G6PT. An understanding of this mechanism has led to a treatment aimed at lowering the concentration of 1,5-AG in blood by treating patients with inhibitors of SGLT2, which inhibits renal glucose reabsorption. The enhanced urinary excretion of glucose inhibits the 1,5-AG transporter, SGLT5, causing a substantial decrease in the concentration of this polyol in blood, an increase in neutrophil counts and function and a remarkable improvement in neutropenia-associated clinical signs and symptoms.

Keywords:  gluconeogenesis; glucose-6-phosphatase; glucose-6-phosphate transporter; infection; metabolite repair; neutropenia; neutrophil

DOI:  https://doi.org/10.3390/diagnostics13101803
J Med Chem. 2023 May 26.

Discovery of 2-(Anilino)pyrimidine-4-carboxamides as Highly Potent, Selective, and Orally Active Glycogen Synthase Kinase-3 (GSK-3) Inhibitors.

Richard A Hartz, Vijay T Ahuja, Guanglin Luo, Ling Chen, Prasanna Sivaprakasam, Hong Xiao, Carol M Krause, Wendy J Clarke, Songmei Xu, John S Tokarski, Kevin Kish, Hal Lewis, Nicolas Szapiel, Ramu Ravirala, Sayali Mutalik, Deepa Nakmode, Devang Shah, Catherine R Burton, John E Macor, Gene M Dubowchik.

Glycogen synthase kinase-3 (GSK-3) is a serine/threonine kinase that serves as an important regulator of a broad range of cellular functions. It has been linked to Alzheimer's disease as well as various other diseases, including mood disorders, type 2 diabetes, and cancer. There is considerable evidence indicating that GSK-3β in the central nervous system plays a role in the production of abnormal, hyperphosphorylated, microtubule-associated tau protein found in neurofibrillary tangles associated with Alzheimer's disease. A series of analogues containing a pyrimidine-based hinge-binding heterocycle was synthesized and evaluated, leading to the identification of highly potent GSK-3 inhibitors with excellent kinase selectivity. Further evaluation of 34 and 40 in vivo demonstrated that these compounds are orally bioavailable, brain-penetrant GSK-3 inhibitors that lowered levels of phosphorylated tau in a triple-transgenic mouse Alzheimer's disease model.

DOI: https://doi.org/10.1021/acs.jmedchem.3c00364
Pharmaceuticals (Basel). 2023 Apr 28. pii: 661. [Epub ahead of print]16(5):

In Silico-Motivated Discovery of Novel Potent Glycogen Synthase-3 Inhibitors: 1-(Alkyl/arylamino)-3H-naphtho[1,2,3-de]quinoline-2,7-dione Identified as a Scaffold for Kinase Inhibitor Development.

Thomas D Emmerich, Joseph M Hayes.

  Glycogen synthase kinase-3 (GSK-3) isoforms α and β have diverse roles within cell biology, and have been linked with multiple diseases that include prominent CNS conditions such as Alzheimer's disease and several psychiatric disorders. In this study, motivated by computation, we aimed to identify novel ATP-binding site inhibitors of GSK-3 with CNS-active potential. A ligand screening (docking) protocol against GSK-3β was first optimized, employing an active/decoy benchmarking set, with the final protocol selected based on statistical performance analysis. The optimized protocol involved pre-filtering of ligands using a three-point 3D-pharmacophore, followed by Glide-SP docking applying hinge region hydrogen bonding constraints. Using this approach, the Biogenic subset of the ZINC15 compound database was screened, focused on compounds with potential for CNS-activity. Twelve compounds (generation I) were selected for experimental validation using in vitro GSK-3β binding assays. Two hit compounds, 1 and 2, with 6-amino-7H-benzo[e]perimidin-7-one and 1-(phenylamino)-3H-naphtho[1,2,3-de]quinoline-2,7-dione type scaffolds were identified with IC50 values of 1.63 µM and 20.55 µM, respectively. Ten analogues of 2 (generation II) were selected for structure activity relationship (SAR) analysis and revealed four low micromolar inhibitors (<10 µM), with 19 (IC50 = 4.1 µM)~five times more potent than initial hit compound 2. Selectivity screening of low micromolar inhibitors 14 and 19 (comparing aryl- and alkyl-substituents) against 10 homologous kinases revealed unique selectivity profiles, with both compounds more potent against the GSK-3α isoform (IC50s~2 µM) and, additionally, inhibitors of PKBβ (IC50s < 25 µM). Compound 14 also inhibited ERK2 and 19, PKCγ, but generally good selectivity for GSK-3 isoforms over the other kinases was observed. The compounds had excellent predicted oral bioavailability and CNS-activity profiles, presenting promising candidates for future testing in cellular models of disease.

Keywords:  AKT2; CNS-active; GSK-3α; GSK-3β; in silico; inhibitors; kinase selectivity

DOI:  https://doi.org/10.3390/ph16050661
ACS Chem Neurosci. 2023 May 23.

PROTAC-Induced Glycogen Synthase Kinase 3β Degradation as a Potential Therapeutic Strategy for Alzheimer's Disease.

Melissa Guardigni, Letizia Pruccoli, Alan Santini, Angela De Simone, Matteo Bersani, Francesca Spyrakis, Flavia Frabetti, Elisa Uliassi, Vincenza Andrisano, Barbara Pagliarani, Paula Fernández-Gómez, Valle Palomo, Maria Laura Bolognesi, Andrea Tarozzi, Andrea Milelli.

  Glycogen synthase kinase 3β (GSK-3β) is a serine/threonine kinase and an attractive therapeutic target for Alzheimer's disease. Based on proteolysis-targeting chimera (PROTAC) technology, a small set of novel GSK-3β degraders was designed and synthesized by linking two different GSK-3β inhibitors, SB-216763 and tideglusib, to pomalidomide, as E3 recruiting element, through linkers of different lengths. Compound 1 emerged as the most effective PROTAC being nontoxic up to 20 μM to neuronal cells and already able to degrade GSK-3β starting from 0.5 μM in a dose-dependent manner. PROTAC 1 significantly reduced the neurotoxicity induced by Aβ25-35 peptide and CuSO4 in SH-SY5Y cells in a dose-dependent manner. Based on its encouraging features, PROTAC 1 may serve as a starting point to develop new GSK-3β degraders as potential therapeutic agents.

Keywords:  Alzheimer’s disease; chemical knockdown; glycogen synthase kinase 3β; protein degradation; proteolysis targeting chimeras

DOI:  https://doi.org/10.1021/acschemneuro.3c00096
Genes (Basel). 2023 Apr 22. pii: 954. [Epub ahead of print]14(5):

Metabolic Myopathies in the Era of Next-Generation Sequencing.

Jon Andoni Urtizberea, Gianmarco Severa, Edoardo Malfatti.

  Metabolic myopathies are rare inherited disorders that deserve more attention from neurologists and pediatricians. Pompe disease and McArdle disease represent some of the most common diseases in clinical practice; however, other less common diseases are now better-known. In general the pathophysiology of metabolic myopathies needs to be better understood. Thanks to the advent of next-generation sequencing (NGS), genetic testing has replaced more invasive investigations and sophisticated enzymatic assays to reach a final diagnosis in many cases. The current diagnostic algorithms for metabolic myopathies have integrated this paradigm shift and restrict invasive investigations for complicated cases. Moreover, NGS contributes to the discovery of novel genes and proteins, providing new insights into muscle metabolism and pathophysiology. More importantly, a growing number of these conditions are amenable to therapeutic approaches such as diets of different kinds, exercise training protocols, and enzyme replacement therapy or gene therapy. Prevention and management-notably of rhabdomyolysis-are key to avoiding serious and potentially life-threatening complications and improving patients' quality of life. Although not devoid of limitations, the newborn screening programs that are currently mushrooming across the globe show that early intervention in metabolic myopathies is a key factor for better therapeutic efficacy and long-term prognosis. As a whole NGS has largely increased the diagnostic yield of metabolic myopathies, but more invasive but classical investigations are still critical when the genetic diagnosis is unclear or when it comes to optimizing the follow-up and care of these muscular disorders.

Keywords:  Cori–Forbes disease; McArdle disease; Pompe disease; TK2 myopathy; Tarui disease; glycogen storage disorders; lipid storage diseases; metabolic myopathies; mitochondrial myopathies; muscle glycogenoses; muscle metabolism; polyglucosan body myopathies

DOI:  https://doi.org/10.3390/genes14050954
Endocr Metab Immune Disord Drug Targets. 2023 May 22.

An Insight into the Development of Potential Antidiabetic Agents along with their Therapeutic Targets.

Siddhita Tiwari, Paranjeet Kaur, Deepali Gupta, Saumik Chaudhury, Manish Chaudhary, Amit Mittal, Shubham Kumar, Sanjeev Kumar Sahu.

  Diabetes is a metabolic disorder that has been reported to increase the mortality rate worldwide. About 40 million people across the globe suffer from diabetes, with people living in developing countries being affected the most due to this deadly disease. Although the therapeutic management of hyperglycaemia can treat diabetes, metabolic disorders associated with this disease are a greater challenge in its treatment. Hence, potential strategies to treat hyperglycaemia and its side effects are needed. In this review, we have summarized several therapeutic targets, like dipeptidyl peptidase-4 (DPP-4), glucagon receptor antagonists, glycogen phosphorylase or fructose-1,6-biphosphatase inhibitors, SGLT inhibitors, 11beta-HSD-1 inhibitors, glucocorticoids receptor antagonists, glucose-6-phosphatase and glycogen phosphorylase inhibitors. These targets can help in designing and developing novel antidiabetic agents.

Keywords:  Hyperglycaemia; Metabolic Syndrome; Pancreas.; Therapeutic Targets; Type-2 Diabetes

DOI:  https://doi.org/10.2174/1871530323666230522112758
Mol Cell Proteomics. 2023 May 22. pii: S1535-9476(23)00093-2. [Epub ahead of print] 100582

Parallel proteomic comparison of mutants with altered carbon metabolism reveals Hik8 regulation of PII phosphorylation and glycogen accumulation in a cyanobacterium.

Chengcheng Huang, Xiaoxiao Duan, Haitao Ge, Zhen Xiao, Limin Zheng, Gaojie Wang, Jinghui Dong, Yan Wang, Yuanya Zhang, Xiahe Huang, Hongyu An, Wu Xu, Yingchun Wang.

  Carbon metabolism is central to photosynthetic organisms and involves coordinated operation and regulation of numerous proteins. In cyanobacteria proteins involved in carbon metabolism are regulated by multiple regulators including the RNA polymerase sigma factor SigE, the histidine kinases Hik8, Hik31 and its plasmid borne paralog Slr6041, and the response regulator Rre37. To understand the specificity and the cross-talk of such regulations, we simultaneously and quantitatively compared the proteomes of the gene knockout mutants for the regulators. A number of proteins showing differential expression in one or more mutants were identified, including four proteins that are unanimously upregulated or downregulated in all the five mutants. These represent the important nodes of the intricate and elegant regulatory network for carbon metabolism. Moreover, serine phosphorylation of PII, a key signaling protein sensing and regulating in vivo carbon/nitrogen (C/N) homeostasis through reversible phosphorylation, is massively increased with concomitant significant decrease of glycogen content only in the hik8-knockout mutant, which also displays impaired dark viability. An unphosphorylatable PII S49A substitution restored the glycogen content and rescued the dark viability of the mutant. Together, our study not only establishes the quantitative relationship between the targets and the corresponding regulators and elucidated their specificity and cross-talk, but also unveils that Hik8 regulates glycogen accumulation through negative regulation of PII phosphorylation, providing the first line of evidence that links the two-component system with PII-mediated signal transduction and implicates them in regulation of carbon metabolism.

Keywords:  Carbon metabolism; Cyanobacteria; Phosphorylation; Proteomics; Synechocystis

DOI:  https://doi.org/10.1016/j.mcpro.2023.100582
Int J Mol Sci. 2023 May 11. pii: 8632. [Epub ahead of print]24(10):

Metabolic Cardiomyopathies and Cardiac Defects in Inherited Disorders of Carbohydrate Metabolism: A Systematic Review.

Federica Conte, Juda-El Sam, Dirk J Lefeber, Robert Passier.

  Heart failure (HF) is a progressive chronic disease that remains a primary cause of death worldwide, affecting over 64 million patients. HF can be caused by cardiomyopathies and congenital cardiac defects with monogenic etiology. The number of genes and monogenic disorders linked to development of cardiac defects is constantly growing and includes inherited metabolic disorders (IMDs). Several IMDs affecting various metabolic pathways have been reported presenting cardiomyopathies and cardiac defects. Considering the pivotal role of sugar metabolism in cardiac tissue, including energy production, nucleic acid synthesis and glycosylation, it is not surprising that an increasing number of IMDs linked to carbohydrate metabolism are described with cardiac manifestations. In this systematic review, we offer a comprehensive overview of IMDs linked to carbohydrate metabolism presenting that present with cardiomyopathies, arrhythmogenic disorders and/or structural cardiac defects. We identified 58 IMDs presenting with cardiac complications: 3 defects of sugar/sugar-linked transporters (GLUT3, GLUT10, THTR1); 2 disorders of the pentose phosphate pathway (G6PDH, TALDO); 9 diseases of glycogen metabolism (GAA, GBE1, GDE, GYG1, GYS1, LAMP2, RBCK1, PRKAG2, G6PT1); 29 congenital disorders of glycosylation (ALG3, ALG6, ALG9, ALG12, ATP6V1A, ATP6V1E1, B3GALTL, B3GAT3, COG1, COG7, DOLK, DPM3, FKRP, FKTN, GMPPB, MPDU1, NPL, PGM1, PIGA, PIGL, PIGN, PIGO, PIGT, PIGV, PMM2, POMT1, POMT2, SRD5A3, XYLT2); 15 carbohydrate-linked lysosomal storage diseases (CTSA, GBA1, GLA, GLB1, HEXB, IDUA, IDS, SGSH, NAGLU, HGSNAT, GNS, GALNS, ARSB, GUSB, ARSK). With this systematic review we aim to raise awareness about the cardiac presentations in carbohydrate-linked IMDs and draw attention to carbohydrate-linked pathogenic mechanisms that may underlie cardiac complications.

Keywords:  arrhythmogenic disorders; cardiomyopathies; congenital disorders of glycosylation; congenital heart disease; disorders of pentose phosphate pathway; disorders of sugar transporters; glycogen storage disorders; heart failure; inborn errors of metabolism; lysosomal storage disorders

DOI:  https://doi.org/10.3390/ijms24108632
Zhonghua Yi Xue Yi Chuan Xue Za Zhi. 2023 Jun 10. 40(6): 711-717

[Analysis of lysosomal enzyme activity and genetic variants in a child with late-onset Pompe disease].

Tiantian He, Jieni Jiang, Yueyue Xiong, Dan Yu, Xuemei Zhang.

OBJECTIVE: To explore the clinical features, lysosomal enzymatic [acid α-glucosidase (GAA)] activities and genetic variants in a child with late-onset Pompe disease (LOPD).
METHODS: Clinical data of a child who had presented at the Genetic Counseling Clinic of West China Second University Hospital in August 2020 was retrospectively analyzed. Blood samples were collected from the patient and her parents for the isolation of leukocytes and lymphocytes as well as DNA extraction. The activity of lysosomal enzyme GAA in leukocytes and lymphocytes was analyzed with or without addition of inhibitor of GAA isozyme. Potential variants in genes associated with neuromuscular disorders were analyzed, in addition with conservation of the variant sites and protein structure. The remaining samples from 20 individuals undergoing peripheral blood lymphocyte chromosomal karyotyping were mixed and used as the normal reference for the enzymatic activities.
RESULTS: The child, a 9-year-old female, had featured delayed language and motor development from 2 years and 11 months. Physical examination revealed unstable walking, difficulty in going upstairs and obvious scoliosis. Her serum creatine kinase was significantly increased, along with abnormal electromyography, whilst no abnormality was found by cardiac ultrasound. Genetic testing revealed that she has harbored compound heterozygous variants of the GAA gene, namely c.1996dupG (p.A666Gfs*71) (maternal) and c.701C>T (p.T234M) (paternal). Based on the guidelines from the American College of Medical Genetics and Genomics, the c.1996dupG (p.A666Gfs*71) was rated as pathogenic (PVS1+PM2_Supporting+PM3), whilst the c.701C>T (p.T234M) was rated as likely pathogenic (PM1+PM2_Supporting+PM3+PM5+PP3). The GAA in the leukocytes from the patient, her father and mother were respectively 76.1%, 91.3% and 95.6% of the normal value without the inhibitor, and 70.8%, 112.9% and 128.2% of the normal value with the inhibitor, whilst the activity of GAA in their leukocytes had decreased by 6 ~ 9 times after adding the inhibitor. GAA in lymphocytes of the patient, her father and mother were 68.3%, 59.0% and 59.5% of the normal value without the inhibitor, and 41.0%, 89.5% and 57.7% of the normal value with the inhibitor, the activity of GAA in lymphocytes has decreased by 2 ~ 5 times after adding the inhibitor.
CONCLUSION: The child was diagnosed with LOPD due to the c.1996dupG and c.701C>T compound heterozygous variants of the GAA gene. The residual activity of GAA among LOPD patients can range widely and the changes may be atypical. The diagnosis of LOPD should not be based solely on the results of enzymatic activity but combined clinical manifestation, genetic testing and measurement of enzymatic activity.

DOI: https://doi.org/10.3760/cma.j.cn511374-20220805-00525