LIVIVO - The Search Portal for Life Sciences

zur deutschen Oberfläche wechseln
Advanced search

Search results

Result 1 - 6 of total 6

Search options

  1. Article ; Online: The structural mechanism of human glycogen synthesis by the GYS1-GYG1 complex.

    Fastman, Nathan M / Liu, Yuxi / Ramanan, Vyas / Merritt, Hanne / Ambing, Eileen / DePaoli-Roach, Anna A / Roach, Peter J / Hurley, Thomas D / Mellem, Kevin T / Ullman, Julie C / Green, Eric / Morgans, David / Tzitzilonis, Christos

    Cell reports

    2022  Volume 40, Issue 1, Page(s) 111041

    Abstract: Glycogen is the primary energy reserve in mammals, and dysregulation of glycogen metabolism can result in glycogen storage diseases (GSDs). In muscle, glycogen synthesis is initiated by the enzymes glycogenin-1 (GYG1), which seeds the molecule by ... ...

    Abstract Glycogen is the primary energy reserve in mammals, and dysregulation of glycogen metabolism can result in glycogen storage diseases (GSDs). In muscle, glycogen synthesis is initiated by the enzymes glycogenin-1 (GYG1), which seeds the molecule by autoglucosylation, and glycogen synthase-1 (GYS1), which extends the glycogen chain. Although both enzymes are required for proper glycogen production, the nature of their interaction has been enigmatic. Here, we present the human GYS1:GYG1 complex in multiple conformations representing different functional states. We observe an asymmetric conformation of GYS1 that exposes an interface for close GYG1 association, and propose this state facilitates handoff of the GYG1-associated glycogen chain to a GYS1 subunit for elongation. Full activation of GYS1 widens the GYG1-binding groove, enabling GYG1 release concomitant with glycogen chain growth. This structural mechanism connecting chain nucleation and extension explains the apparent stepwise nature of glycogen synthesis and suggests distinct states to target for GSD-modifying therapeutics.
    MeSH term(s) Glucosyltransferases/metabolism ; Glycogen/metabolism ; Glycogen Synthase/metabolism ; Glycogenolysis ; Glycoproteins/metabolism ; Humans
    Chemical Substances Glycoproteins ; glycogenin ; Glycogen (9005-79-2) ; Glucosyltransferases (EC 2.4.1.-) ; Glycogen Synthase (EC 2.4.1.11)
    Language English
    Publishing date 2022-07-03
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2649101-1
    ISSN 2211-1247 ; 2211-1247
    ISSN (online) 2211-1247
    ISSN 2211-1247
    DOI 10.1016/j.celrep.2022.111041
    Database MEDical Literature Analysis and Retrieval System OnLINE

    More links

    Kategorien

    Order via subito

    This service is chargeable due to the Delivery terms set by subito. Orders including an article and supplementary material will be classified as separate orders. In these cases, fees will be demanded for each order.

  2. Article ; Online: Small-molecule inhibition of glycogen synthase 1 for the treatment of Pompe disease and other glycogen storage disorders.

    Ullman, Julie C / Mellem, Kevin T / Xi, Yannan / Ramanan, Vyas / Merritt, Hanne / Choy, Rebeca / Gujral, Tarunmeet / Young, Lyndsay E A / Blake, Kerrigan / Tep, Samnang / Homburger, Julian R / O'Regan, Adam / Ganesh, Sandya / Wong, Perryn / Satterfield, Terrence F / Lin, Baiwei / Situ, Eva / Yu, Cecile / Espanol, Bryan /
    Sarwaikar, Richa / Fastman, Nathan / Tzitzilonis, Christos / Lee, Patrick / Reiton, Daniel / Morton, Vivian / Santiago, Pam / Won, Walter / Powers, Hannah / Cummings, Beryl B / Hoek, Maarten / Graham, Robert R / Chandriani, Sanjay J / Bainer, Russell / DePaoli-Roach, Anna A / Roach, Peter J / Hurley, Thomas D / Sun, Ramon C / Gentry, Matthew S / Sinz, Christopher / Dick, Ryan A / Noonberg, Sarah B / Beattie, David T / Morgans, David J / Green, Eric M

    Science translational medicine

    2024  Volume 16, Issue 730, Page(s) eadf1691

    Abstract: Glycogen synthase 1 (GYS1), the rate-limiting enzyme in muscle glycogen synthesis, plays a central role in energy homeostasis and has been proposed as a therapeutic target in multiple glycogen storage diseases. Despite decades of investigation, there are ...

    Abstract Glycogen synthase 1 (GYS1), the rate-limiting enzyme in muscle glycogen synthesis, plays a central role in energy homeostasis and has been proposed as a therapeutic target in multiple glycogen storage diseases. Despite decades of investigation, there are no known potent, selective small-molecule inhibitors of this enzyme. Here, we report the preclinical characterization of MZ-101, a small molecule that potently inhibits GYS1 in vitro and in vivo without inhibiting GYS2, a related isoform essential for synthesizing liver glycogen. Chronic treatment with MZ-101 depleted muscle glycogen and was well tolerated in mice. Pompe disease, a glycogen storage disease caused by mutations in acid α glucosidase (GAA), results in pathological accumulation of glycogen and consequent autophagolysosomal abnormalities, metabolic dysregulation, and muscle atrophy. Enzyme replacement therapy (ERT) with recombinant GAA is the only approved treatment for Pompe disease, but it requires frequent infusions, and efficacy is limited by suboptimal skeletal muscle distribution. In a mouse model of Pompe disease, chronic oral administration of MZ-101 alone reduced glycogen buildup in skeletal muscle with comparable efficacy to ERT. In addition, treatment with MZ-101 in combination with ERT had an additive effect and could normalize muscle glycogen concentrations. Biochemical, metabolomic, and transcriptomic analyses of muscle tissue demonstrated that lowering of glycogen concentrations with MZ-101, alone or in combination with ERT, corrected the cellular pathology in this mouse model. These data suggest that substrate reduction therapy with GYS1 inhibition may be a promising therapeutic approach for Pompe disease and other glycogen storage diseases.
    MeSH term(s) Mice ; Animals ; Glycogen Storage Disease Type II/drug therapy ; Glycogen Synthase/metabolism ; Glycogen Synthase/pharmacology ; Mice, Knockout ; Glycogen/metabolism ; Muscle, Skeletal/metabolism ; Enzyme Replacement Therapy/methods
    Chemical Substances Glycogen Synthase (EC 2.4.1.11) ; Glycogen (9005-79-2)
    Language English
    Publishing date 2024-01-17
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2518854-9
    ISSN 1946-6242 ; 1946-6234
    ISSN (online) 1946-6242
    ISSN 1946-6234
    DOI 10.1126/scitranslmed.adf1691
    Database MEDical Literature Analysis and Retrieval System OnLINE

    More links

    Kategorien

    In stock of ZB MED Cologne/Königswinter

    Zs.A 6941: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 2021: Bestellungen von Artikeln über das Online-Bestellformular
    ab Jg. 2022: Lesesaal (EG)

    Order via subito

    This service is chargeable due to the Delivery terms set by subito. Orders including an article and supplementary material will be classified as separate orders. In these cases, fees will be demanded for each order.

  3. Article ; Online: A mouse model of autism implicates endosome pH in the regulation of presynaptic calcium entry.

    Ullman, Julie C / Yang, Jing / Sullivan, Michael / Bendor, Jacob / Levy, Jonathan / Pham, Ellen / Silm, Katlin / Seifikar, Helia / Sohal, Vikaas S / Nicoll, Roger A / Edwards, Robert H

    Nature communications

    2018  Volume 9, Issue 1, Page(s) 330

    Abstract: Psychoactive compounds such as chloroquine and amphetamine act by dissipating the pH gradient across intracellular membranes, but the physiological mechanisms that normally regulate organelle pH remain poorly understood. Interestingly, recent human ... ...

    Abstract Psychoactive compounds such as chloroquine and amphetamine act by dissipating the pH gradient across intracellular membranes, but the physiological mechanisms that normally regulate organelle pH remain poorly understood. Interestingly, recent human genetic studies have implicated the endosomal Na
    MeSH term(s) Animals ; Attention Deficit Disorder with Hyperactivity/genetics ; Attention Deficit Disorder with Hyperactivity/metabolism ; Attention Deficit Disorder with Hyperactivity/physiopathology ; Autism Spectrum Disorder/genetics ; Autism Spectrum Disorder/metabolism ; Autism Spectrum Disorder/physiopathology ; Behavior, Animal ; Calcium/metabolism ; Disease Models, Animal ; Electroencephalography ; Endosomes/metabolism ; Endosomes/pathology ; Female ; Gene Expression ; Glutamic Acid/metabolism ; Hippocampus/metabolism ; Hippocampus/physiopathology ; Humans ; Hydrogen-Ion Concentration ; Male ; Mice ; Mice, Knockout ; Neurons/metabolism ; Neurons/pathology ; Presynaptic Terminals/metabolism ; Presynaptic Terminals/pathology ; Primary Cell Culture ; Sodium-Hydrogen Exchangers/deficiency ; Sodium-Hydrogen Exchangers/genetics ; Synaptic Transmission/physiology ; Synaptic Vesicles/metabolism ; Synaptic Vesicles/pathology
    Chemical Substances NHE9 protein, mouse ; Sodium-Hydrogen Exchangers ; Glutamic Acid (3KX376GY7L) ; Calcium (SY7Q814VUP)
    Language English
    Publishing date 2018-01-23
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ISSN 2041-1723
    ISSN (online) 2041-1723
    DOI 10.1038/s41467-017-02716-5
    Database MEDical Literature Analysis and Retrieval System OnLINE

    More links

    Kategorien

    Order via subito

    This service is chargeable due to the Delivery terms set by subito. Orders including an article and supplementary material will be classified as separate orders. In these cases, fees will be demanded for each order.

    Inter-library loan at ZB MED

    Your chosen title can be delivered directly to ZB MED Cologne location if you are registered as a user at ZB MED Cologne.

  4. Article ; Online: Molecular architecture determines brain delivery of a transferrin receptor-targeted lysosomal enzyme.

    Arguello, Annie / Mahon, Cathal S / Calvert, Meredith E K / Chan, Darren / Dugas, Jason C / Pizzo, Michelle E / Thomsen, Elliot R / Chau, Roni / Damo, Lorna A / Duque, Joseph / Fang, Meng / Giese, Tina / Kim, Do Jin / Liang, Nicholas / Nguyen, Hoang N / Solanoy, Hilda / Tsogtbaatar, Buyankhishig / Ullman, Julie C / Wang, Junhua /
    Dennis, Mark S / Diaz, Dolores / Gunasekaran, Kannan / Henne, Kirk R / Lewcock, Joseph W / Sanchez, Pascal E / Troyer, Matthew D / Harris, Jeffrey M / Scearce-Levie, Kimberly / Shan, Lu / Watts, Ryan J / Thorne, Robert G / Henry, Anastasia G / Kariolis, Mihalis S

    The Journal of experimental medicine

    2022  Volume 219, Issue 3

    Abstract: Delivery of biotherapeutics across the blood-brain barrier (BBB) is a challenge. Many approaches fuse biotherapeutics to platforms that bind the transferrin receptor (TfR), a brain endothelial cell target, to facilitate receptor-mediated transcytosis ... ...

    Abstract Delivery of biotherapeutics across the blood-brain barrier (BBB) is a challenge. Many approaches fuse biotherapeutics to platforms that bind the transferrin receptor (TfR), a brain endothelial cell target, to facilitate receptor-mediated transcytosis across the BBB. Here, we characterized the pharmacological behavior of two distinct TfR-targeted platforms fused to iduronate 2-sulfatase (IDS), a lysosomal enzyme deficient in mucopolysaccharidosis type II (MPS II), and compared the relative brain exposures and functional activities of both approaches in mouse models. IDS fused to a moderate-affinity, monovalent TfR-binding enzyme transport vehicle (ETV:IDS) resulted in widespread brain exposure, internalization by parenchymal cells, and significant substrate reduction in the CNS of an MPS II mouse model. In contrast, IDS fused to a standard high-affinity bivalent antibody (IgG:IDS) resulted in lower brain uptake, limited biodistribution beyond brain endothelial cells, and reduced brain substrate reduction. These results highlight important features likely to impact the clinical development of TfR-targeting platforms in MPS II and potentially other CNS diseases.
    MeSH term(s) Animals ; Blood-Brain Barrier/metabolism ; Brain/metabolism ; Disease Models, Animal ; Endothelial Cells/metabolism ; Iduronate Sulfatase/metabolism ; Iduronate Sulfatase/pharmacology ; Lysosomes/metabolism ; Mice ; Mucopolysaccharidosis II/metabolism ; Receptors, Transferrin/metabolism ; Recombinant Fusion Proteins/metabolism ; Recombinant Fusion Proteins/pharmacology ; Tissue Distribution
    Chemical Substances Receptors, Transferrin ; Recombinant Fusion Proteins ; Iduronate Sulfatase (EC 3.1.6.13)
    Language English
    Publishing date 2022-02-28
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 218343-2
    ISSN 1540-9538 ; 0022-1007
    ISSN (online) 1540-9538
    ISSN 0022-1007
    DOI 10.1084/jem.20211057
    Database MEDical Literature Analysis and Retrieval System OnLINE

    More links

    Kategorien

    In stock of ZB MED Cologne/Königswinter

    Ua VI Zs.107: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 2021: Bestellungen von Artikeln über das Online-Bestellformular
    ab Jg. 2022: Lesesaal (EG)
    Zs.MG 45: Show issues

    Order via subito

    This service is chargeable due to the Delivery terms set by subito. Orders including an article and supplementary material will be classified as separate orders. In these cases, fees will be demanded for each order.

  5. Article ; Online: High-Throughput Liquid Chromatography-Tandem Mass Spectrometry Quantification of Glycosaminoglycans as Biomarkers of Mucopolysaccharidosis II.

    Wang, Junhua / Bhalla, Akhil / Ullman, Julie C / Fang, Meng / Ravi, Ritesh / Arguello, Annie / Thomsen, Elliot / Tsogtbaatar, Buyankhishig / Guo, Jing L / Skuja, Lukas L / Dugas, Jason C / Davis, Sonnet S / Poda, Suresh B / Gunasekaran, Kannan / Costanzo, Simona / Sweeney, Zachary K / Henry, Anastasia G / Harris, Jeffrey M / Henne, Kirk R /
    Astarita, Giuseppe

    International journal of molecular sciences

    2020  Volume 21, Issue 15

    Abstract: We recently developed a blood-brain barrier (BBB)-penetrating enzyme transport vehicle (ETV) fused to the lysosomal enzyme iduronate 2-sulfatase (ETV:IDS) and demonstrated its ability to reduce glycosaminoglycan (GAG) accumulation in the brains of a ... ...

    Abstract We recently developed a blood-brain barrier (BBB)-penetrating enzyme transport vehicle (ETV) fused to the lysosomal enzyme iduronate 2-sulfatase (ETV:IDS) and demonstrated its ability to reduce glycosaminoglycan (GAG) accumulation in the brains of a mouse model of mucopolysaccharidosis (MPS) II. To accurately quantify GAGs, we developed a plate-based high-throughput enzymatic digestion assay coupled with liquid chromatography-tandem mass spectrometry (LC-MS/MS) to simultaneously measure heparan sulfate and dermatan sulfate derived disaccharides in tissue, cerebrospinal fluid (CSF) and individual cell populations isolated from mouse brain. The method offers ultra-high sensitivity enabling quantitation of specific GAG species in as low as 100,000 isolated neurons and a low volume of CSF. With an LOD at 3 ng/mL and LLOQs at 5-10 ng/mL, this method is at least five times more sensitive than previously reported approaches. Our analysis demonstrated that the accumulation of CSF and brain GAGs are in good correlation, supporting the potential use of CSF GAGs as a surrogate biomarker for brain GAGs. The bioanalytical method was qualified through the generation of standard curves in matrix for preclinical studies of CSF, demonstrating the feasibility of this assay for evaluating therapeutic effects of ETV:IDS in future studies and applications in a wide variety of MPS disorders.
    MeSH term(s) Animals ; Biomarkers/metabolism ; Blood-Brain Barrier/drug effects ; Blood-Brain Barrier/metabolism ; Brain/metabolism ; Brain/pathology ; Chromatography, Liquid ; Dermatan Sulfate/pharmacology ; Disaccharides/chemistry ; Disease Models, Animal ; Glycosaminoglycans/genetics ; Glycosaminoglycans/isolation & purification ; Glycosaminoglycans/metabolism ; Heparitin Sulfate/pharmacology ; Humans ; Iduronate Sulfatase/genetics ; Iduronate Sulfatase/metabolism ; Mice ; Mucopolysaccharidosis II/diagnosis ; Mucopolysaccharidosis II/genetics ; Mucopolysaccharidosis II/pathology ; Tandem Mass Spectrometry
    Chemical Substances Biomarkers ; Disaccharides ; Glycosaminoglycans ; Dermatan Sulfate (24967-94-0) ; Heparitin Sulfate (9050-30-0) ; Iduronate Sulfatase (EC 3.1.6.13)
    Language English
    Publishing date 2020-07-30
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2019364-6
    ISSN 1422-0067 ; 1422-0067 ; 1661-6596
    ISSN (online) 1422-0067
    ISSN 1422-0067 ; 1661-6596
    DOI 10.3390/ijms21155449
    Database MEDical Literature Analysis and Retrieval System OnLINE

    More links

    Kategorien

    Order via subito

    This service is chargeable due to the Delivery terms set by subito. Orders including an article and supplementary material will be classified as separate orders. In these cases, fees will be demanded for each order.

  6. Article ; Online: Brain delivery and activity of a lysosomal enzyme using a blood-brain barrier transport vehicle in mice.

    Ullman, Julie C / Arguello, Annie / Getz, Jennifer A / Bhalla, Akhil / Mahon, Cathal S / Wang, Junhua / Giese, Tina / Bedard, Catherine / Kim, Do Jin / Blumenfeld, Jessica R / Liang, Nicholas / Ravi, Ritesh / Nugent, Alicia A / Davis, Sonnet S / Ha, Connie / Duque, Joseph / Tran, Hai L / Wells, Robert C / Lianoglou, Steve /
    Daryani, Vinay M / Kwan, Wanda / Solanoy, Hilda / Nguyen, Hoang / Earr, Timothy / Dugas, Jason C / Tuck, Michael D / Harvey, Jennifer L / Reyzer, Michelle L / Caprioli, Richard M / Hall, Sejal / Poda, Suresh / Sanchez, Pascal E / Dennis, Mark S / Gunasekaran, Kannan / Srivastava, Ankita / Sandmann, Thomas / Henne, Kirk R / Thorne, Robert G / Di Paolo, Gilbert / Astarita, Giuseppe / Diaz, Dolores / Silverman, Adam P / Watts, Ryan J / Sweeney, Zachary K / Kariolis, Mihalis S / Henry, Anastasia G

    Science translational medicine

    2020  Volume 12, Issue 545

    Abstract: Most lysosomal storage diseases (LSDs) involve progressive central nervous system (CNS) impairment, resulting from deficiency of a lysosomal enzyme. Treatment of neuronopathic LSDs remains a considerable challenge, as approved intravenously administered ... ...

    Abstract Most lysosomal storage diseases (LSDs) involve progressive central nervous system (CNS) impairment, resulting from deficiency of a lysosomal enzyme. Treatment of neuronopathic LSDs remains a considerable challenge, as approved intravenously administered enzyme therapies are ineffective in modifying CNS disease because they do not effectively cross the blood-brain barrier (BBB). We describe a therapeutic platform for increasing the brain exposure of enzyme replacement therapies. The enzyme transport vehicle (ETV) is a lysosomal enzyme fused to an Fc domain that has been engineered to bind to the transferrin receptor, which facilitates receptor-mediated transcytosis across the BBB. We demonstrate that ETV fusions containing iduronate 2-sulfatase (ETV:IDS), the lysosomal enzyme deficient in mucopolysaccharidosis type II, exhibited high intrinsic activity and degraded accumulated substrates in both IDS-deficient cell and in vivo models. ETV substantially improved brain delivery of IDS in a preclinical model of disease, enabling enhanced cellular distribution to neurons, astrocytes, and microglia throughout the brain. Improved brain exposure for ETV:IDS translated to a reduction in accumulated substrates in these CNS cell types and peripheral tissues and resulted in a complete correction of downstream disease-relevant pathologies in the brain, including secondary accumulation of lysosomal lipids, perturbed gene expression, neuroinflammation, and neuroaxonal damage. These data highlight the therapeutic potential of the ETV platform for LSDs and provide preclinical proof of concept for TV-enabled therapeutics to treat CNS diseases more broadly.
    MeSH term(s) Animals ; Blood-Brain Barrier ; Brain ; Disease Models, Animal ; Enzyme Replacement Therapy ; Iduronate Sulfatase ; Lysosomes ; Mice
    Chemical Substances Iduronate Sulfatase (EC 3.1.6.13)
    Language English
    Publishing date 2020-05-26
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2518854-9
    ISSN 1946-6242 ; 1946-6234
    ISSN (online) 1946-6242
    ISSN 1946-6234
    DOI 10.1126/scitranslmed.aay1163
    Database MEDical Literature Analysis and Retrieval System OnLINE

    More links

    Kategorien

    In stock of ZB MED Cologne/Königswinter

    Zs.A 6941: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 2021: Bestellungen von Artikeln über das Online-Bestellformular
    ab Jg. 2022: Lesesaal (EG)

    Order via subito

    This service is chargeable due to the Delivery terms set by subito. Orders including an article and supplementary material will be classified as separate orders. In these cases, fees will be demanded for each order.

To top