Browsing by Author "Ullman, Julie C."

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    Small-molecule inhibition of glycogen synthase 1 for the treatment of Pompe disease and other glycogen storage disorders
    (American Association for the Advancement of Science, 2024) 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., Jr.; Green, Eric M.; Biochemistry and Molecular Biology, School of Medicine
    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.
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    The structural mechanism of human glycogen synthesis by the GYS1-GYG1 complex
    (Elsevier, 2022) 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, Jr.; Tzitzilonis, Christos; Biochemistry and Molecular Biology, School of Medicine
    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.