Lack of Glycogenin Causes Glycogen Accumulation and Muscle Function Impairment

Testoni, G; Durán, Jordi; Garcı́a-Rocha, Mar; Vilaplana, Francisco; Serrano, Antonio L.; Sebastián, David; López-Soldado, Iliana; Sullivan, Mitchell A.; Slebe, Felipe; Vilaseca, Marta; Muñoz‐Cánoves, Pura; Guinovart, Joan J.

doi:10.1016/j.cmet.2017.06.008

Cited by 69 publications

(64 citation statements)

References 39 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In addition, the protein acquired a C-terminal glycogen synthase binding domain of unknown function (Fig. 3A; Zequiraj et al, 2014) Past and recent studies indicate that, despite the compelling in vitro data, glycogenin is not required for glycogen synthesis in yeast and mice (Torija et al, 2005;Testoni et al, 2017). Nevertheless, glycogen levels are affected in a manner that is currently unexplained.…”

Section: Discussionmentioning

confidence: 99%

A glycogenin homolog controls Toxoplasma gondii growth via glycosylation of an E3 ubiquitin ligase

Mandalasi¹,

Kim²,

Thieker³

et al. 2019

Preprint

View full text Add to dashboard Cite

Skp1, a subunit of E3-Skp1/Cullin-1/F-box protein ubiquitin ligases, is uniquely modified in protists by an O 2 -dependent prolyl hydroxylase, which forms the attachment site for a novel pentasaccharide. Mutational studies demonstrate the importance of the core glycan for growth of the parasite Toxoplasma gondii in fibroblasts, but the significance of the non-reducing terminal sugar is unknown. Here we investigated a homolog of glycogenin, an enzyme that can initiate and prime glycogen synthesis in yeast and animals. Gat1 is required for pentasaccharide assembly in cells and catalyzes the addition of an α galactose in 3-linkage to the subterminal α 3-linked glucose residue in vitro. A strong selectivity of Gat1 for Skp1 in extracts is consistent with evidence that Skp1 is the sole target of the glycosyltransferase pathway. gat1-disruption resulted in slow growth indicating the importance of the complete glycan. Molecular dynamics simulations suggested that the full glycan helps organize Skp1 as previously described in the amoebozoan Dictyostelium where a distinct glycosyltransferase assembles a different terminal disaccharide. The crystal structure of Gat1 from the plant pathogen Pythium ultimum confirmed the striking similarity to glycogenin, with differences in the active sites providing an explanation for its distinct substrate preference and regiospecificity. Gat1 also exhibited low α -glucosyltransferase activity like glycogenin, but autoglycosylation was not detected and gat1-disruption revealed no effect on starch accumulation in Toxoplasma. A phylogenetic analysis suggested that Gat1 was a progenitor of glycogenin, and acquired its role in glycogen formation following the ancestral disappearance of the underlying Skp1 glycosyltransferase Glt1 prior to amoebozoan evolution.

show abstract

Section: Discussionmentioning

confidence: 99%

A glycogenin homolog controls Toxoplasma gondii growth via glycosylation of an E3 ubiquitin ligase

Mandalasi¹,

Kim²,

Thieker³

et al. 2019

Preprint

View full text Add to dashboard Cite

show abstract

“…Glycogen synthesis is initiated by GN ( Figure 3), which catalyzes the transfer of glucose residues from UDP-glucose to Tyr-194 of a separate GN molecule, thereby forming α-1, 4-glycosidic linkages to create a linear glucose polymer of approximately 10-20 glucose residues. 49 In humans, there are two GN isoforms. GN1 (encoded by the GYG1 gene) is widely expressed, whereas GN2 (encoded by the GYG2 gene) is primarily located in human liver.…”

Section: Initiation Of Glycogen Synthesismentioning

confidence: 99%

“…14 Liver glycogen is involved in maintaining blood glucose homeostasis. 20,21 Therefore, in the current review, we will not focus on SM glycogen. In diabetic mouse liver, it has been shown that the α particles of glycogen are molecularly fragile over the feeding and fasting cycle: they easily degrade into small β particles in the presence of dimethyl sulfoxide (DMSO), which is an H-bond disruptor.…”

Section: Introductionmentioning

confidence: 99%

Is liver glycogen fragility a possible drug target for diabetes?

Cheng

2019

The FASEB Journal

View full text Add to dashboard Cite

Liver glycogen α particles are molecularly fragile in diabetic mice, and readily form smaller β particles, which degrade more rapidly to glucose. This effect is well associated with the loss of blood-glucose homeostasis in diabetes. The biological mechanism of such fragility is still unknown; therefore, there are perceived opportunities that could eventually lead to new means to manage type 2 diabetes. The hierarchical structures of glycogen particles are controlled by the underlying biosynthesis/degradation process that involves various enzymes, including, for example, glycogen synthase (GS) and glycogen-branching enzyme (GBE). Recent studies have shown that fragile glycogen α particles in diabetic mice have longer chains and a higher molecular density compared to wild-type mice, indicating an enhanced enzymatic activity ratio of GS to GBE in diabetes. Furthermore, it has been shown that with an improved blood glucose homeostasis, the glycogen fragility in diabetic mice can be restored by treatment with active ingredients from traditional Chinese medicine, yet the underlying mechanism is unknown. In this review, we summarize recent advances in understandings glycogen fragility from the perspectives of glycogen biosynthesis/degradation, glycogen hierarchical structures, and its relation to diabetes. Importantly, we for the first time set GS/GBE activity ratio as the therapeutic target for diabetes. K E Y W O R D Schain-length distribution, glycogen biosynthesis, glycogen degradation, particle size distribution 4 | LI and HU ACKNOWLEDGMENTSWe would like to thank Prof. Robert G. Gilbert (The University of Queensland) for his mentor guidance and intelligent work in the research field of studying molecular structure of glycogen. We would also like to thank the financial support from

show abstract

“…The synthesis of a de novo glycogen granule is thought to be initiated by glycogenin. Glycogenin glycosylates itself at a tyrosine residue and catalyzes the extension of glycan chains (Cao, Mahrenholz, DePaoli‐Roach, & Roach, ; Smythe & Cohen, ), although recent studies with glycogenin‐deficient mice indicate other mechanisms are likely possible (Testoni et al, ). The glycan chains then serve as a primer for glycogen synthetase, which catalyzes the formation of α‐1, 4‐glycosidic linkages of glycogen.…”

Section: Glycogen Metabolismmentioning

confidence: 99%

Methodological considerations for studies of brain glycogen

Wong

Swanson

2019

J of Neuroscience Research

View full text Add to dashboard Cite

Glycogen stores in the brain have been recognized for decades, but the underlying physiological function of this energy reserve remains elusive. This uncertainty stems in part from several technical challenges inherent in the study of brain glycogen metabolism. These include low glycogen content in the brain, non‐homogeneous labeling of glycogen by radiotracers, rapid glycogenolysis during postmortem tissue handling, and effects of the stress response on brain glycogen turnover. Here we briefly review the aspects of the glycogen structure and metabolism that bear on these technical challenges and present ways they can be addressed.

show abstract

Lack of Glycogenin Causes Glycogen Accumulation and Muscle Function Impairment

Cited by 69 publications

References 39 publications

A glycogenin homolog controls Toxoplasma gondii growth via glycosylation of an E3 ubiquitin ligase

A glycogenin homolog controls Toxoplasma gondii growth via glycosylation of an E3 ubiquitin ligase

Is liver glycogen fragility a possible drug target for diabetes?

Methodological considerations for studies of brain glycogen

Contact Info

Product

Resources

About