Peter Roach

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..The hypothesis is that glycogen phosphorylation can be considered a catalytic error and laforin a repair enzyme...

..Defects in the basic metabolizing enzymes lead to severe consequences whereas, with some exceptions, mutations in the regulatory proteins appear to cause a more subtle phenotypic change...

..Possibly the initial glucosylation is via inter-dimeric catalysis with an intra-molecular mechanism employed later in oligosaccharide synthesis...

..GNIPs may represent a novel participant in the initiation of glycogen synthesis...

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..These studies provide genetic evidence that in mice muscle glycogen is not essential for strenuous exercise and has relatively little effect on endurance...

..Here, we show that the cyclin-dependent protein kinase, Pho85p, which we have previously found to regulate glycogen synthase also controls the phosphorylation state of phosphorylase...

..These data support a role for aspartate 162 in the chemical step for the glucosyltransferase reaction and a role for aspartate 159 in binding and activating the acceptor molecule...

..The results from this assay provide new insight into the mechanism by which glycogenin catalyzes the initiation reaction...

..We demonstrate that the COOH-terminal fragment of glycogenin can be used as an effective high affinity reagent for the purification of glycogen synthase from skeletal muscle and liver...

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..This suggested the existence of inputs from Pho85p into glycogen storage, independent of Pcl8p and Pcl10p, and acting antagonistically...

..However, this compared with an increase in glycogen synthase of some 50-fold, so that the increase in branching enzyme in response to overexpression of glycogen synthase was insufficient to synthesize normally branched glycogen...

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..This study provides a molecular link between an observed biochemical property of laforin and the phenotype of a mouse model of Lafora disease. The results also have important implications for glycogen metabolism generally...

..However, the role must differ subtly between the mammalian and the yeast enzymes...

..A recently characterized enzyme, PAS kinase, may be a new member of this group of nutritional transducers...

..This is the first direct demonstration that activation of glycogen synthase by glucose-6-P in vivo is necessary for normal glycogen accumulation...

..21, 5742-5752). Autophagy delivers glycogen to the vacuole, and we propose that the impaired vacuolar function associated with ATPase mutants (vma10 or vma22) results in reduced degradation and subsequent hyperaccumulation of glycogen...

..We propose, therefore, that laforin senses cytosolic glycogen accumulation which in turn determines the level of laforin protein...

..Particularly interesting is the observation that 11 of these genes encode cardiac or slow-twitch isoforms of muscle contractile proteins, and are upregulated in muscle that has a greater oxidative capacity in MGSKO mice...

..Although disruption of the GYS1 gene negatively affects muscle glucose uptake, overall glucose tolerance is actually improved, possibly because of a role for GYS1 in tissues other than muscle...

..Heterologous interactions between GNIP1 and GNIP2 were also detected. Since glycogenin is also a dimer, higher order multimeric complexes between glycogenin and GNIPs would be possible...

..This result suggests that increased muscle glycogen stores do not necessarily improve exercise performance in mice...

..We conclude that Stbd1 is involved in glycogen metabolism by binding to glycogen and anchoring it to membranes, thereby affecting its cellular localization and its intracellular trafficking to lysosomes...

..This mouse model mimics the pathophysiology of glycogen storage disease 0 patients and highlights the importance of liver glycogen stores in whole body glucose homeostasis...

..Sequence alignments and database searches revealed related proteins in species as distant as Drosophila melanogaster and Caenorhabditis elegans...

..We propose that laforin functions to suppress excessive glycogen phosphorylation and is an essential component of the metabolism of normally structured glycogen...

..Whenever glycogen storage was elevated, the polysaccharide formed was found to be less branched but normal branching could be restored by overexpression of branching enzyme...

..However, the functional implications of the mutation were not known. The objective of this study was to characterise the molecular and physiological consequences of this genetic variant...

..While the entire GSN was required for full interaction, the C-terminus in GNN was more important. Furthermore, mutation in the GNN glucosylation sites did not impair the interaction with GSN...

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..This mode of regulation provides a mechanism for metabolic status to impinge directly on the cellular decision of whether to store or use available energy...

..Northern blot analysis showed that the gnn gene was induced during vegetative growth and was repressed upon carbon starvation...

..The research proposed in this application seeks to understand what is wrong with glycogen storage in Lafora disease, which could help provide clues to new treatment regimens. ..

..We will also attempt to assess in animal models the roles of phosphorylation and G6P activation of GS in controlling glycogen synthesis ..

..Yeast has proven to be a useful experimental system to study vesicular trafficking and such may be true for the study of autophagy and its relationship to glycogen metabolism (aim iii). ..

..Its action could therefore profoundly affect glycogen metabolism. The goal of this aim is to establish whether UGPPase influences UDP-glucose and glycogen levels in vivo. ..

..abstract_text> ..

..The research proposed in this application seeks to understand what is wrong with glycogen storage in Lafora disease, which could help provide clues to new treatment regimens. ..

..This study of yeast may help give a broader perspective on intracellular signaling that can be relevant to the control of cellular events such as growth, proliferation and metabolism, in mammalian systems. ..

..Success would significantly extend knowledge of the mechanisms of action of several hormones, notably insulin, of obvious relevance to better understanding of situations of impaired insulin control such as in diabetes...

..The research, though fundamental in nature, is relevant to situations of impaired hormonal control, such as in diabetes...