Glycogen storage disease type Ia: Linkage of glucose, glycogen, lactic acid, triglyceride, and uric acid metabolism

Sever, Sakine; Weinstein, David A.; Wolfsdorf, Joseph I.; Gedik, Reyhan; Schaefer, Ernst J.

doi:10.1016/j.jacl.2012.08.005

Cited by 19 publications

(12 citation statements)

References 16 publications

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“…S1A) to any other amino acid residue, including Lys, also abolished enzyme activity (21). In particular, mutation of R83C has been directly related to glycogen storage disease type 1a (10,22). Similarly, in ecPgpB, Arg201 (3.02) interacts with His163 (2.04) .…”

Section: Resultsmentioning

confidence: 99%

Crystal structure of lipid phosphatase Escherichia coli phosphatidylglycerophosphate phosphatase B

Fan

Jiang

Zhao

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Membrane-integrated type II phosphatidic acid phosphatases (PAP2s) are important for numerous bacterial to human biological processes, including glucose transport, lipid metabolism, and signaling. Escherichia coli phosphatidylglycerol-phosphate phosphatase B (ecPgpB) catalyzes removing the terminal phosphate group from a lipid carrier, undecaprenyl pyrophosphate, and is essential for transport of many hydrophilic small molecules across the membrane. We determined the crystal structure of ecPgpB at a resolution of 3.2 Å. This structure shares a similar folding topology and a nearly identical active site with soluble PAP2 enzymes. However, the substrate binding mechanism appears to be fundamentally different from that in soluble PAP2 enzymes. In ecPgpB, the potential substrate entrance to the active site is located in a cleft formed by a V-shaped transmembrane helix pair, allowing lateral movement of the lipid substrate entering the active site from the membrane lipid bilayer. Activity assays of point mutations confirmed the importance of the catalytic residues and potential residues involved in phosphate binding. The structure also suggests an induced-fit mechanism for the substrate binding. The 3D structure of ecPgpB serves as a prototype to study eukaryotic PAP2 enzymes, including human glucose-6-phosphatase, a key enzyme in the homeostatic regulation of blood glucose concentrations.T ype II phosphatidic acid phosphatases (PAP2s) are a large family of phosphatases important for lipid metabolism and signaling (1, 2). PAP2 proteins have been found in all life kingdoms from bacteria to mammals. They catalyze dephosphorylation of broad substrates by specifically hydrolyzing phosphoric monoester bonds. Their substrates include variety of phosphorylated carbohydrates, peptides, and lipids. PAP2s are involved in vesicular trafficking, secretion, and endocytosis (e.g., the enzyme phosphatidate phosphatase APP1 in yeast) (3); protein glycosylation [e.g., dolichyl pyrophosphate phosphatase 1 (DOLPP1) in the mouse] (4); energy storage (e.g., triacylglycerol biosynthesis) (5); and stress response (6). In contrast to type I PAP enzymes, which are Mg 2+ -dependent and usually soluble, PAP2 proteins are Mg 2+ -independent, and many of PAP2 enzymes are integral transmembrane (TM) proteins (7). Whereas the soluble branch of PAP2s is called class A nonspecific acid phosphatases (NSAPs) (8), the TM branch of the PAP2 family is also called the lipid phosphatase/phosphotransferase family (2) or lipid phosphate phosphatase family (9). Human glucose-6-phosphatase (G6Pase), the key enzyme in the homeostatic regulation of blood glucose concentrations, belongs to the TM PAP2 subfamily (10). Thus, the TM property is unique to the PAP2 family.In Escherichia coli, undecaprenyl phosphate (C 55 -P), a 55-carbon single-lipid chain phospholipid, serves as a carrier lipid to transfer a variety of phosphate-linked polymers across the periplasmic membrane from the cytosol to the periplasmic space. Recently, the crystal structure of phospho-N-acet...

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Section: Resultsmentioning

confidence: 99%

Crystal structure of lipid phosphatase Escherichia coli phosphatidylglycerophosphate phosphatase B

Fan

Jiang

Zhao

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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“…As G6PC is involved in hepatic glucose 503 production it influences both FG and FI levels. Previous studies have also established a potential role for 504 G6PC in influencing lipid and urate levels (Dewey et al, 2016;Sever et al, 2012). In contrast, due to its 505 restricted expression in the islet beta cell, variants in G6PC2 only influence FG and HbA1c due to a beta 506 cell-driven effect.…”

Section: G6pc2 Regulates Basal Insulin Secretion In Human Beta Cells mentioning

confidence: 98%

Tissue-Specific Alteration of Metabolic Pathways Influences Glycemic Regulation

Willems

Fernández

et al. 2019

Preprint

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SummaryMetabolic dysregulation in multiple tissues alters glucose homeostasis and influences risk for type 2 diabetes (T2D). To identify pathways and tissues influencing T2D-relevant glycemic traits (fasting glucose [FG], fasting insulin [FI], two-hour glucose [2hGlu] and glycated hemoglobin [HbA1c]), we investigated associations of exome-array variants in up to 144,060 individuals without diabetes of multiple ancestries. Single-variant analyses identified novel associations at 21 coding variants in 18 novel loci, whilst gene-based tests revealed signals at two genes, TF (HbA1c) and G6PC (FG, FI). Pathway and tissue enrichment analyses of trait-associated transcripts confirmed the importance of liver and kidney for FI and pancreatic islets for FG regulation, implicated adipose tissue in FI and the gut in 2hGlu, and suggested a role for the non-endocrine pancreas in glucose homeostasis. Functional studies demonstrated that a novel FG/FI association at the liver-enriched G6PC transcript was driven by multiple rare loss-of-function variants. The FG/HbA1c-associated, islet-specific G6PC2 transcript also contained multiple rare functional variants, including two alleles within the same codon with divergent effects on glucose levels. Our findings highlight the value of integrating genomic and functional data to maximize biological inference.Highlights23 novel coding variant associations (single-point and gene-based) for glycemic traits51 effector transcripts highlighted different pathway/tissue signatures for each traitThe exocrine pancreas and gut influence fasting and 2h glucose, respectivelyMultiple variants in liver-enriched G6PC and islet-specific G6PC2 influence glycemia

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“…The symptoms include severe hypoglycemia, renal disease, hypertriglyceridemia, and anemia. 102 While the patients with end-stage renal failure are treated with kidney transplantation, there is no option to cure the metabolic abnormalities. 103 Recently, a liver-directed gene therapy using adenoviral vectors was shown to potentially correct G6P gene in deficient mice, resulting in 19% restoration of G6P function and normalization of glucose, lipid, and uric acid levels.…”

Section: Thrombotic Thrombocytopenic Purpuramentioning

confidence: 99%