Glycogen Metabolism & Glycogen Storage Diseases

Flashcards reviewing key concepts, enzymes, regulatory mechanisms, and clinical conditions related to glycogen metabolism and glycogen storage diseases.

glycogen

A large, highly branched polymer of glucose residues that serves as the primary readily mobilized storage form of glucose in animals.

glycogenesis

The anabolic biochemical pathway responsible for synthesizing glycogen from glucose molecules.

α-1,4 glycosidic bond

The dominant chemical bond linking consecutive glucose residues along the linear chains of glycogen.

α-1,6 glycosidic bond

The glycosidic linkage that creates branch points in glycogen, occurring approximately every tenth glucose residue.

amylose

A linear, unbranched structural component of starch that is insoluble in water.

amylopectin

A branched structural component of starch that is soluble in water, structurally analogous to glycogen.

liver glycogen

Glycogen stores in hepatocytes (about 90 g in a 70-kg human) used primarily to maintain and regulate systemic blood glucose levels.

muscle glycogen

Glycogen stores in skeletal muscle (about 245 g in a 70-kg human) used exclusively as an internal fuel source for generating ATP during contraction.

glycogenesis - steps

phosphoglucomutase

The enzyme that reversibly isomerizes glucose 6-phosphate to glucose 1-phosphate during glycogenesis and glycogenolysis.

glucose 1-phosphate uridyl transferase

The enzyme that catalyzes the reaction between glucose 1-phosphate and UTP to synthesize UDP-glucose and pyrophosphate.

UDP-glucose

Uridine diphosphate glucose, the activated high-energy glucosyl donor required for glycogen chain elongation.

glycogenin

A self-glucosylation primer protein composed of two identical subunits, each catalyzing the addition of eight glucose units to initiate a new glycogen granule.

glycogen synthase

The key regulatory enzyme of glycogenesis that transfers the glucosyl moiety of UDP-glucose to a nonreducing C-4 hydroxyl terminus of glycogen via an $\alpha\text{-1,4-glycosidic}$ bond.

branching enzyme (4:6-transferase)

The enzyme (glycosyl $\alpha 1,4:\alpha 1,6$ transferase) that hydrolyzes an $\alpha\text{-1,4}$ bond in a linear polyglucose chain and attaches the fragment via an $\alpha\text{-1,6}$ linkage to form a branch.

glycogenolysis

The catabolic biochemical process of breaking down stored glycogen into glucose 1-phosphate and free glucose molecules.

glycogen phosphorylase

The rate-limiting enzyme of glycogenolysis that cleaves $\alpha\text{-1,4-glycosidic}$ bonds phosphorolytically from the nonreducing outer ends of glycogen to produce glucose 1-phosphate.

pyridoxal phosphate (PLP)

The active coenzyme derivative of vitamin B₆ required by glycogen phosphorylase for catalytic activity.

debranching enzyme

A bifunctional enzyme containing $\alpha 1,4:\alpha 1,4$ transferase and $\alpha\text{-1,6-glucosidase}$ activities necessary to clear branch points during glycogen degradation.

Limit Dextrin

The branched glycogen remnant left after glycogen phosphorylase has degraded outer chains down to four glucose residues from an $\alpha\text{-1,6}$ branch point.

Glucose 6-phosphatase

An ER-bound enzyme present in hepatocytes and kidney cells—but lacking in skeletal muscle—that converts glucose 6-phosphate into free glucose for systemic circulation.

Glucagon

A pancreatic hormone released during fasting that binds GPCRs (Gs) in the liver to elevate cAMP, stimulating glycogenolysis and inhibiting glycogenesis.

Epinephrine

A stress hormone that activates cAMP-dependent PKA pathways in muscle and liver, as well as $\text{Ca}^{2+}$ signaling in liver, to rapidly stimulate glycogen breakdown.

Insulin

An anabolic hormone elevated in the fed state that activates Protein Phosphatase 1 (PP-1), promoting dephosphorylation to activate glycogen synthase and inhibit glycogen degradation.

Protein Kinase A (PKA)

A cAMP-activated kinase that phosphorylates glycogen synthase (inactivating it) and phosphorylase kinase (activating it).

Phosphorylase Kinase

An enzyme activated by PKA-mediated phosphorylation or $\text{Ca}^{2+}\text{-calmodulin}$ binding that phosphorylates and activates glycogen phosphorylase.

Protein Phosphatase 1 (PP-1)

An insulin-stimulated enzyme that dephosphorylates glycogen synthase, phosphorylase kinase, and glycogen phosphorylase to promote glycogen synthesis.

Adenylate Cyclase

A plasma membrane enzyme activated by Gs-protein signaling that synthesizes cyclic AMP (cAMP) from ATP.

Calmodulin

A calcium-binding protein subunit of phosphorylase kinase that directly activates glycogenolysis in response to rising cytosolic $\text{Ca}^{2+}$ levels.

Phospholipase C (PLC)

An enzyme activated downstream of $\text{G}_q$ receptors by epinephrine in hepatocytes that cleaves $\text{PIP}_2$ into DAG and $\text{IP}_3$.

Inositol Trisphosphate ($\text{IP}_3$)

A second messenger produced by PLC that triggers the release of stored $\text{Ca}^{2+}$ from the endoplasmic reticulum into the cytoplasm.

Diacylglycerol (DAG)

A lipophilic second messenger generated alongside $\text{IP}_3$ during PLC-mediated cleavage of $\text{PIP}_2$.

glycogen storage siseases (GSDs)

A group of at least 10 inherited metabolic disorders caused by specific enzyme defects in glycogen synthesis, degradation, or glycolysis.

Von Gierke disease (GSD type Ia)

An autosomal recessive deficiency of glucose 6-phosphatase causing severe fasting hypoglycemia, massive hepatomegaly, lactic acidosis, hyperlipidemia, and hyperuricemia.

glucose 6-phosphate translocase deficiency (GSD Type Ib)

A subtype of GSD Type I caused by a defect in transporting glucose 6-phosphate across the endoplasmic reticulum membrane.

Pompe disease (GSD type II)

An autosomal recessive disorder caused by lysosomal $\alpha\text{-1,4-glucosidase}$ (acid maltase) deficiency, leading to glycogen accumulation in lysosomes, hypertrophic cardiomyopathy, and severe muscle weakness.

Lysosomal $\alpha\text{-1,4-glucosidase}$ (Acid Maltase)

An enzyme inside lysosomes responsible for degrading small amounts of glycogen; its deficiency causes Pompe disease.

Cori disease (GSD type III)

An autosomal recessive deficiency of debranching enzyme ($\alpha\text{-1,6-glucosidase}$) resulting in the accumulation of abnormally structured glycogen with short outer branches (limit dextrinosis).

Andersen disease (GSD type IV)

An autosomal recessive deficiency of branching enzyme leading to abnormal glycogen with long unbranched chains (amylopectinosis) that trigger immune attack, progressive cirrhosis, and early death.

McArdle disease (GSD type V)

An autosomal recessive disorder caused by myophosphorylase deficiency, leading to exercise-induced muscle cramps, myoglobinuria, and lack of blood lactate rise during exercise.

Myophosphorylase

The skeletal muscle-specific isoform of glycogen phosphorylase that is mutated and deficient in McArdle disease.

Second-wind Phenomenon

A clinical feature in McArdle disease patients where muscle fatigue and pain subside during sustained moderate exercise due to increased blood flow and alternative fuel delivery.

Hers disease (GSD type VI)

An autosomal recessive deficiency of liver glycogen phosphorylase causing hepatomegaly, mild fasting hypoglycemia, and growth retardation.

Tarui disease (GSD type VII)

An autosomal recessive deficiency of muscle and red blood cell phosphofructokinase-1 (PFK-1), resulting in muscle cramping, lack of exercise lactate elevation, and exertional hemolysis.

Hepatomegaly

Abdominal organ enlargement of the liver characteristically seen in hepatic GSDs (Types I, III, IV, and VI) due to glycogen accumulation.

Lactic Acidosis in GSD Type I

A condition in Von Gierke disease resulting from excessive accumulation of glucose 6-phosphate that gets shunted through glycolysis to produce excess lactic acid.

Hyperuricemia in GSD Type I

Elevated serum uric acid in Von Gierke disease caused by increased ribose 5-phosphate synthesis via the pentose phosphate pathway and decreased renal clearance.

Hyperlipidemia in GSD Type I

Marked elevations of blood triglycerides, cholesterol, and phospholipids in Von Gierke disease secondary to excess acetyl-CoA production and lipogenesis.

Doll-like Facial Appearance

A classic clinical physical feature seen in infants with Von Gierke disease characterized by chubby cheeks from facial fat deposition.

Hypertrophic Cardiomyopathy

Severe enlargement and thickening of heart muscle walls characteristic of infantile Pompe disease due to lysosomal glycogen accumulation.

Floppy Infant Syndrome

Infantile muscle hypotonia and severe generalized weakness associated with Pompe disease (Type II) and Andersen disease (Type IV).

Myoglobinuria

The excretion of muscle myoglobin in urine following strenuous activity, causing dark brown or 'cherry soda' colored urine in McArdle disease.

Forearm Nonischemic Exercise Test

A diagnostic procedure used to evaluate glycogenolysis in which a lack of post-exercise blood lactate elevation indicates a defect in muscle glycogen breakdown or glycolysis.

Uncooked Cornstarch Therapy

A therapeutic dietary regimen provided between meals and overnight to prevent fasting hypoglycemia in patients with hepatic glycogen storage diseases.

Enzyme Replacement Therapy (ERT)

A targeted medical treatment for Pompe disease involving regular intravenous infusions of recombinant human acid $\alpha\text{-glucosidase}$.

Phosphorolytic Cleavage

The cleavage of a chemical bond by the addition of inorganic phosphate ($\text{P}_i$) rather than water, conserving energy by directly yielding phosphorylated sugar.

Nonreducing End

The terminal C-4 hydroxyl glucose residue of a glycogen chain where metabolic enzymes add or remove individual glucosyl units.

Glycogen Granule

An intracellular cytoplasmic particle composed of a glycogen polymer complexed with the enzymes needed for its synthesis, regulation, and degradation.

Amylo-1,6-glucosidase

The specific hydrolytic activity of debranching enzyme that cleaves the single remaining $\alpha\text{-1,6-linked}$ glucose residue at a branch point as free glucose.

Phosphorolysis Energy Advantage

The thermodynamic benefit where glycogen-derived glucose yields a net of 3 ATP in anaerobic glycolysis (versus 2 ATP from free glucose) because the hexokinase step is bypassed.

Glycogen is a storage form of glucose.

When glucose is incorporated into liver glycogen, which of the following is required as the direct glucosyl donor?

UDP-glucose

A sprinter is trying to optimize his performance. He has calculated that, even under anaerobic conditions, his glycogen stores will supply him with enough energy to last the race.

What would the energy difference be between using glucose from a dietary source vs solely relying solely on glucose from glycogen sores as fuel for his race?

Using glucose from glycogen stores yields 3 ATP per glucose molecule compared to 2 ATP from dietary glucose, providing a net energy advantage of 1 ATP per molecule.