Glycogen Metabolism and Carbohydrates

Metabolism of Glycogen

• In plants, glucose is made from carbon dioxide and water through photosynthesis.
• Plants store glucose as starch or use it to make cellulose, which forms the plant's structure.
• Animals can make carbohydrate from lipid glycerol and amino acids, but most animal carbohydrate ultimately comes from plants.
• Glucose is a crucial carbohydrate that enters the bloodstream after dietary carbohydrate absorption.
• Other sugars are converted into glucose in the liver.
• Glucose serves as the primary metabolic fuel for mammals, excluding ruminants, and is a universal fuel for fetuses.
• It's the precursor for making all other carbohydrates in the body, including glycogen, ribose, deoxyribose, and galactose.
• Several diseases are associated with carbohydrate metabolism, including diabetes mellitus, galactosemia, glycogen storage diseases, and lactose intolerance.

Types of Carbohydrates

• Monosaccharides cannot be broken down into simpler carbohydrates and are classified based on the number of carbon atoms they have (trioses, tetroses, etc.) and whether they contain an aldehyde (aldoses) or ketone (ketoses) group.
• Disaccharides are formed when two monosaccharide units are linked together.
• Maltose and sucrose are examples.
• Oligosaccharides result from the joining of two to ten monosaccharides
• Maltotriose is an example.
• Polysaccharides consist of more than ten monosaccharide units; starches and dextrins are examples.
• They can be linear or branched polymers and are categorized as hexosans or pentosans based on their monosaccharide composition.

Important Sugars

• Key aldoses include glycerose, erythrose, ribose, and glucose.
• Key ketoses include dihydroxyacetone, erythrulose, ribulose, and fructose.
• The configurations at the anomeric carbon (marked with an asterisk) determine whether a sugar is α or β.
• When the anomeric carbon of the second residue participates in forming a glycosidic bond (as in sucrose), the residue becomes a glycoside, known as a furanoside or pyranoside.
• If a disaccharide lacks a free potential aldehyde or ketone group on its anomeric carbon, it will not exhibit reducing properties.

Starch Structure

• Starch has two main components: amylose, which has a helical coil structure, and amylopectin, which features 1→6 branch points.
• Glycogen molecules are spherical, roughly 21 nm in diameter, and can be seen using electron microscopes.
• They have a molecular mass of 107 Da and comprise polysaccharide chains, each having around 13 glucose residues, arranged in 12 concentric layers.
• Branched chains are located in the inner layers, while unbranched chains are in the outer layer.
• Glycogenin acts as the primer molecule for glycogen synthesis.

Biomedical Importance of Glycogen

• Glycogen is the main storage carbohydrate in animals, equivalent to starch in plants.
• It is a branched polymer of α-D-glucose, found primarily in the liver (up to 6%) and muscle (rarely exceeding 1%).
• Muscle contains three to four times the total amount of glycogen compared to the liver due to its mass.
• Muscle glycogen is a readily available glucose source for glycolysis within the muscle itself.
• Liver glycogen stores and releases glucose to maintain blood glucose levels between meals.
• After 12–18 hours of fasting, liver glycogen is almost entirely depleted.
• Glycogen storage diseases are inherited conditions characterized by impaired glycogen mobilization or abnormal glycogen deposition, leading to muscle weakness and other health issues.

Glycogenesis in Muscle and Liver

• Glycogen biosynthesis follows a pathway involving a special nucleotide of glucose.
• Glucose is phosphorylated to glucose 6-phosphate by hexokinase (muscle) or glucokinase (liver).
• Glucose 6-phosphate is then isomerized to glucose 1-phosphate by phosphoglucomutase, an enzyme that requires glucose 1,6-bisphosphate as an intermediate.
• Glucose 1-phosphate reacts with uridine triphosphate (UTP) to form UDPGIc and pyrophosphate, a reaction catalyzed by UDPGIc pyrophosphorylase. Two high-energy phosphates help incorporate glucose into glycogen.
• Insulin reduces cAMP levels, reversing the effects of glucagon or epinephrine.
• Glucagon is effective in heart muscle but not in skeletal muscles.
• Glucan transferase and debranching enzyme are likely two distinct functions of the same enzyme.

Glycogen Synthesis

• Pyrophosphatase hydrolyzes pyrophosphate into two inorganic phosphate molecules, driving the main reaction forward.
• Glycogen synthase facilitates the formation of glycosidic bonds between C1 of activated UDPGIc glucose and C4 of the terminal glucose residue in glycogen, releasing uridine diphosphate (UDP).
• A preexisting glycogen molecule acts as a "glycogen primer," which is required to initiate this reaction.
• Glycogenin, a 37-kDa protein that is glycosylated on a specific tyrosine residue by UDPGIc, may form glygogen primer.
• Further glucose residues attach in the 1→4 position to make a short chain that is a substrate for glycogen synthase.
• Glycogenin remains attached to the center of glycogen molecules in skeletal muscle but in the liver, the number of glycogen molecules exceeds that of glycogenin molecules.

Glycogen Branching

• The addition of a glucose residue to a pre-existing glycogen chain or primer occurs at the nonreducing outer end.
• This allows branches to elongate through successive 1→4 linkages.
• Branching enzyme transfers a part of a 1→4 chain (at least six glucose residues) to form a 1→6 linkage, creating a branch point in a chain with at least 11 residues.

Glycogenolysis

• Glycogenolysis follows a separate pathway and is not the reverse of glycogenesis.
• Glycogen phosphorylase catalyzes the rate-limiting step by promoting the cleavage via inorganic phosphate of the 1→4 linkages in glycogen to yield glucose 1-phosphate.
• Terminal glucosyl residues are removed until approximately four glucose residues remain on either side of a 1→6 branch.
• Glucan transferase transfers a trisaccharide unit from one branch to another, exposing the 1→6 branch point.
• Debranching enzyme hydrolyzes the 1→6 linkages, allowing phosphorylase to continue.
• Phosphoglucomutase then catalyzes the reversible conversion of glucose 1-phosphate to glucose 6-phosphate.
• The liver and kidney contain glucose-6-phosphatase, which hydrolyzes glucose 6-phosphate into glucose, increasing blood glucose concentration.

Hormonal Regulation

• The principal enzymes regulating glycogen metabolism are glycogen phosphorylase and glycogen synthase.
• These enzymes are controlled through allosteric mechanisms and covalent modifications like reversible phosphorylation and dephosphorylation.
• Cyclic AMP (cAMP) is created from ATP by adenylyl cyclase and acts as a secondary messenger.
• Hormones like epinephrine, norepinephrine, and glucagon facilitate cAMP's roles.
• cAMP is broken down by phosphodiesterase, ending hormone action.
• Insulin boosts phosphodiesterase activity in the liver.

Phosphorylase Differences in Liver and Muscle

• In the liver, phosphorylase a's serine hydroxyl groups are phosphorylated. It is deactivated by protein phosphatase-1, which removes the phosphate to form phosphorylase b.
• Reactivation involves rephosphorylation, which phosphorylase kinase catalyzes.
• Muscle phosphorylase is a dimer, with each monomer having pyridoxal phosphate (vitamin B6).
• It has two forms: phosphorylase a (phosphorylated, active whether or not 5'-AMP is present) and phosphorylase b (dephosphorylated, active only when 5'-AMP is present). During exercise, 5'-AMP levels rise, providing fuel for the muscle.

Muscle Phosphorylase Activation

• Muscle phosphorylase activates via cAMP in response to epinephrine.
• Increased cAMP concentrations activate cAMP-dependent protein kinase, which phosphorylates inactive phosphorylase kinase b, converting it to active phosphorylase kinase a.
• Phosphorylase kinase a then phosphorylates phosphorylase b, activating it to phosphorylase a.

Calcium's Role in Muscle Contraction

• Glycogenolysis increases significantly in contracting muscle.
• Calcium ions (Ca2+) facilitate the rapid activation of phosphorylase by phosphorylase kinase, using the same signal as nerve stimulation for contraction.
• Muscle phosphorylase kinase contains four subunits (α, β, γ, and δ) and is structured as (αβγδ)4.
• The α and β subunits have cAMP dependent protein kinase phosphorylate serine residues.
• The δ subunit binds four Ca2+ ions and resembles calmodulin.
• Ca2+ binding activates the catalytic site on the γ subunit, even in the dephosphorylated state.
• The binding of a second calmodulin facilitates further activation.

cAMP-Independent Glycogenolysis

• In addition to glucagon, α1-adrenergic receptors mediate glycogenolysis in the liver via epinephrine and norepinephrine.
• This activates phosphorylase kinase through a Ca2+/calmodulin-sensitive process.
• Vasopressin, oxytocin, and angiotensin II also stimulate cAMP-independent glycogenolysis through calcium signals or the phosphatidylinositol bisphosphate pathway.

Protein Phosphatase-1 & Glycogen

• Protein phosphatase-1 dephosphorylates and inactivates both phosphorylase a and phosphorylase kinase a.
• It is inhibited by inhibitor-1, which becomes active after being phosphorylated by cAMP-dependent protein kinase.
• Insulin inhibits phosphorylase b activation, enhancing glucose uptake and increasing glucose 6-phosphate, which inhibits phosphorylase kinase.

Glycogen Synthase Regulation

• Like phosphorylase, glycogen synthase has phosphorylated and nonphosphorylated forms.
• Glycogen synthase b is inactive and gets phosphorylated.
• Two protein kinases are dependent or calmodulin-dependent.
• Insulin promotes glycogenesis and inhibits glycogenolysis, increasing glucose 6-phosphate concentrations to activate glycogen synthase.
• Protein phosphatase-1, controlled by cAMP-dependent protein kinase, dephosphorylates glycogen synthase b.

Conclusion to Glycogen Metabolism

• Glycogen synthase and phosphorylase are reciprocally regulated; cAMP concentrations control these actions.
• Protein phosphatase-1 is inhibited by cAMP-dependent protein kinase via inhibitor-1, affecting overall glycogen metabolism.
• Key enzymes are reversibly phosphorylated on multiple sites by separate factors, which modifies their sensitivity.

Clinical Aspects

• Glycogen storage diseases are inherited disorders involving abnormal glycogen regulation.
• Deficiencies in adenyl kinase and cAMP-dependent protein kinase have been reported.
• Symptoms may be alleviated through liver transplantation.
• Glycogen mainly stores carbohydrate in the liver and muscle in mammals.
• The liver provides glucose and muscle to use metabolic fuel, and glucose forms glycogen via glycogenogenesis and it is then broken down.
• cAMP regulates glycogenolysis, and glycogenesis, and insulin affects liver and muscle reciprocally.
• Inherited enzyme deficiencies cause glycogen storage diseases.