Gluconeogenesis and Glycogen Metabolism

Gluconeogenesis and Glycogen Metabolism

• Gluconeogenesis is an anabolic pathway synthesizing glucose from non-glucose precursors like lactate, amino acids, and glycerol
• Location: The pathway begins in the mitochondrion and ends in the cytoplasm

Pathway Reaction Steps: Gluconeogenesis

• Gluconeogenesis necessitates six enzymes to bypass the irreversible steps of glycolysis: hexokinase, phosphofructokinase (PFK), and pyruvate kinase, as well as the remaining glycolytic steps
• The gluconeogenic pathway is not simply the reverse of glycolysis

Bypass for Pyruvate Kinase

• The bypass includes the enzyme pyruvate carboxylase
• Pyruvate carboxylase: Carboxylation of pyruvate produces oxaloacetate (OAA); requires ATP
• Malate dehydrogenase (mitochondrial): Reduction of OAA produces malate, which can be transported out of the mitochondrion
• Malate dehydrogenase (cytoplasmic): Oxidation of malate in the cytoplasm regenerates OAA and nicotine adenine dinucleotide
• Phosphoenolpyruvate carboxykinase: Decarboxylation of OAA produces phosphoenolpyruvate; phosphorylation uses GTP instead of ATP

Bypass for Phosphofructokinase

• Fructose 1,6-bisphosphatase dephosphorylates fructose 1,6-bisphosphate, yielding fructose 6-phosphate and inorganic phosphate

Bypass for Hexokinase

• Glucose-6-phosphatase dephosphorylates glucose 6-phosphate (G6P), leading to free glucose release into the bloodstream

Unique Characteristics: Gluconeogenesis

• Energy Cost: 6 ATP
• Carbon Skeletons Sources: amino acids, lactate, and glycerol, but not acetyl-CoA

Glycogen Metabolism: Glucose 6-Phosphate to and from Glycogen

• Glycogen function: Provides a rapid source of glucose
• Glycogen Synthesis (Glycogenesis): it involves creation of an activated precursor, then precursor is linked into a linear growing polymer.
• Glycogenolysis: relatively simple, and only one enzyme is needed to release most of the glucose from glycogen

Three Reactions Create the Glucose Donor Uridine Diphosphate Glucose

• Phosphoglucomutase: G6P converts to glucose 1-phosphate (G1P) in a reversible reaction
• Uridine diphosphate glucose pyrophosphorylase: G1P esterifies with uridine triphosphate, yielding uridine diphosphate (UDP)-glucose and pyrophosphate
• Pyrophosphatase: It produces inorganic phosphate, driving glycogen synthesis

Two Reactions Use Uridine Diphosphate Glucose to Build Glycogen

• Glycogen synthase is responsible for adding glucose units from UDP-glucose to the C4 terminus of an amylose chain via an α-1,4 linkage
• Branching Enzyme: Removes terminal residues from an 11-residue amylose chain and reattaches them via α-1,6 linkage to form a branch point

One Reaction Depolymerizes Glycogen

• Glycogen phosphorylase cleaves the glycosidic α-1,4 bond with inorganic phosphate producing G1P monomers and requiring pyridoxal 5′-phosphate as a cofactor

One Enzyme Catalyzes Two Reactions to Debranch Glycogen

• Debranching enzyme contains a glucosyltransferase and a glucosidase, which remove branches in glycogen

Glycogen Metabolism Key Facts

• Synthesis and degradation flow through G1P in equilibrium with G6P
• The D form of glycogen synthase is allosterically activated by G6P for quick response to changes in blood glucose
• The highly branched structure allows for rapid release of glucose
• UDP-glucose helps detoxify waste products and drugs
• Two high-energy bonds are consumed for each glucose stored in glycogen
• cAMP-directed phosphorylation reciprocally regulates glycogen synthase (inhibition) and phosphorylase (activation)

Regulated Reactions: Regulation of Gluconeogenesis

• Gluconeogenesis and glycolysis are reciprocally regulated.
• Regulation occurs at the pyruvate carboxylase reaction, requiring acetyl-CoA as a positive allosteric effector
• Overexpression of pyruvate carboxylase in mice results in diabetes

Unique Characteristics: Glucose Regulation

• Energy Cost: 4 ATP + 2 GTP
• Regulation of pyruvate carboxylase and fructose 1,6-bisphosphatase (F1,6-BP) during gluconeogenesis.

Regulation of Glycogen Metabolism

• Glycogen synthesis is regulated by the number and size of molecules and the rate of polymerization
• Glycogen synthesis stops when glycogen synthase separates from the glycogenin primer

Interface with Other Pathways

• It has several interfaces with other pathways

Related Diseases

• Genetic deficiencies in glycogen metabolism lead to abnormalities in glycogen amount/structure and other metabolic issues
• Glucose 6-Phosphatase Deficiency: A deficiency leads to glycogen storage disease, lactic acidosis, ketoacidosis, hyperlipidemia, abnormal platelet, and hyperuricemia (Gout).