Metabolism and Glycolysis Overview

The Central Role of Glucose in Metabolism

• Glucose is the primary energy source for most cells in the body.
• It plays a central role in metabolic pathways.
• The breakdown of glucose is essential for ATP (energy) production.

Glycolysis

• Glycolysis is the first stage of glucose metabolism.
• It occurs in the cytoplasm of cells.
• It is a 10-step process that breaks down glucose into pyruvate.
• There are three irreversible steps that are regulated:
  • Phosphorylation of glucose
  • Phosphorylation of fructose-6-phosphate
  • Transfer of a phosphate group from PEP to ATP to produce pyruvate
• Two types of glycolysis:
  • Aerobic glycolysis: This happens in the presence of oxygen and results in pyruvate.
  • Anaerobic glycolysis: Lack of oxygen results in lactate production.
• Net synthesis: 2 ATP molecules

Gluconeogenesis, Glycogenolysis, and Glycogenesis

• Gluconeogenesis: Synthesis of glucose from non-carbohydrate sources (e.g. pyruvate, lactate, glycerol, and amino acids).
• Glycogenolysis: Breakdown of glycogen into glucose.
• Glycogenesis: Synthesis of glycogen from glucose.

Hexose Monophosphate Pathway (HMP)

• Also known as the pentose phosphate pathway (PPP) or phosphogluconate pathway.
• Occurs in the cytosol.
• It is an alternative pathway for glucose metabolism.
• Produces:
  • Reducing equivalents (NADPH) for reductive biosynthesis
  • Ribose-5-phosphate for nucleotide synthesis
• No net energy production or consumption.
• Two main phases:
  • Oxidative phase: generates NADPH and produces ribulose-5-phosphate
  • Non-oxidative phase: Interconverts sugars with different carbon lengths using multiple enzymes.

Metabolism of Other Carbohydrates (fructose, galactose)

• Fructose:
  • Phosphorylated to fructose-6-phosphate by hexokinase.
  • Can enter the glycolytic pathway at the second step.
• Galactose:
  • Needs to be converted to glucose-1-phosphate before entering glycolysis.
  • Galactose is phosphorylated to galactose-1-phosphate by galactokinase.
  • Galactose-1-phosphate is then converted to glucose-1-phosphate by galactose-1-phosphate uridyltransferase (GALT).

Ketone Body Metabolism

• Ketone bodies are produced when there’s an excess of glycerol and fatty acids compared to carbohydrates and proteins.
• They are synthesized from acetyl-CoA.
• They become a major energy source particularly in type I diabetic individuals who lack insulin.
• They are oxidized to produce ATP and H+, making the cellular environment acidic.
• Excessive ketone bodies lead to diabetic ketoacidosis.

Glycogen Metabolism Overview

• Glycogen is the primary storage form of glucose in animals.
• In the liver, glucose-6-phosphate can be converted to glucose and released into the bloodstream.
• Glycogenesis (glycogen synthesis):
  • Occurs when there’s an excess of glucose.
  • Glucose is converted to glucose-6-phosphate and then glucose-1-phosphate.
  • UDP-glucose is the precursor for glycogen synthesis.
  • Catalyzed by glycogen synthase and branching enzyme.
• Glycogenolysis (glycogen breakdown):
  • Occurs when glucose levels are low.
  • Catalyzed by glycogen phosphorylase and debranching enzyme.
  • Glucose-1-phosphate is then converted to glucose-6-phosphate.

Glycogenesis: Step-by-Step Breakdown

• Step 1: Phosphorylation:
  • Glucose enters the cells via GLUT transporters (GLUT2 in hepatocytes and GLUT4 in myocytes and adipocytes).
  • It is phosphorylated to glucose-6-phosphate by hexokinase (muscle) or glucokinase (liver).
• Step 2: Isomerization:
  • Glucose-6-phosphate is converted to glucose-1-phosphate by phosphoglucomutase.
• Step 3: UDP-Glucose formation:
  • Glucose-1-phosphate and UTP react to form UDP-glucose and pyrophosphate.
  • Catalyzed by UDPG pyrophosphorylase.
  • Hydrolysis of pyrophosphate by pyrophosphatase favors the forward reaction.
• Step 4: Chain initiation:
  • Glycogenin acts as a primer for initial glucose attachment.
  • UDP-glucose attaches to the tyrosine residue of glycogenin.
• Step 5: Chain Extension:
  • Glycogen synthase catalyzes the formation of glycosidic bonds between UDP-glucose and the terminal glucose of glycogen.
  • UDP is released.
  • Glucose is added to the non-reducing end of the glycogen chain.
• Step 6: Branching:
  • Branching enzyme transfers glucose residues from the non-reducing end of the chain, forming alpha-1,6 glycosidic bonds.
  • This creates branches in the glycogen molecule.

Key Enzymes in Glycogen Metabolism

• Glycogen synthase: Catalyzes glycogen synthesis.
• Branching enzyme: Creates branches in the glycogen molecule.
• Glycogen phosphorylase: Catalyzes glycogen breakdown.
• Debranching enzyme: Removes branches from the glycogen molecule.
• Hexokinase/Glucokinase: Phosphorylates glucose.
• Phosphoglucomutase: Converts glucose-6-phosphate to glucose-1-phosphate.
• UDPG pyrophosphorylase: Catalyzes the formation of UDP-glucose.