🔬Biological Chemistry I Unit 7 – Glycolysis and Gluconeogenesis

Key Concepts and Definitions

• Glycolysis breaks down glucose into pyruvate through a series of enzymatic reactions
• Gluconeogenesis synthesizes glucose from non-carbohydrate precursors (lactate, amino acids, glycerol)
• ATP (adenosine triphosphate) is the primary energy currency of the cell
• NAD+ (nicotinamide adenine dinucleotide) is an essential cofactor in redox reactions
  • Oxidized form (NAD+) accepts electrons
  • Reduced form (NADH) donates electrons
• Substrate-level phosphorylation directly transfers a phosphate group from a substrate to ADP to form ATP
• Oxidative phosphorylation generates ATP through the electron transport chain and chemiosmosis
• Catabolism breaks down complex molecules into simpler ones, releasing energy
• Anabolism builds complex molecules from simpler ones, requiring energy input

Glycolysis Overview

• Glycolysis is a 10-step pathway that occurs in the cytosol of cells
• Glucose ($C_6H_{12}O_6$) is converted into two molecules of pyruvate ($CH_3COCOO^-$)
• Net yield of glycolysis is 2 ATP and 2 NADH per glucose molecule
• Glycolysis can function under anaerobic conditions
  • In the absence of oxygen, pyruvate is reduced to lactate by lactate dehydrogenase
• Glycolysis is a central pathway in cellular metabolism
  • Provides energy (ATP) and reducing power (NADH)
  • Generates precursors for biosynthetic pathways (amino acids, fatty acids)
• Key regulatory enzymes in glycolysis include hexokinase, phosphofructokinase, and pyruvate kinase

Gluconeogenesis Overview

• Gluconeogenesis is the synthesis of glucose from non-carbohydrate precursors
• Occurs primarily in the liver and to a lesser extent in the kidneys
• Key substrates for gluconeogenesis include lactate, amino acids (alanine, glutamine), and glycerol
• Gluconeogenesis is not a simple reversal of glycolysis
  • Irreversible steps in glycolysis are bypassed by alternative enzymes
• Gluconeogenesis is an energy-consuming process, requiring 6 ATP per glucose molecule synthesized
• Gluconeogenesis is crucial for maintaining blood glucose levels during fasting or prolonged exercise
• Hormones (glucagon, cortisol) and low blood glucose levels stimulate gluconeogenesis

Enzymes and Reactions

• Hexokinase/glucokinase catalyzes the phosphorylation of glucose to glucose-6-phosphate
  • Hexokinase has a low $K_m$ and is inhibited by its product (glucose-6-phosphate)
  • Glucokinase has a high $K_m$ and is not inhibited by glucose-6-phosphate
• Phosphofructokinase (PFK) catalyzes the phosphorylation of fructose-6-phosphate to fructose-1,6-bisphosphate
  • Allosterically regulated by ATP (inhibitor) and AMP (activator)
• Aldolase cleaves fructose-1,6-bisphosphate into glyceraldehyde-3-phosphate (GAP) and dihydroxyacetone phosphate (DHAP)
• Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) oxidizes GAP to 1,3-bisphosphoglycerate, reducing NAD+ to NADH
• Pyruvate kinase catalyzes the conversion of phosphoenolpyruvate (PEP) to pyruvate, generating ATP
• Phosphoenolpyruvate carboxykinase (PEPCK) catalyzes the decarboxylation and phosphorylation of oxaloacetate to PEP in gluconeogenesis
• Fructose-1,6-bisphosphatase hydrolyzes fructose-1,6-bisphosphate to fructose-6-phosphate in gluconeogenesis

Energy and Regulation

• Glycolysis is regulated to meet the cell's energy demands and maintain homeostasis
• ATP and citrate are allosteric inhibitors of phosphofructokinase, slowing glycolysis when energy is abundant
• AMP and fructose-2,6-bisphosphate are allosteric activators of phosphofructokinase, stimulating glycolysis when energy is needed
• Pyruvate kinase is allosterically inhibited by ATP and alanine, and activated by fructose-1,6-bisphosphate
• Gluconeogenesis is regulated by the availability of substrates and hormonal signals
  • Glucagon stimulates gluconeogenesis by increasing PEPCK and fructose-1,6-bisphosphatase activity
  • Insulin inhibits gluconeogenesis by decreasing the activity of these enzymes
• Reciprocal regulation of glycolysis and gluconeogenesis prevents futile cycling and maintains glucose homeostasis

Metabolic Pathways and Integration

• Glycolysis is interconnected with other metabolic pathways
  • Pyruvate can enter the citric acid cycle for further oxidation
  • Pyruvate can be converted to lactate or alanine
  • Intermediates (glucose-6-phosphate, fructose-6-phosphate) can enter the pentose phosphate pathway
• Gluconeogenesis is integrated with other metabolic processes
  • Lactate from anaerobic glycolysis in muscles is converted back to glucose in the liver (Cori cycle)
  • Amino acids from protein breakdown can be used as substrates for gluconeogenesis
  • Glycerol from lipolysis can be converted to glucose
• Glycolysis and gluconeogenesis are regulated in response to the body's nutritional state
  • During fasting, gluconeogenesis is stimulated to maintain blood glucose levels
  • After a meal, glycolysis is favored to utilize dietary glucose and store excess as glycogen

Clinical Relevance and Disorders

• Diabetes mellitus is characterized by impaired glucose metabolism and hyperglycemia
  • Type 1 diabetes results from insufficient insulin production
  • Type 2 diabetes involves insulin resistance and reduced insulin secretion
• Glycogen storage diseases are inherited disorders affecting enzymes involved in glycogen metabolism
  • Von Gierke disease (type I) is caused by a deficiency in glucose-6-phosphatase
  • Pompe disease (type II) is caused by a deficiency in lysosomal α-1,4-glucosidase
• Lactic acidosis can occur when lactate production exceeds its clearance
  • Causes include hypoxia, sepsis, and certain medications (metformin)
• Fructose intolerance is caused by a deficiency in aldolase B, leading to an accumulation of fructose-1-phosphate
• Galactosemia is caused by a deficiency in galactose-1-phosphate uridylyltransferase, resulting in an accumulation of galactose-1-phosphate

Study Tips and Exam Prep

• Create a concept map linking glycolysis, gluconeogenesis, and related pathways
• Memorize the key enzymes and their roles in glycolysis and gluconeogenesis
  • Pay attention to the irreversible steps and the enzymes that bypass them
• Understand the regulation of glycolysis and gluconeogenesis by allosteric effectors and hormones
  • Know how ATP, AMP, citrate, and fructose-2,6-bisphosphate affect phosphofructokinase
  • Recognize the effects of glucagon and insulin on gluconeogenesis
• Practice drawing the glycolysis and gluconeogenesis pathways, including substrates, products, and enzymes
• Solve problems involving the energy yield (ATP and NADH) of glycolysis and the energy cost of gluconeogenesis
• Review the clinical manifestations and underlying biochemical causes of disorders related to glucose metabolism
• Integrate your knowledge of glycolysis and gluconeogenesis with other metabolic pathways (citric acid cycle, pentose phosphate pathway, glycogen metabolism)
• Test your understanding using practice questions and past exam materials provided by your instructor