Catabolism and Anabolism

Classification of Metabolic Pathways

Metabolic pathways are divided into two main types: catabolic (degradative) and anabolic (biosynthetic) pathways.

• Catabolic pathways: Break down complex molecules into simpler ones, releasing energy (e.g., glycolysis, fatty acid oxidation).

• Anabolic pathways: Synthesize complex molecules from simpler precursors, consuming energy (e.g., gluconeogenesis, fatty acid synthesis).

Biological Energy Production and Consumption

• Cells produce energy mainly through the oxidation of nutrients, capturing energy in the form of ATP (adenosine triphosphate).

• Energy is consumed in biosynthetic reactions, active transport, and mechanical work.

ATP: Favorable Cleavage and Cellular Stability

• ATP hydrolysis is highly exergonic due to relief of electrostatic repulsion, resonance stabilization of products, and increased entropy:

• Despite its high energy, ATP is not spontaneously hydrolyzed in cells due to kinetic barriers and enzyme regulation.

ATP Coupling to Drive Unfavorable Reactions

• ATP hydrolysis can be coupled to endergonic reactions to make them favorable overall.

Example: Glucose phosphorylation

(unfavorable) (favorable) Overall:

• The free energy change for the overall process is the sum of the individual reactions.

Cofactors in Metabolism

• Cofactors such as NAD+, FAD, Coenzyme A, and biotin play essential roles in metabolic reactions as electron carriers or group transfer agents.

Links Between Catabolism and Anabolism

• Intermediates from catabolic pathways often serve as precursors for anabolic pathways (e.g., pyruvate, acetyl-CoA).

Carbohydrate Metabolism

Glycolysis: Overview and Oxygen Requirement

• Glycolysis is the metabolic pathway that converts glucose to pyruvate.

• It does not require oxygen (anaerobic process).

Stoichiometry of Glycolysis

• One molecule of glucose (6C) is split into two molecules of pyruvate (3C each) via a series of enzyme-catalyzed steps.

Role and Origin of NAD+ in Glycolysis

• NAD+ acts as an electron acceptor, being reduced to NADH during glycolysis.

• NAD+ is derived from the vitamin niacin (vitamin B3).

Fate of NADH and Pyruvate

• Aerobic conditions: NADH is reoxidized via the electron transport chain; pyruvate enters the mitochondria for further oxidation (citric acid cycle).

• Anaerobic conditions: NADH is reoxidized by reducing pyruvate to lactate (in animals) or ethanol (in yeast), regenerating NAD+.

The Cori Cycle

• The Cori cycle describes the metabolic cooperation between muscle and liver during anaerobic glycolysis.

• Lactate produced in muscle is transported to the liver, converted back to glucose via gluconeogenesis, and returned to muscle.

Oxygen Levels and Pyruvate Fate in Prokaryotes and Eukaryotes

• In prokaryotes, pyruvate can be fermented or oxidized depending on O2 availability.

• In eukaryotes, pyruvate is transported into mitochondria for aerobic metabolism or reduced to lactate anaerobically.

Glycolysis

Enzymes, Substrates, and Products

• Glycolysis involves 10 enzymes, each catalyzing a specific step:

Substrate-Level Phosphorylation

• Direct synthesis of ATP from ADP by transfer of a phosphate group from a high-energy intermediate.

• Occurs at steps catalyzed by phosphoglycerate kinase and pyruvate kinase.

Cofactors in Glycolysis

• Key cofactors include Mg2+ (for kinases), NAD+ (for dehydrogenase), and ADP/ATP.

ATP Yield in Glycolysis

• Total ATP produced: 4 ATP (2 per triose), but 2 ATP are consumed in early steps.

• Net ATP gain: 2 ATP per glucose molecule.

Final Products of Glycolysis

• 2 Pyruvate, 2 ATP (net), 2 NADH, and 2 H2O per glucose.

Regulation of Glycolysis

Dual Role of Glycolysis

• Provides ATP for energy and intermediates for biosynthetic pathways.

Regulation of Glycolytic Flux

• Regulated at three irreversible steps: hexokinase, phosphofructokinase-1 (PFK-1), and pyruvate kinase.

• Regulation occurs via allosteric effectors, covalent modification, and changes in enzyme expression.

Control of Regulated Enzymes

• Hexokinase: Inhibited by its product, glucose-6-phosphate.

• PFK-1: Activated by AMP, ADP, and fructose-2,6-bisphosphate; inhibited by ATP and citrate.

• Pyruvate kinase: Activated by fructose-1,6-bisphosphate; inhibited by ATP and alanine.

Glycolysis and Cancer

• Cancer cells exhibit increased glucose uptake and glycolysis (Warburg effect).

• Key enzymes affected include hexokinase and PFK-1.

Hepatic Fructose and Galactose Pathways

• Fructose and galactose are converted to intermediates of glycolysis in the liver.

• Fructose enters as dihydroxyacetone phosphate and glyceraldehyde; galactose enters as glucose-6-phosphate.

Fructose Intolerance

• Caused by deficiency of aldolase B, leading to accumulation of fructose-1-phosphate and hypoglycemia.

Gluconeogenesis

Physiological Significance

• Gluconeogenesis synthesizes glucose from non-carbohydrate precursors, maintaining blood glucose during fasting.

Cori Cycle and Gluconeogenesis

• Lactate from muscle is converted to glucose in the liver via gluconeogenesis, completing the Cori cycle.

Precursors and Entry Points

• Major precursors: lactate, alanine, glycerol, and propionate.

• Entry points: pyruvate, dihydroxyacetone phosphate, and oxaloacetate.

Fatty Acids and Glucose Synthesis

• Fatty acids (except odd-chain) cannot serve as glucose precursors because their catabolism yields acetyl-CoA, which cannot be converted to pyruvate or oxaloacetate in animals.

Thermodynamics and Need for Gluconeogenesis

• Some glycolytic steps are irreversible; gluconeogenesis uses bypass reactions to overcome these barriers.

• Reciprocal regulation prevents futile cycling between glycolysis and gluconeogenesis.

Irreversible Steps and Bypass Reactions

Organs and Cellular Location

• Occurs mainly in the liver (and kidney cortex).

• Cellular location: mitochondria and cytosol.

Role of Biotin

• Biotin is a coenzyme for carboxylase enzymes (e.g., pyruvate carboxylase), facilitating CO2 transfer.

Regulation of Gluconeogenesis

Energetic Cost

• Gluconeogenesis is energetically expensive: 6 high-energy phosphate bonds (4 ATP, 2 GTP) are consumed per glucose synthesized.

Key Regulation Points

• Regulated at fructose-1,6-bisphosphatase, pyruvate carboxylase, and PEP carboxykinase.

• Allosteric and hormonal regulation ensures reciprocal control with glycolysis.

Role of Acetyl-CoA

• Acetyl-CoA activates pyruvate carboxylase, signaling abundant energy and promoting gluconeogenesis.

Hormonal Regulation

• Insulin: Inhibits gluconeogenesis.

• Glucagon and epinephrine: Stimulate gluconeogenesis during fasting or stress.

Effect of Ethanol Metabolism

• Ethanol metabolism increases NADH, inhibiting gluconeogenesis by altering redox balance and depleting precursors.

Pentose Phosphate Pathway (PPP)

Oxidative vs. Non-Oxidative Branches

• Oxidative branch: Generates NADPH and ribulose-5-phosphate from glucose-6-phosphate.

• Non-oxidative branch: Interconverts sugars (e.g., ribose-5-phosphate, fructose-6-phosphate) for nucleotide synthesis or glycolysis.

Key Enzymes and Cofactors

• Oxidative: Glucose-6-phosphate dehydrogenase (G6PDH), 6-phosphogluconate dehydrogenase.

• Non-oxidative: Transketolase (requires thiamine), transaldolase.

Key Intermediates

• Ribulose-5-phosphate, ribose-5-phosphate, xylulose-5-phosphate, sedoheptulose-7-phosphate.

Reduction Reactions

• NADP+ is reduced to NADPH during the oxidative phase, providing reducing power for biosynthesis and antioxidant defense.

Regulation of the Pentose Phosphate Pathway

Regulation Point and Mode

• Key regulatory enzyme: Glucose-6-phosphate dehydrogenase (G6PDH).

• Regulated by NADP+ (activator) and NADPH (inhibitor).

Roles of NADPH and Ribose-5-Phosphate

• NADPH: Used in fatty acid synthesis, glutathione reduction, and detoxification reactions.

• Ribose-5-phosphate: Precursor for nucleotide and nucleic acid synthesis.

Meeting Cellular Needs

• The pathway can adjust flux through oxidative and non-oxidative branches to meet varying demands for NADPH and ribose-5-phosphate.

Pentose Phosphate Pathway and G6PDH Defects

Protection Against Oxidants

• NADPH produced by the PPP is essential for maintaining reduced glutathione, which protects cells from oxidative damage.

Diseases from PPP Enzyme Defects

• G6PDH deficiency: Leads to hemolytic anemia due to impaired antioxidant defense, especially under oxidative stress (e.g., certain drugs, fava beans).

Impact of Nutritional Deficiencies

• Deficiency of vitamins (e.g., thiamine for transketolase) can impair the non-oxidative branch of the PPP.