Cellular Metabolism: Mechanisms, Regulation, and Integration of Biochemical Pathways

1. Introduction

Metabolism is the sum total of all chemical reactions that occur within a living cell or organism to maintain life. These reactions are essential for energy production, growth, repair, and maintaining cellular structures. Metabolic pathways are tightly regulated and interconnected, ensuring that the cell functions efficiently under various environmental conditions.

2. Types of Metabolism

Metabolism is broadly divided into two categories:

2.1 Catabolism

• Involves the breakdown of complex molecules into simpler ones.
• Releases energy, usually in the form of ATP (adenosine triphosphate).
• Examples:
• Breakdown of glucose in glycolysis.
• Degradation of fatty acids in β-oxidation.

2.2 Anabolism

• Involves the synthesis of complex molecules from simpler ones.
• Requires energy input, often from ATP.
• Examples:
• Synthesis of proteins from amino acids.
• DNA replication from nucleotides.

3. Key Components of Metabolic Reactions

3.1 Enzymes

• Biological catalysts that speed up metabolic reactions.
• Highly specific for their substrates.
• Activity is affected by pH, temperature, and inhibitors.

3.2 ATP (Adenosine Triphosphate)

• The primary energy currency of the cell.
• Energy is stored in high-energy phosphate bonds.
• Hydrolysis of ATP to ADP + Pi releases energy for cellular processes.

3.3 NAD⁺, FAD, NADP⁺

• Act as electron carriers in redox reactions.
• Essential in respiration and photosynthesis.

4. Major Metabolic Pathways

4.1 Glycolysis

• Occurs in the cytoplasm.
• Converts glucose (6C) into pyruvate (3C) molecules.
• Produces a net gain of 2 ATP and 2 NADH.
• Anaerobic (does not require oxygen).

 

4.2 Krebs Cycle (Citric Acid Cycle)

• Takes place in the mitochondrial matrix.
• Pyruvate is further broken down to release CO₂, NADH, FADH₂, and ATP.
• A central hub for catabolism of carbohydrates, fats, and proteins.

4.3 Electron Transport Chain (ETC) and Oxidative Phosphorylation

• Located in the inner mitochondrial membrane.
• Uses NADH and FADH₂ to produce a proton gradient.
• Drives ATP synthesis via ATP synthase.
• Produces up to 34 ATP molecules from one glucose.

4.4 Fermentation

• Anaerobic process.
• Converts pyruvate into lactic acid or ethanol.
• Regenerates NAD⁺ for glycolysis.

5. Anabolic Pathways

5.1 Gluconeogenesis

• Formation of glucose from non-carbohydrate sources (like amino acids).
• Important during fasting or starvation.

5.2 Lipid Biosynthesis

• Acetyl-CoA is used to synthesize fatty acids and cholesterol.
• Occurs mainly in the cytoplasm of liver cells.

5.3 Protein Synthesis

• Involves transcription and translation.
• Amino acids are assembled into polypeptides using ribosomes.

6. Regulation of Metabolism

6.1 Enzyme Regulation

• Allosteric regulation.
• Feedback inhibition.
• Covalent modification (e.g., phosphorylation).

6.2 Hormonal Regulation

• Insulin: Stimulates anabolic processes (e.g., glycogen synthesis).
• Glucagon and Epinephrine: Stimulate catabolic processes (e.g., glycogen breakdown).

6.3 Compartmentalization

• Different pathways occur in specific organelles (e.g., glycolysis in cytosol, TCA in mitochondria).

7. Integration of Metabolism

• Carbohydrate, fat, and protein metabolism are interconnected.
• For example:
• Excess glucose → stored as glycogen or converted to fat.
• Amino acids can enter the TCA cycle or be used for gluconeogenesis.

8. Metabolic Disorders

8.1 Diabetes Mellitus

• Defective insulin signaling affects glucose metabolism.
• Results in high blood glucose levels.

8.2 Phenylketonuria (PKU)

• Genetic disorder.
• Deficiency of enzyme phenylalanine hydroxylase.
• Leads to toxic buildup of phenylalanine.

8.3 Obesity and Metabolic Syndrome

• Linked to disrupted energy balance and insulin resistance.

9. Diagrams for Better Understanding

Here are the essential diagrams typically included in a textbook chapter on metabolism:

1.     Overview of Metabolism – Central map showing glycolysis, TCA cycle, ETC, lipid and protein metabolism.

2.     Glycolysis Pathway – Steps from glucose to pyruvate with ATP and NADH yields.

3.     Krebs Cycle – Circular pathway with intermediates and energy carriers.

4.     Electron Transport Chain – Mitochondrial membrane with complexes and ATP synthase.

5.     ATP Structure and Hydrolysis – High-energy phosphate bond diagram.

6.     Enzyme Function – Substrate binding and catalysis.

7.     Interconnection of Metabolic Pathways – Flow of carbon and energy across pathways.

10. Conclusion

Metabolism is a highly regulated and dynamic set of processes that ensures the survival and proper functioning of cells. Understanding metabolism provides insights into how organisms derive energy, build biomolecules, and maintain homeostasis. It also forms the foundation for understanding diseases, nutrition, and therapeutic interventions.

Multiple-choice questions (MCQs)

1. Which of the following best explains the thermodynamic favorability of ATP hydrolysis?

A. Hydrolysis increases entropy and decreases enthalpy.
B. ATP has high kinetic stability and low thermodynamic stability.
C. Hydrolysis products (ADP and Pi) are more stable due to resonance and hydration.
D. ATP has unstable sugar-phosphate bonds that readily hydrolyze.

Answer: C

2. In the electron transport chain, which complex does NOT pump protons across the inner mitochondrial membrane?

A. Complex I
B. Complex II
C. Complex III
D. Complex IV

Answer: B

3. During gluconeogenesis, which of the following enzymes bypasses the irreversible glycolytic step catalyzed by pyruvate kinase?

A. Hexokinase
B. Phosphoenolpyruvate carboxykinase (PEPCK)
C. Fructose-1,6-bisphosphatase
D. Pyruvate dehydrogenase

Answer: B

4. Which intermediate connects glycolysis, the TCA cycle, and amino acid metabolism?

A. Citrate
B. Acetyl-CoA
C. α-Ketoglutarate
D. Succinyl-CoA

Answer: C

5. In oxidative phosphorylation, the chemiosmotic hypothesis proposes that:

A. Electrons directly synthesize ATP via a redox reaction.
B. The electrochemical gradient of H⁺ across the mitochondrial membrane drives ATP synthesis.
C. ADP is phosphorylated via substrate-level phosphorylation.
D. NADH transfers a phosphate group directly to ADP.

Answer: B

6. What is the main reason why fatty acid oxidation yields more ATP per molecule than glucose oxidation?

A. Fatty acids are oxidized in the cytoplasm.
B. Each carbon in fatty acids is more reduced than in glucose.
C. Fatty acid oxidation does not require ATP.
D. Fatty acids bypass the TCA cycle entirely.

Answer: B

7. Which coenzyme is required for the decarboxylation of pyruvate in the pyruvate dehydrogenase complex?

A. NADP⁺
B. Biotin
C. Thiamine pyrophosphate (TPP)
D. Pyridoxal phosphate (PLP)

Answer: C

8. Which statement about anaplerotic reactions is TRUE?

A. They remove intermediates from the TCA cycle for biosynthesis.
B. They replenish intermediates of the TCA cycle.
C. They are specific to catabolism of lipids.
D. They generate glucose from non-carbohydrate sources.

Answer: B

9. In which organelle does the urea cycle intersect with the TCA cycle via the intermediate fumarate?

A. Cytoplasm
B. Nucleus
C. Mitochondria
D. Peroxisome

Answer: A

10. Which metabolic condition would most likely result in lactic acidosis?

A. Excess ATP production
B. Increased oxygen availability
C. Deficiency in mitochondrial oxidative phosphorylation
D. Enhanced activity of the Krebs cycle

Answer: C