Introduction to Metabolism

Principles of Energy Flow

Metabolism encompasses all chemical reactions that occur within living organisms to maintain life. These reactions are organized into metabolic pathways, which are sequences of enzymatically catalyzed steps. The flow of energy through these pathways is essential for cellular function and survival.

• Catabolism: The breakdown of complex molecules into simpler ones, releasing energy.

• Anabolism: The synthesis of complex molecules from simpler ones, requiring energy input.

• Both catabolic and anabolic pathways typically proceed through three stages: (1) breakdown of macromolecules, (2) conversion to simple intermediates, (3) final oxidation or biosynthesis.

ATP (Adenosine Triphosphate) serves as the universal energy currency, coupling energy-releasing and energy-consuming processes.

Types of Biochemical Reactions

• There are five main types of biochemical reactions in metabolism:

  1. Oxidation-Reduction (Redox) reactions

  2. Group Transfer reactions

  3. Hydrolysis reactions

  4. Lyase reactions (addition or removal of groups to form double bonds)

  5. Isomerization reactions

• Oxidation and reduction are especially important for energy production, as they involve the transfer of electrons and are central to processes like cellular respiration.

Metabolic Control Mechanisms

• Metabolic pathways are tightly regulated to meet cellular needs and maintain homeostasis.

• Control mechanisms include allosteric regulation, covalent modification (e.g., phosphorylation), and changes in gene expression.

Key Metabolic Pathways

Glycolysis

Glycolysis is the central pathway for glucose catabolism, converting glucose into pyruvate with the net production of ATP and NADH.

• Occurs in the cytoplasm.

• Net reaction:

• Key intermediates: glucose-6-phosphate, fructose-1,6-bisphosphate, phosphoenolpyruvate.

Gluconeogenesis

Gluconeogenesis is the process of synthesizing glucose from non-carbohydrate precursors, essentially reversing glycolysis with some bypass steps.

• Occurs mainly in the liver.

• Important for maintaining blood glucose during fasting.

Entry of Other Sugars

• Other sugars (e.g., fructose, galactose) can enter glycolysis after conversion to intermediates such as glucose-6-phosphate or fructose-6-phosphate.

Pyruvate Oxidation

Pyruvate, the end product of glycolysis, is transported into mitochondria and oxidized to acetyl-CoA by the pyruvate dehydrogenase complex.

Citric Acid Cycle (Krebs Cycle)

The citric acid cycle is a series of reactions that oxidize acetyl-CoA to CO2, generating NADH, FADH2, and GTP/ATP.

• Occurs in the mitochondrial matrix.

• Key intermediates: citrate, α-ketoglutarate, succinate, oxaloacetate.

Electron Transport Chain (ETC) and Oxidative Phosphorylation

The ETC consists of four protein complexes embedded in the inner mitochondrial membrane. Electrons from NADH and FADH2 are transferred through these complexes, ultimately reducing O2 to H2O.

• Electron flow drives the pumping of protons across the membrane, creating a proton motive force.

• ATP synthase uses this proton gradient to synthesize ATP from ADP and Pi.

• Reactive oxygen species (ROS) can be generated as byproducts, potentially causing cellular damage.

Carbohydrate Metabolism

Glycogen and Glycogen Metabolism

Glycogen is a branched polymer of glucose that serves as a storage form of energy in animals.

• Glycogenolysis: Breakdown of glycogen to glucose-1-phosphate.

• Glycogenesis: Synthesis of glycogen from glucose.

• Regulated by hormones such as insulin and glucagon.

Pentose Phosphate Pathway (PPP)

The PPP is an alternative pathway for glucose oxidation, generating NADPH and ribose-5-phosphate for biosynthetic reactions.

• NADPH is essential for reductive biosynthesis and antioxidant defense.

Disorders of Glycogen Metabolism

• Genetic defects in enzymes of glycogen metabolism can lead to glycogen storage diseases (e.g., von Gierke's disease, Pompe disease).

Nitrogen and Amino Acid Metabolism

Nitrogen Fixation

Nitrogen fixation is the process by which atmospheric nitrogen (N2) is converted into ammonia (NH3), primarily by certain bacteria.

Amino Acid Biosynthesis and Degradation

• Amino acids are synthesized from key metabolic intermediates (e.g., pyruvate, oxaloacetate, α-ketoglutarate).

• Degradation of amino acids produces intermediates that enter the citric acid cycle or are used for gluconeogenesis or ketogenesis.

• Disorders can arise from defects in amino acid metabolism (e.g., phenylketonuria).

Essential vs. Non-Essential Amino Acids

• Essential amino acids must be obtained from the diet.

• Non-essential amino acids can be synthesized by the body.

• Example: Cysteine is unique due to its sulfur content.

Urea Cycle

The urea cycle disposes of excess nitrogen by converting ammonia to urea for excretion.

• Transamination reactions transfer amino groups between amino acids and α-keto acids, facilitating nitrogen disposal.

Nucleotide Metabolism

Salvage and De Novo Synthesis

• Nucleotides can be synthesized de novo from simple precursors or salvaged from degraded nucleic acids.

• Purine and pyrimidine synthesis require important cofactors such as pyridoxal phosphate (PLP) and tetrahydrofolate (THF).

• Both ribonucleotides and deoxyribonucleotides are produced for RNA and DNA synthesis, respectively.

Lipid Metabolism

Fatty Acids and Their Transport

• Fatty acids are transported in the blood bound to albumin or as part of lipoproteins.

• Transport into mitochondria for oxidation requires the carnitine shuttle.

Fatty Acid Oxidation and Energy Generation

• Fatty acid β-oxidation occurs in the mitochondrial matrix, producing acetyl-CoA, NADH, and FADH2.

• Acetyl-CoA enters the citric acid cycle for further energy extraction.

Energetics of Metabolism

ATP Production and Free Energy Changes

• ATP is produced at several points in metabolism: substrate-level phosphorylation (glycolysis, citric acid cycle) and oxidative phosphorylation (ETC).

• Large negative changes in free energy () drive metabolic reactions forward.

Proton Generation and Electron Flow

• Protons are generated and translocated during electron transport, creating the proton motive force used for ATP synthesis.

• Electron flow through the ETC is central to energy transformation in cells.

Summary Table: Key Metabolic Pathways and Their Features

General Study Goals

• Understand the main objectives of metabolism, especially ATP production.

• Be able to explain how ATP is generated in different pathways and the significance of electron and proton movement.

• Focus on the big picture: major pathways, key intermediates, and their roles in cellular metabolism.

Example Application: If given a metabolic disorder, be able to trace which pathway is affected, predict the metabolic consequences, and suggest possible compensatory mechanisms.