chp15 metabolism

UNIVERSITY OF WATERLOO

FACULTY OF APPLIED HEALTH SCIENCES

Chapter 15: Metabolism: Basic Concepts and Design

Introduction to Metabolism

• ATP:

  • Identified as the currency of metabolism.

Energy from Food

Stages of Energy Extraction

• Stage 2 and Stage 3 of Energy from Food:

  • Involves the digestion process (discussed in Chapter 14).

  • Small molecules are processed into key molecules, particularly acetyl CoA (formed by acetate + CoA).

  • Complete oxidation of acetyl CoA results in the production of ATP.

Metabolism and Energy Generation

Energy Needs

• Energy is crucial for various cellular activities:

  • Movement:

  • Muscle contraction.

  • Cellular movement.

  • Active transport:

  • Transport of molecules and ions.

  • Biosynthesis:

  • The process of building complex molecules from simpler ones.

• Ultimate Energy Source:

  • All energy can trace back to sunlight, captured by phototrophs.

  • Humans and many other organisms are classified as chemotrophs, obtaining energy from oxidizing carbon fuels.

• Energy Currency:

  • Life utilizes ATP to synchronize energy release with energy utilization.

  • Oxidation of carbon fuels produces ATP.

Metabolic Pathways

Definitions and Examples

• Metabolic Pathways:

  • Describe stepwise reactions that either break down or synthesize molecules.

  • Reaction types are limited and often feature common intermediates.

  • Defined by specific substrates converting to defined endpoints.

  • Examples on conversion of Glucose:

  • Glucose to pyruvate.

  • Glucose to acetyl-CoA.

  • Glucose to CO2, water, and ATP.

Intermediary Metabolism

• Pathways Interaction:

  • All reactions within a cell are considered Intermediary Metabolism.

  • Traditionally studied in isolation to identify mechanisms, understand regulation, and evaluate pathway links at interaction points.

• Systems Biology:

  • An emerging field that studies interconnected pathways simultaneously.

  • Relies on advanced omic analyses.

  • Requires comprehensive understanding of metabolism.

Types of Metabolic Pathways

Categories

• Catabolic Pathways (Breakdown):

  • Convert energy from fuel into ATP.

  • Example: Glycolysis.

• Anabolic Pathways (Construction):

  • Require energy for synthesis.

  • Example: Gluconeogenesis.

  • Catabolic-related anabolic pathways often share enzymes and reactions.

• Key Reactions:

  • Certain regulated and irreversible reactions differentiate distinct pathways.

Amphibolic Pathways

• Definition:

  • Pathways capable of functioning as either catabolic or anabolic depending on the energy status of the cell.

• Example:

  • TCA Cycle:

  • Converts acetyl-CoA to energy while also providing carbon backbones for synthesis processes.

Thermodynamics of Metabolic Pathways

• Each reaction within a pathway must be specifically favorable regarding thermodynamics.

• Coupling Reactions:

  • Unfavorable reactions can occur by coupling them with more favorable reactions.

• Example of Glucose Phosphorylation:

  • I: $ext{Glc} + ext{Pi} <br>ightarrow ext{Glc-6-P} + ext{H}_2 ext{O}$

  • $ext{ΔG} = +13.8 ext{ kJ/mol}$

  • II: $ext{ATP} + ext{H}_2 ext{O} <br>ightarrow ext{ADP} + ext{Pi}$

  • $ext{ΔG} = -30.5 ext{ kJ/mol}$

  • Net Reaction:

  • $ext{Glc} + ext{ATP} <br>ightarrow ext{Glc-6-P} + ext{ADP}$

  • $ext{ΔG} = -16.7 ext{ kJ/mol}$

ATP and Energy

High-Energy Phosphates

• Phosphoryl groups in cellular compounds:

  • Variations in energy outputs of different types of phosphoryl groups:

  • 'Low'-energy phosphoryl group:

  • Example: AMP hydrolysis results in $-14.2 ext{ kJ/mol}$.

  • 'High'-energy phosphoryl groups:

  • ADP hydrolysis results in $-30.5 ext{ kJ/mol}$.

  • ATP hydrolysis also results in $-30.5 ext{ kJ/mol}$.

Factors Influencing Energy Release

• Electrostatic Repulsion:

  • At physiological pH (7.4), phosphates carry negative charges.

  • Triphosphate of ATP carries four negative charges leading to repulsion.

• Resonance Stabilization:

  • Refers to the ability to share electrons across molecules, enhancing stability.

  • Individual orthophosphate (Pi) allows for better electron sharing compared to anhydride bond in ATP.

• Increase in Entropy:

  • Hydrolysis of ATP results in two molecules being formed, thus increasing disorder/entropy.

• Stabilization due to Hydration:

  • Water molecules can hydrogen bond to ADP and Pi more effectively than ATP, enhancing stability and inhibiting reverse reactions.

Phosphoryl Transfer Reactions

• Definition:

  • Phosphoryl-transfer refers to the ability to transfer phosphate groups.

• ATP acts as an intermediate carrier of phosphoryl groups due to its phosphoryl-transfer potential.

Clinical Insights on Exercise

• Muscle ATP Levels:

  • Resting muscle [ATP] averages approximately 4 mM.

  • [Creatine phosphate] levels can reach approximately 25 mM.

• Energy Sources During Muscle Activity:

  • Muscle ATP is rapidly utilized during exercise.

  • Creatine phosphate acts as a rapid source of energy due to its high phosphoryl-transfer potential.

• Buffers exist to regenerate ATP but eventually deplete creatine phosphate, leading to increased anaerobic support followed by a need for aerobic respiration.

Regulatory Mechanisms of Metabolism

Overview

• Metabolism is regulated primarily in three ways:

  • Enzyme Amount Regulation:

  • Variation in enzyme quantities based on metabolic needs.

  • Gene Expression Changes:

  • Upregulating or downregulating gene expression for enzyme production.

  • Enzyme Degradation:

  • Proteases play a key role in regulating enzyme levels.

  • Enzyme Activity Regulation:

  • Achieved through allosteric regulation and covalent modifications like phosphorylation.

  • Second Messenger Regulatory Systems:

  • Substrate Accessibility:

  • Controlled through compartmentalization of reactions in specific cell locations.

  • Flux between these compartments is tightly regulated.