Metabolism 1.2 Energy Reactions in Cells

Homeostasis

• Definition: Regulation of the internal environment to keep it steady and relatively constant, operating as a dynamic equilibrium.

  • Failure to maintain homeostasis leads to disease.

• Levels at which homeostasis is maintained:

  • Cell level (e.g., regulation of intracellular $Ca^{2+}$).

  • Tissue level (e.g., balance between cell proliferation and cell death, apoptosis).

  • Organ level (e.g., kidney regulates water and ion concentrations in blood).

  • Organism level (e.g., maintenance of body temperature).

• Key idea: Homeostatic mechanisms exist at all organizational levels to counteract imbalances.

Plasma glucose homeostasis

• Normal reference: Plasma glucose is approximately $5\,\mathrm{mmol/L}$.

• Fed state vs fasted state (feedback control):

  • Fed state: Plasma glucose increases; pancreas releases insulin; tissues take up glucose; liver stores glucose as glycogen.

  • Fasted state: Plasma glucose decreases; pancreas releases glucagon; liver breaks down glycogen and releases glucose into blood.

• Hormonal players:

  • Insulin promotes glucose uptake/storage.

  • Glucagon promotes glucose release from the liver.

• Concept: Homeostatic control of plasma glucose involves insulin and glucagon to keep blood glucose around $5\,\mathrm{mM}$.

Body fluid compartments

• Total body water (for a 70 kg person): Approximately $42\,\mathrm{L}$.

• Major compartments:

  • Intracellular fluid (ICF): Approximately $28\,\mathrm{L}$ (inside cells).

  • Extracellular fluid (ECF): Approximately $14\,\mathrm{L}$ (outside cells).

  • Interstitial fluid: Fluid found between cells.

  • Plasma: Fluid circulating within blood vessels.

• Balance principle: Fluid gain must balance fluid loss to maintain optimal levels.

Blood: functions

• Transport:

  • Oxygen, nutrients for utilization, storage, and interconversion.

  • Disposal of wastes ($\mathrm{CO*2}$, urea, lactic acid).

• Signalling: Hormones.

• Coagulation.

• Immune functions.

• Homeostasis roles:

  • Regulation of blood pH.

  • Regulation of core body temperature.

  • Hydraulic functions (blood contributes to pressure and volume).

Metabolite measurements in blood

• Rationale:

  • Tissue biopsies can be difficult/expensive.

  • Blood tests are readily obtainable and relatively inexpensive.

  • Abnormal concentrations help indicate problems.

• Typical fasting plasma concentrations (mmol/L):

  • Glucose: $5$

  • Amino acids: $3$

  • Triacylglycerols: $2$

  • Cholesterol: $5$

  • Fatty acids: $0.5$

  • Lactic acid: <1

  • Total $\mathrm{CO<em>2}$ (mostly $\mathrm{HCO</em>3}^-$): $27$

  • Urea: $5$

  • $\mathrm{NH*3}$: $0.025$

• Notes:

  • Values are typical, not absolute.

  • Normal ranges vary with age/sex.

  • Laboratories publish guideline ranges; always check units.

Energy: the capacity to do work

• Living cells require energy for:

  • Biosynthetic work: Synthesis of cellular components.

  • Transport work: Movement of ions/nutrients across membranes.

  • Mechanical work: Muscle contraction.

  • Electrical work: Nervous conduction.

  • Osmotic work: Kidney functions.

• Energy forms (interconvertible):

  • Chemical bond energy, gravity, elastic potential, nuclear, magnetic, light, heat, electrical, sound.

• Core idea: All cells use chemical bond energy to power energy-requiring activities.

Chemical bond energy

• All chemical reactions involve:

  • Breaking bonds (releases energy).

  • Making bonds (consumes energy).

• Exergonic reactions: Release more energy than used.

• Endergonic reactions: Require more energy than released.

Free energy (Gibbs free energy, G)

• Definition: Free energy (G) is the energy released in an exergonic reaction that is available to do work. Exergonic reactions occur spontaneously and drive endergonic reactions.

• Free energy change ($\Delta G$):

  • If \Delta G < 0: Net loss of energy; reaction can occur spontaneously.

  • Example: $\mathrm{ATP} + \mathrm{H<em>2O} \rightarrow \mathrm{ADP} + \mathrm{P</em>i}$.

  • If \Delta G > 0: Reaction requires input of free energy and must be coupled to an an exergonic reaction.

  • Example: $\mathrm{ADP} + \mathrm{P<em>i} \rightarrow \mathrm{ATP} + \mathrm{H</em>2O}$.

Cellular metabolism: overview

• Metabolic pathways: Form an integrated network with:

  • Start points, intermediates (metabolites), end points, and interconnections.

• Reference: iPath for interactive exploration.

Two main types of metabolic reactions

• Catabolic reactions:

  • Break down larger molecules into smaller ones.

  • Release large amounts of free energy (exergonic).

  • Oxidative – release H atoms; provide reducing power.

  • Most cellular respiration reactions are catabolic.

• Anabolic reactions:

  • Synthesize larger molecules from smaller ones.

  • Use energy (as ATP) released from catabolism (endergonic).

  • Reductive – use H atoms released in catabolism.

• Mnemonic: Break create energy; Make require energy.

Oxidation and redox chemistry

• Fuel energy release: Chemical bond energy of fuels is released by oxidation reactions.

• Oxidation: Removal of electrons ($\text{e}^-$) or removal of H atoms ($\mathrm{H}^+ + \mathrm{e}^-$).

• Oxidative phosphorylation: Fuel is oxidized to $\mathrm{CO<em>2}$ and $\mathrm{H</em>2O}$ with release of energy to generate ATP.

• REDOX REACTIONS: All oxidation reactions are accompanied by reductive reactions; coupling mechanism known as REDOX REACTIONS, summarized as OIL RIG.

  • OIL RIG: Oxidation Is Loss, Reduction Is Gain.

H-carrier molecules (reducing power carriers)

• Role: Carriers of reducing power for ATP production or biosynthesis.

• Constant concentration: Total concentration of oxidized and reduced carriers remains constant; reduced carriers are quickly re-oxidized.

• Major carriers:

  • Nicotinamide adenine dinucleotide: $\text{NAD}^+ \quad /\quad \text{NADH} + \text{H}^+$ .

  • Nicotinamide adenine dinucleotide phosphate: $\text{NADP}^+ \quad /\quad \text{NADPH} + \text{H}^+$.

  • Flavin adenine dinucleotide: $\text{FAD} \quad /\quad \text{FADH}_2$ .

• Vitamins:

  • Riboflavin ($\mathrm{B*2}$) provides flavin.

  • Niacin ($\mathrm{B*3}$) provides nicotinamide.

Oxidation of fuels and ATP generation

• Process:

  • Fuel molecules are oxidized to $\mathrm{CO*2}$.

  • H atoms transferred to carrier molecules (reduced carriers).

  • Electrons transferred to $\mathrm{O*2}$.

  • Free energy from electron transport is used to synthesize ATP.

  • Carrier molecules become re-oxidized (lose H atoms).

Overview of catabolism (substrates to CO2)

• Nutrients feeding catabolism:

  • Amino acids, Glucose, Fatty acids, Alcohol.

• Digestion breaks down biomolecules into smaller nutrients:

  • Carbohydrates $\rightarrow$ Monosaccharides.

  • Fats $\rightarrow$ Fatty acids.

  • Proteins $\rightarrow$ Amino acids.

• Key intermediates and outputs:

  • Keto-acids, Pyruvate.

  • Acetyl-CoA.

  • $\mathrm{CO*2}$.

Four stages of catabolism

1. Dietary macronutrients broken down: To cellular fuel molecules.

2. Transformation of fuel molecules: To metabolic intermediates (reducing power and some energy release).

3. Tricarboxylic acid (TCA) cycle (also called Krebs cycle or citric acid cycle): Generates reducing power and some energy release.

4. Oxidative phosphorylation: Conversion of reducing power into ATP.

Energy usage in metabolism

• Energy used for:

  • Ion transport, muscle contraction, biosynthesis, thermogenesis, detoxification.

• Overall: Energy produced by oxidation of lipids, carbohydrates, proteins, and (ethanol) is captured to form ATP via $\mathrm{ADP + P_i \rightarrow ATP}$ .

• Central coupling concept: ATP-ADP cycle.

• Overall equation for ATP production from energy release:

  • $\mathrm{ADP + P_i \rightarrow ATP}$ (uses energy).

  • ATP hydrolysis $\rightarrow \mathrm{ADP + P_i}$ releases energy for work.

High-energy and low-energy signals in metabolism

• High-energy signals (promote anabolic pathways):

  • ATP, $\text{NADH} + \text{H}^+$, $\text{NADPH} + \text{H}^+$, $\text{FADH}_2$ .

• Low-energy signals (promote catabolic pathways):

  • ADP, AMP, $\text{NAD}^+$, $\text{NADP}^+$, FAD.

• Coordination: These signals coordinate whether cells build up (anabolic) or break down (catabolic) macromolecules.

ATP synthesis under anaerobic conditions (creatine phosphate system)

• During exercise: Creatine phosphate donates phosphate to ADP via creatine kinase to rapidly regenerate ATP.

  • $\mathrm{ADP + P_i \rightleftharpoons ATP + Creatine}$.

• At rest: ATP accumulates and is used to synthesize creatine phosphate.

• Function: This system provides a rapid, short-term buffer of ATP when energy demand rises quickly.

Energy stores

• Very short-term stores (seconds): Creatine phosphate in muscle.

• Carbohydrate stores for immediate use:

  • Muscle glycogen (local) and liver glycogen (whole body) for rest/ongoing activity; storage duration depends on activity level.

  • In between meals, cells utilize stored glycogen.

• Long-term stores:

  • Fat in adipose tissue (approximately 40 days' worth; $\approx 12\,\text{kg} \approx 37,000\,\text{kJ}$).

  • In between meals, cells utilize stored triglycerides.

• Typical body composition examples (for illustration):

  • 70 kg man: Carbohydrate 1 kg; Lipid 12 kg; Protein 11 kg; Minerals 4 kg; Water 42 kg.

  • 100 kg man: Carbohydrate 1 kg; Lipid 40 kg; Protein 12 kg; Minerals 4 kg; Water 43 kg.

• Note: These numbers illustrate relative stores; exact values vary between individuals.

Summary (key takeaways)

• Homeostasis: A dynamic equilibrium; disruption leads to disease.

• Metabolism: An integrated network of chemical reactions with two main types:

  • Catabolism: Exergonic, energy-releasing; converges to acetyl-CoA.

  • Anabolism: Endergonic, energy-requiring; diverges from acetyl-CoA.

• Reaction coupling: Reactions are coupled (REDOX) and powered by the ATP-ADP cycle.

• Energy stores: Range from very short-term (creatine phosphate) to immediate carbohydrate stores to long-term fat stores.

• Metabolic regulation: High-energy signals promote anabolism; low-energy signals promote catabolism.

• Fuel oxidation: The body uses various carrier molecules ($\text{NADH}$, $\text{NADPH}$, $\text{FADH}_2$) to shuttle reducing equivalents; oxidation of fuels powers ATP production via oxidative phosphorylation.

Further reading and resources

• Biomolecules on the Menu.

• Interactive metabolic pathways:

  • https://pathways.embl.de/ipath3.cgi

  • http://interactivepathways.stanford.edu/

• Metabolism learning resources:

  • https://learn.genetics.utah.edu/content/metabolism/

• Dawson, J. BIOC*2580: Introduction to Biochemistry.

• ATP Synthesis | HHMI BioInteractive Video.