Kinetics & Enzyme Catalysis

Electrochemistry and Redox Reactions in Biology

Introduction

Oxidation and reduction reactions — collectively termed redox reactions — are the driving force behind cellular energy production, detoxification, signalling, and antimicrobial defence. From the electron transport chain generating ATP to the cytochrome P450 enzymes metabolising drugs, understanding redox chemistry is fundamental to understanding human physiology and pharmacology.

Core Concepts: Oxidation and Reduction

Oxidation is the loss of electrons (or gain of oxygen, or loss of hydrogen). Reduction is the gain of electrons (or loss of oxygen, or gain of hydrogen). A useful mnemonic: OIL RIG — Oxidation Is Loss, Reduction Is Gain. In every redox reaction, an oxidising agent accepts electrons and is itself reduced; a reducing agent donates electrons and is itself oxidised. These always occur together — you cannot have oxidation without reduction.

Standard reduction potential (E°') measures the tendency of a species to accept electrons relative to the standard hydrogen electrode (SHE). Species with more positive E°' have greater electron affinity and are stronger oxidising agents. Redox reactions proceed spontaneously when electrons flow from species with more negative E°' to those with more positive E°'.

The Nernst Equation

The actual reduction potential under non-standard conditions is given by the Nernst equation:

E = E°' − (RT/nF) × ln([reduced]/[oxidised])

At 25°C: E = E°' − (0.0257/n) × ln Q, where n = number of electrons transferred and Q = reaction quotient. The Nernst equation explains how electrode potentials (and thus Gibbs free energy, ΔG = −nFΔE) change with reactant concentrations — directly applicable to ion channels (Nernst potential for individual ions) and biochemical reactions.

Biological Electron Carriers

Living systems use specialised molecules to safely transfer electrons:

| Carrier | Reduced Form | Oxidised Form | Electrons Transferred | Role |

|---|---|---|---|---|

| NAD⁺ | NADH | NAD⁺ | 2e⁻ (+ H⁺) | Glycolysis, Krebs cycle, beta-oxidation |

| FAD | FADH₂ | FAD | 2e⁻ | Krebs cycle (succinate dehydrogenase) |

| Coenzyme Q (ubiquinone) | QH₂ (ubiquinol) | Q | 2e⁻ | Mobile carrier in ETC (Complex I/III) |

| Cytochrome c | Fe²⁺ | Fe³⁺ | 1e⁻ | Mobile carrier between Complex III/IV |

The reduction potential increases along the electron transport chain from NADH (E°' = −0.32 V) to O₂ (E°' = +0.82 V), a difference of 1.14 V. This drives proton pumping across the inner mitochondrial membrane, generating the proton-motive force that powers ATP synthase. The ΔG for NADH oxidation by O₂ is approximately −220 kJ/mol — more than enough to drive ATP synthesis (ΔG ≈ +30 kJ/mol per ATP).

Reactive Oxygen Species (ROS) and Antioxidants

Partial reduction of O₂ in the electron transport chain inevitably produces reactive oxygen species:

• Superoxide (O₂•⁻) — one-electron reduction of O₂, produced mainly at Complex I and III
• Hydrogen peroxide (H₂O₂) — two-electron reduction, less reactive but diffusible
• Hydroxyl radical (•OH) — Fenton reaction (Fe²⁺ + H₂O₂ → Fe³⁺ + •OH + OH⁻), extremely reactive

ROS oxidise DNA (forming 8-oxoguanine, a premutagenic lesion), proteins (carbonylation, disulfide formation), and membrane lipids (lipid peroxidation — chain reaction generating malondialdehyde, 4-HNE).

Antioxidant defences:

• Superoxide dismutase (SOD): 2 O₂•⁻ + 2H⁺ → H₂O₂ + O₂ (Cu/Zn-SOD in cytoplasm; Mn-SOD in mitochondria)
• Catalase: 2 H₂O₂ → 2 H₂O + O₂ (in peroxisomes)
• Glutathione peroxidase (GPx): H₂O₂ + 2 GSH → GSSG + 2 H₂O (uses reduced glutathione GSH)
• Thioredoxin/thioredoxin reductase system: regenerates reduced thioredoxin using NADPH
• Vitamins E (tocopherol) — lipid-soluble, terminates lipid radical chain; C (ascorbate) — water-soluble, regenerates vitamin E

Clinical Applications

Cytochrome P450 and Drug Oxidation

CYP450 enzymes in the liver endoplasmic reticulum use NADPH and O₂ to perform mixed-function oxidation of drugs and xenobiotics:

Drug + NADPH + H⁺ + O₂ → Drug-OH + NADP⁺ + H₂O

The iron haem centre of CYP450 cycles between Fe³⁺ and Fe²⁺ states during catalysis. Genetic polymorphisms in CYP2D6, CYP2C9, and CYP2C19 affect drug metabolism rates — poor metabolisers accumulate drugs (toxicity risk), ultrarapid metabolisers have subtherapeutic levels.

Carbon Monoxide Poisoning

CO binds haem iron (Fe²⁺) with ~250× greater affinity than O₂, forming carboxyhaemoglobin (COHb) and also inhibiting cytochrome c oxidase (Complex IV), blocking the final step of electron transfer to O₂. Treatment: high-flow 100% O₂ displaces CO (reduces COHb half-life from ~5 h on room air to ~60–90 min); hyperbaric O₂ (3 atm) for severe poisoning.

Methylene Blue and Methaemoglobinaemia

Methaemoglobin (metHb) contains Fe³⁺ instead of Fe²⁺ and cannot bind O₂. It is reduced back to Hb by NADH methaemoglobin reductase normally. In G6PD-deficient patients, NADPH production is impaired; methylene blue (which normally reduces metHb via NADPH) is ineffective, requiring ascorbic acid therapy or exchange transfusion instead.

Summary

Redox chemistry forms the molecular backbone of energy metabolism, drug biotransformation, and cellular defence against oxidative damage. The thermodynamics of electron transfer — standard reduction potentials, the Nernst equation, and Gibbs free energy — determine whether biological oxidation reactions proceed spontaneously and how much energy they release. Clinicians encounter these principles in interpreting toxicology, managing metabolic disorders, and understanding the mechanism of many drugs and poisons.