What Is Metabolism?
Metabolism encompasses all the chemical reactions occurring in a living cell. These reactions fall into two broad categories:
- Catabolism: breakdown of molecules to release energy (e.g., breaking down glucose)
- Anabolism: synthesis of complex molecules using energy (e.g., building proteins)
The key currency of cellular energy is adenosine triphosphate (ATP) — a molecule that stores and releases chemical energy through the hydrolysis of its phosphate bonds.
ATP: The Energy Currency of Life
ATP consists of adenine (a nitrogenous base), ribose (a five-carbon sugar), and three phosphate groups linked by high-energy phosphoanhydride bonds. When the terminal phosphate is hydrolyzed:
ATP + H₂O → ADP + Pᵢ + ~30.5 kJ/mol
This released energy drives otherwise unfavorable reactions — muscle contraction, active transport, biosynthesis — when coupled to them. A typical human cell regenerates approximately 40 kg of ATP per day through the continuous recycling of ADP back to ATP.
Overview of Cellular Respiration
Cellular respiration is the process by which cells extract energy from glucose (C₆H₁₂O₆) and store it as ATP. The overall reaction:
C₆H₁₂O₆ + 6O₂ → 6CO₂ + 6H₂O + ~30–32 ATP
This process occurs in three main stages: glycolysis, the Krebs cycle (citric acid cycle), and oxidative phosphorylation via the electron transport chain.
Stage 1: Glycolysis
Glycolysis occurs in the cytoplasm and does not require oxygen. It converts one molecule of glucose (6 carbons) into two molecules of pyruvate (3 carbons each).
Key Steps
- Energy investment phase (steps 1–5): 2 ATP are consumed to phosphorylate glucose and split it into two three-carbon sugars.
- Energy payoff phase (steps 6–10): each three-carbon sugar is oxidized and converted to pyruvate, yielding 4 ATP and 2 NADH.
Net yield per glucose: 2 ATP + 2 NADH + 2 pyruvate
The NADH molecules carry high-energy electrons to the electron transport chain for further ATP synthesis.
Pyruvate Processing: The Bridge Reaction
Before entering the Krebs cycle, pyruvate is transported into the mitochondrial matrix and converted to acetyl-CoA by the pyruvate dehydrogenase complex:
Pyruvate + CoA + NAD⁺ → Acetyl-CoA + CO₂ + NADH
This irreversible reaction releases one CO₂ per pyruvate and reduces NAD⁺ to NADH. The two-carbon acetyl group is attached to coenzyme A (CoA), a carrier molecule derived from pantothenic acid (vitamin B₅).
Stage 2: The Krebs Cycle (Citric Acid Cycle)
The Krebs cycle operates in the mitochondrial matrix and completes the oxidation of glucose carbon skeletons to CO₂. Named after Hans Krebs, who elucidated it in 1937, the cycle turns twice per glucose molecule (once per acetyl-CoA).
Key Events Per Turn
- Acetyl-CoA (2C) condenses with oxaloacetate (4C) to form citrate (6C)
- Two oxidative decarboxylations release 2 CO₂
- Four oxidation steps reduce 3 NAD⁺ → 3 NADH and 1 FAD → 1 FADH₂
- One substrate-level phosphorylation produces 1 GTP (equivalent to ATP)
- Oxaloacetate is regenerated to accept another acetyl-CoA
Net yield per glucose (2 turns): 2 ATP + 6 NADH + 2 FADH₂ + 4 CO₂
At this stage, all six carbons of glucose have been released as CO₂. The energy is now predominantly stored in the electron carriers NADH and FADH₂.
Stage 3: Oxidative Phosphorylation
This stage, occurring on the inner mitochondrial membrane, accounts for approximately 90% of ATP production from glucose. It consists of the electron transport chain (ETC) and ATP synthase.
The Electron Transport Chain
NADH and FADH₂ donate their electrons to a series of protein complexes (Complexes I–IV) embedded in the inner mitochondrial membrane:
- Complex I (NADH dehydrogenase): oxidizes NADH, pumps 4 H⁺
- Complex II (succinate dehydrogenase): oxidizes FADH₂, no H⁺ pumping
- Complex III (cytochrome bc₁): transfers electrons via ubiquinone, pumps 4 H⁺
- Complex IV (cytochrome c oxidase): transfers electrons to O₂, forming H₂O; pumps 2 H⁺
The pumping of protons (H⁺) across the inner membrane creates a proton gradient — an electrochemical gradient called the proton motive force. Oxygen is the final electron acceptor; without it, electron flow stops and ATP synthesis halts.
ATP Synthase: A Molecular Turbine
ATP synthase (Complex V) is a remarkable molecular machine. Protons flowing down their concentration gradient back into the mitochondrial matrix pass through ATP synthase, causing its rotor subunit to spin. This mechanical rotation drives the synthesis of ATP from ADP and inorganic phosphate:
ADP + Pᵢ → ATP
This mechanism — chemiosmosis — was proposed by Peter Mitchell in 1961 and earned him the Nobel Prize. Each full rotation of the ATP synthase generates approximately 3 ATP molecules.
ATP yield per NADH: ~2.5 ATP ATP yield per FADH₂: ~1.5 ATP
Total ATP yield per glucose: approximately 30–32 ATP (updated from the older estimate of 36–38)
Anaerobic Metabolism and Fermentation
When oxygen is unavailable, cells switch to fermentation to regenerate NAD⁺ (needed for glycolysis to continue). Two major types:
- Lactic acid fermentation: pyruvate + NADH → lactate + NAD⁺ (muscle cells during intense exercise)
- Alcoholic fermentation: pyruvate → acetaldehyde + CO₂; acetaldehyde + NADH → ethanol + NAD⁺ (yeast)
Fermentation yields only 2 ATP per glucose — far less efficient than aerobic respiration.
Regulation of Metabolism
Metabolic pathways are tightly regulated to match energy supply with demand:
- Phosphofructokinase-1 (PFK-1), the key regulatory enzyme of glycolysis, is inhibited by high ATP and activated by AMP and ADP — a classic example of allosteric feedback regulation.
- High NADH/NAD⁺ ratios inhibit Krebs cycle enzymes.
- Insulin and glucagon hormonally regulate glucose uptake, glycolysis, and glycogen synthesis/breakdown at the whole-organism level.
Metabolism of Other Fuels
While glucose is the primary fuel, cells also oxidize: - Fatty acids: broken down by β-oxidation into acetyl-CoA (entering the Krebs cycle), yielding far more ATP per carbon than glucose (e.g., palmitate yields ~129 ATP) - Amino acids: deaminated and converted to Krebs cycle intermediates; used during starvation or excess protein intake - Ketone bodies: acetoacetate and β-hydroxybutyrate, produced from fatty acids in the liver during fasting, used by the brain when glucose is scarce
The metabolic pathways of cellular respiration represent billions of years of evolutionary optimization — a chemical framework that efficiently extracts and stores energy from organic molecules to power all life.