ATP and Cellular Energy Metabolism

ATP (adenosine triphosphate) is the main energy currency of the cell: its hydrolysis to ADP and inorganic phosphate releases about 30.5 kJ/mol under standard biochemical conditions (and 50–60 kJ/mol in the cell) and is coupled to energy-requiring processes, while cellular respiration regenerates ATP from the oxidation of food. In brief: the complete oxidation of one glucose molecule yields about 30–32 ATP, and a human turns over roughly their own body mass of ATP every day, although only about 50 g is present at any moment.

Cells need a steady supply of energy for muscle contraction, nerve signals, active transport and the synthesis of macromolecules. They do not use the energy of food directly, but convert it into the form of ATP, which is then used wherever it is needed. This article explains the structure of ATP, why its hydrolysis releases energy, how coupling lets unfavorable reactions go, how glycolysis, the citric acid cycle and oxidative phosphorylation make ATP, with a table of yields, and gives calculations of energy and turnover.

What is the structure of ATP?

ATP consists of the base adenine, the sugar ribose (together adenosine) and a chain of three phosphate groups (α, β and γ) attached to the 5′ carbon. The phosphates are linked by two phosphoanhydride bonds, which are often called “high-energy bonds”. The molar mass of ATP is 507.18 g/mol (as the free acid). At physiological pH, ATP carries about four negative charges, and is usually complexed with Mg²⁺.

Why does ATP hydrolysis release energy?

The reaction is ATP + H₂O → ADP + P_i + H⁺, with ΔG°′ = −30.5 kJ/mol (−7.3 kcal/mol) at pH 7. In the cell, where the concentrations of ATP, ADP and P_i are far from standard (the ratio of ATP to ADP is kept high), ΔG is more negative, about −50 to −65 kJ/mol. The energy is released not because the bond itself is “high energy”, but because the products are more stable than the reactants:

• Charge repulsion: the four negative charges of the triphosphate are close together and repel each other. Hydrolysis relieves this strain.
• Resonance stabilization: inorganic phosphate has more resonance forms than the phosphate group in ATP.
• Solvation: the products, ADP and P_i, are better hydrated than ATP.
• Entropy: one molecule becomes two.

The reaction is not fast without an enzyme, so ATP is kinetically stable in the cell, and releases its energy only when an enzyme catalyzes the reaction in a coupled process.

How does energy coupling work?

A reaction with a positive ΔG can be driven if it is coupled to the hydrolysis of ATP, because the free energy changes add. An example is the first step of glycolysis, catalyzed by hexokinase: glucose + P_i → glucose-6-phosphate + H₂O, ΔG°′ = +13.8 kJ/mol; ATP + H₂O → ADP + P_i, ΔG°′ = −30.5 kJ/mol. The sum is glucose + ATP → glucose-6-phosphate + ADP, ΔG°′ = 13.8 − 30.5 = −16.7 kJ/mol. The ATP donates its phosphate group to glucose, via a phosphorylated intermediate. In the same way, ATP powers the sodium–potassium pump, muscle contraction (myosin), the synthesis of macromolecules and the transport of molecules into the cell.

How is ATP made?

• Substrate-level phosphorylation: a phosphate group is transferred directly from a high-energy intermediate to ADP (for example from phosphoenolpyruvate in glycolysis).
• Oxidative phosphorylation: in the mitochondria, electrons from NADH and FADH₂ pass along the electron transport chain to oxygen, and the energy released is used to pump protons across the inner membrane. The proton gradient drives ATP synthase. This produces about 90 % of the ATP in aerobic cells.
• Photophosphorylation: in the chloroplasts, light energy is used to create a proton gradient that drives ATP synthesis.

The oxidation of glucose in aerobic respiration, C₆H₁₂O₆ + 6O₂ → 6CO₂ + 6H₂O (ΔG°′ ≈ −2870 kJ/mol), takes place in four stages: glycolysis (in the cytoplasm), the oxidation of pyruvate to acetyl-CoA, the citric acid (Krebs) cycle (in the mitochondrial matrix) and oxidative phosphorylation (in the inner mitochondrial membrane). Without oxygen, glycolysis continues, and pyruvate is converted to lactate (in muscle) or to ethanol and CO₂ (in yeast), which allows 2 ATP per glucose.

ATP yield from glucose

Each NADH gives about 2.5 ATP in oxidative phosphorylation and each FADH₂ about 1.5 (older textbooks used 3 and 2, and so gave a total of 36–38). The exact value depends on the number of protons pumped per electron pair and on the number of protons required by ATP synthase (about 4 H⁺ per ATP, including the transport of phosphate), and on the shuttle used for NADH from the cytoplasm.

What is chemiosmosis?

Peter Mitchell proposed in 1961 that the energy of electron transport is stored as a proton gradient across the inner mitochondrial membrane, and that the return flow of protons through ATP synthase drives the synthesis of ATP. The proton-motive force has an electrical part (about 150–180 mV, negative inside) and a chemical part (a pH difference of about 0.5–1 unit, alkaline inside the matrix). ATP synthase is a rotary molecular motor: the flow of protons turns the rotor (the c-ring and the central stalk), which changes the shape of the three catalytic sites in the head, so that each makes one ATP per turn of 120°. It can rotate at about 100 revolutions per second.

Worked examples

Example 1: the efficiency of glucose oxidation

The oxidation of one glucose yields about 30 ATP. If each ATP stores 30.5 kJ/mol under standard conditions: 30 × 30.5 = 915 kJ out of 2870 kJ, which is 32 % efficiency. With the actual free energy of ATP hydrolysis in the cell of about 50 kJ/mol: 30 × 50 = 1500 kJ, or 52 %. The rest is released as heat, which keeps the body warm.

Example 2: ATP turnover in a human

An adult uses about 8400 kJ (2000 kcal) per day. If all this energy could be taken up in ATP at 50 kJ/mol, then 8400 / 50 = 168 mol of ATP would be made and used per day. With a molar mass of 507 g/mol, that is 168 × 507 = 85 kg. Even if only about 40 % of the energy is captured as ATP, the amount turned over is about 35 kg a day, which is about half the body mass. The body contains only about 50 g of ATP at any time (about 0.1 mol), so each ATP molecule is hydrolyzed and regenerated about 1000 times each day.

Example 3: coupling of reactions

A biosynthetic reaction has ΔG°′ = +17.0 kJ/mol. Coupled to the hydrolysis of one ATP (ΔG°′ = −30.5), the overall ΔG°′ = 17.0 − 30.5 = −13.5 kJ/mol, so the process can go. The equilibrium constant for the coupled reaction at 37 °C (RT = 2.58 kJ/mol) is K = e^13.5/2.58 = e^5.23 = 190.

Example 4: moles of ATP from glucose

How many moles of ATP are formed from the oxidation of 18.0 g of glucose (0.100 mol), at 30 ATP per glucose? 3.0 mol, which is 3.0 × 507 = 1520 g of ATP formed. The energy captured under standard conditions is 3.0 × 30.5 = 92 kJ, out of the 0.100 × 2870 = 287 kJ released by the oxidation of the glucose.

Example 5: anaerobic compared with aerobic

Fermentation gives 2 ATP per glucose and respiration gives about 30, so aerobic respiration is 15 times more efficient. A sprinter who runs for 10 s uses mainly the ATP and creatine phosphate stores and anaerobic glycolysis, while a marathon runner relies on aerobic respiration.

How was ATP discovered?

Karl Lohmann discovered ATP in 1929 in muscle extracts, and Cyrus Fiske and Yellapragada Subbarow isolated it independently in the same year. Fritz Lipmann proposed in 1941 that ATP is the universal link between energy-yielding and energy-requiring reactions, with the concept of “energy-rich phosphate bonds”, and he shared the Nobel Prize in Physiology or Medicine in 1953 (with Hans Krebs, who described the citric acid cycle in 1937). Peter Mitchell’s chemiosmotic hypothesis (1961) was at first controversial, but received the Nobel Prize in Chemistry in 1978. Paul Boyer and John Walker, who explained the mechanism and structure of ATP synthase, shared the Nobel Prize in Chemistry in 1997 with Jens Skou.

Which mistakes are common?

• Saying that ATP is stored in large amounts: the cell holds a small pool that is recycled constantly.
• Thinking that the energy is in the bond: it comes from the difference between the reactants and the products.
• Using the figure of 36–38 ATP without qualification: current estimates are 30–32.
• Forgetting that ATP is consumed in the first steps of glycolysis: the net yield is 2, not 4.
• Confusing the standard free energy with the value in the cell: the latter is more negative.