Every time you walk, eat, or think, your cells extract energy from food. Inside mitochondria, a series of chemical reactions breaks down nutrients, releasing energy for ATP production. This process, known as the Krebs cycle, converts carbon-based molecules into usable energy, keeping cells active and functioning.
The Krebs cycle, also called the citric acid cycle, takes place in the mitochondrial matrix. It begins with acetyl-CoA and produces NADH, FADH₂, and GTP, which drive ATP synthesis. This study guide explains each step, the molecules involved, energy transfer, metabolic connections, and conditions that affect the cycle.
Krebs Cycle: Quick Summary
Do you just need the basics? Here’s a simple explanation of what the Krebs cycle is and how it works:
🟠 The Krebs cycle is a series of chemical reactions inside the mitochondria that break down acetyl-CoA to release energy.
🟠 Each turn of the cycle produces NADH and FADH₂, which carry electrons to the electron transport chain for ATP production.
🟠 Carbohydrates, fats, and proteins provide acetyl-CoA or other intermediates that enter the cycle at different points.
🟠 Cells regulate the cycle using enzymes like citrate synthase and isocitrate dehydrogenase, which respond to ATP and NADH levels.
🟠 Some metabolic disorders, such as pyruvate dehydrogenase deficiency and thiamine deficiency, disrupt the cycle and reduce energy production.
🟠 In certain cancers, mutations in isocitrate dehydrogenase produce abnormal metabolites that interfere with normal cell function.
What Is the Krebs Cycle?
Every second, your cells break down food to release energy. The Krebs cycle, also called the citric acid cycle, is a set of chemical reactions that convert acetyl-CoA into carbon dioxide, generating molecules that store energy. This process happens inside mitochondria, where enzymes transfer electrons to NADH and FADH₂. These molecules then supply energy to the electron transport chain, leading to ATP production.
The Krebs cycle connects to multiple metabolic pathways. Carbohydrates, fats, and proteins all break down into acetyl-CoA, which fuels the reactions. Each turn of the cycle produces three NADH, one FADH₂, and one GTP. These molecules store energy that cells later use for different processes.
Where Does the Krebs Cycle Happen?
- Mitochondrial matrix in eukaryotic cells
- Cytoplasm in prokaryotic cells
Molecules Involved in the Krebs Cycle
- Reactants: Acetyl-CoA, NAD⁺, FAD, GDP, Pi
- Products: CO₂, NADH, FADH₂, GTP
Molecules in Each Step of the Krebs Cycle
| Step | Reactant | Product | Enzyme |
| 1 | Acetyl-CoA + Oxaloacetate | Citrate | Citrate synthase |
| 2 | Citrate | Isocitrate | Aconitase |
| 3 | Isocitrate | α-Ketoglutarate | Isocitrate dehydrogenase |
| 4 | α-Ketoglutarate | Succinyl-CoA | α-Ketoglutarate dehydrogenase |
| 5 | Succinyl-CoA | Succinate | Succinyl-CoA synthetase |
| 6 | Succinate | Fumarate | Succinate dehydrogenase |
| 7 | Fumarate | Malate | Fumarase |
| 8 | Malate | Oxaloacetate | Malate dehydrogenase |
Steps of the Citric Acid Cycle – From Acetyl-CoA to Energy
Cells break down nutrients to release energy. The Krebs cycle begins when acetyl-CoA combines with oxaloacetate, forming a six-carbon molecule. As the cycle progresses, carbon atoms are removed as carbon dioxide, and high-energy electrons are transferred to NADH and FADH₂. At the end of each cycle, oxaloacetate is regenerated, allowing the process to continue.
Each turn of the cycle breaks down one acetyl-CoA, producing three NADH, one FADH₂, one GTP, and two CO₂. These molecules later provide energy for ATP synthesis in the electron transport chain.
Step-by-Step Breakdown of the Krebs Cycle
- Citrate formation – Acetyl-CoA (2C) reacts with oxaloacetate (4C) to form citrate (6C).
- Isomerization – Citrate rearranges into isocitrate.
- First decarboxylation – Isocitrate loses CO₂ and forms α-ketoglutarate (5C). NADH is produced.
- Second decarboxylation – α-Ketoglutarate loses another CO₂ and forms succinyl-CoA (4C). Another NADH is generated.
- Substrate-level phosphorylation – Succinyl-CoA converts to succinate, producing GTP, which can be converted to ATP.
- Oxidation – Succinate oxidizes to fumarate, transferring electrons to FADH₂.
- Hydration – Fumarate gains a water molecule, forming malate.
- Final oxidation – Malate oxidizes to oxaloacetate, generating NADH and completing the cycle.
Since each glucose molecule produces two acetyl-CoA, the Krebs cycle runs twice per glucose, doubling NADH, FADH₂, and GTP production.
How the Krebs Cycle Produces ATP – Energy Transfer Explained
Cells rely on ATP for energy, but the Krebs cycle does not produce ATP directly. Instead, it generates NADH and FADH₂, which store high-energy electrons. These molecules carry electrons to the electron transport chain (ETC), where ATP is synthesized.
Each turn of the Krebs cycle produces three NADH, one FADH₂, and one GTP. GTP can be converted into ATP, but most of the energy comes from NADH and FADH₂. Inside the mitochondria, these electron carriers transfer their energy to the ETC.
NADH donates electrons to Complex I, which pumps protons across the mitochondrial membrane, generating enough energy to form about three ATP molecules per NADH. FADH₂ enters at Complex II, bypassing the first step and producing around two ATP molecules per FADH₂. This process, known as oxidative phosphorylation, allows cells to produce large amounts of ATP efficiently.
When a single glucose molecule is fully broken down, glycolysis, the Krebs cycle, and the ETC work together to generate ATP. Glycolysis provides a small amount, the Krebs cycle supplies high-energy electron carriers, and the ETC produces most of the ATP. After two turns of the Krebs cycle, one glucose molecule leads to the production of approximately 30 to 38 ATP, depending on conditions inside the cell.
How the Krebs Cycle Produces ATP – Energy Transfer Explained
Cells need a constant supply of ATP to function. The Krebs cycle does not directly produce large amounts of ATP, but it generates NADH and FADH₂, which power ATP production in the electron transport chain (ETC). These molecules carry high-energy electrons to the mitochondria’s inner membrane, where ATP is synthesized through oxidative phosphorylation.
Each turn of the Krebs cycle produces three NADH, one FADH₂, and one GTP. GTP can be converted into ATP, but most ATP comes from NADH and FADH₂. These molecules donate electrons to the ETC, where energy is used to pump protons across the mitochondrial membrane, creating a gradient that drives ATP synthesis.
ATP Yield from the Krebs Cycle
NADH and FADH₂ deliver electrons to different points in the electron transport chain, affecting how much ATP they produce. NADH enters at Complex I, releasing enough energy to generate about three ATP per molecule. FADH₂ enters at Complex II, which bypasses the first proton pump and produces around two ATP per molecule.
Because each glucose molecule produces two acetyl-CoA, the Krebs cycle runs twice per glucose, doubling the NADH and FADH₂ available for ATP production.
Electron Carriers – NADH and FADH₂
NADH donates electrons at Complex I, starting the process of oxidative phosphorylation. This electron transfer allows protons to be pumped across the mitochondrial membrane, creating the gradient that fuels ATP synthase.
FADH₂ delivers electrons to Complex II, which does not pump protons as efficiently as Complex I. As a result, electrons from FADH₂ produce less ATP than those from NADH.
Total Energy Yield from One Glucose Molecule
Glycolysis, the Krebs cycle, and the electron transport chain work together to maximize ATP production.
- Glycolysis produces 2 ATP and 2 NADH.
- The Krebs cycle (two turns per glucose) generates 2 GTP, 6 NADH, and 2 FADH₂.
- The electron transport chain converts the NADH and FADH₂ into ATP, producing up to 34 ATP.
In total, one glucose molecule generates about 30 to 38 ATP, depending on conditions inside the cell. Most of this ATP comes from the electron transport chain, which uses NADH and FADH₂ as energy sources.
Medical Conditions Related to the Krebs Cycle
The Krebs cycle keeps cells supplied with energy, but some conditions disrupt its function. When enzymes or coenzymes in the cycle are defective, cells struggle to produce ATP, and harmful byproducts can build up. Many of these disorders affect the nervous system, which depends on a constant energy supply.
Pyruvate Dehydrogenase Deficiency
Pyruvate dehydrogenase converts pyruvate into acetyl-CoA, the molecule that enters the Krebs cycle. When this enzyme is defective, pyruvate builds up and is converted into lactate instead. The result is lactic acidosis, which lowers blood pH and damages tissues. People with this condition often experience muscle weakness, developmental delays, and neurological problems. The brain is especially affected because it relies on glucose metabolism for energy.
Thiamine (Vitamin B1) Deficiency
Thiamine is a coenzyme for α-ketoglutarate dehydrogenase, one of the enzymes in the Krebs cycle. A lack of thiamine slows ATP production, leading to symptoms that affect the nerves, muscles, and heart. Beriberi causes muscle weakness, nerve damage, and heart failure. In alcohol-related Wernicke-Korsakoff syndrome, thiamine deficiency leads to confusion, memory loss, and poor coordination.
Isocitrate Dehydrogenase Mutations in Cancer
In some cancers, isocitrate dehydrogenase mutates and starts producing 2-hydroxyglutarate, a compound that disrupts gene regulation. This leads to abnormal cell growth and tumor formation. These mutations are common in brain tumors (gliomas) and leukemia, where they interfere with normal cell division and DNA repair.
Evolution of the Krebs Cycle – How It Developed in Early Life
The Krebs cycle likely evolved from simpler metabolic pathways used by early anaerobic organisms. Before oxygen was abundant, primitive cells relied on reactions similar to those in the cycle but running in reverse. Some modern bacteria still use a reverse Krebs cycle to build organic molecules from carbon dioxide instead of breaking them down for energy. This suggests that the cycle’s core reactions existed long before aerobic respiration developed. Over time, as oxygen became available, these pathways adapted into the Krebs cycle, allowing cells to extract more energy from nutrients through oxidative metabolism.
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Krebs Cycle: Frequently Asked Questions
1. What is the Krebs cycle?
The Krebs cycle is a sequence of reactions in the mitochondria that breaks down acetyl-CoA to produce energy-rich molecules like NADH and FADH₂.
2. Where does the Krebs cycle take place?
The Krebs cycle occurs in the mitochondrial matrix in eukaryotic cells and in the cytoplasm of prokaryotic cells.
3. What does the Krebs cycle produce?
Each turn of the Krebs cycle generates 3 NADH, 1 FADH₂, 1 GTP (or ATP), and 2 CO₂ molecules.
4. How is the Krebs cycle connected to glycolysis?
Glycolysis produces pyruvate, which is converted into acetyl-CoA, the molecule that enters the Krebs cycle.
5. How do fats enter the Krebs cycle?
Fatty acids undergo β-oxidation, which generates acetyl-CoA, allowing them to enter the Krebs cycle for further energy production.
6. How do proteins contribute to the Krebs cycle?
Amino acids are broken down into Krebs cycle intermediates, which can be used for energy or biosynthesis.
7. How is the Krebs cycle regulated?
The Krebs cycle is controlled by enzyme activity, with ATP and NADH slowing it down and ADP speeding it up.
8. What diseases affect the Krebs cycle?
Conditions like pyruvate dehydrogenase deficiency, thiamine deficiency, and isocitrate dehydrogenase mutations disrupt the Krebs cycle, leading to energy deficits.
Sources:
1. NCBI
2. Britannica
3. Wikipedia
Krebs cycle connections to glycolysis and metabolism
