Summary
Highlights
The Krebs cycle, also known as the Hans Krebs cycle or citric acid cycle, was discovered by Hans Adolphe Krebs in 1937, earning him a Nobel Prize. It's a key metabolic pathway connecting carbohydrate, fat, and protein metabolisms, generating NADH and FADH2, which are then used to produce ATP. It also provides raw materials like amino acids. An interesting fact is its potential abiogenic origin, meaning it might have existed before life began.
The Krebs cycle is a central metabolic pathway because initial metabolic pathways from food digestion (carbohydrates, fats, proteins) lead to common products, like pyruvate from glucose, which then feed into the Krebs cycle to produce energy. Energy production occurs through the oxidation of these compounds. Glucose is broken down into acetate, a two-carbon compound, which enters the cycle. For each turn, the cycle releases two carbon dioxide molecules (from the added acetate) and generates electrons that form NADH and FADH2, crucial for ATP production in the electron transport chain.
In eukaryotic cells, the Krebs cycle occurs in the mitochondrial matrix, while in prokaryotic cells, it happens in the cytosol. Its mitochondrial location is vital due to the electron transport chain being in the mitochondrial membrane. The cycle begins with Acetyl CoA, which is produced from pyruvate (a product of glycolysis) through the action of the pyruvate dehydrogenase complex. Acetyl CoA is a two-carbon compound where coenzyme A acts as a carrier for these carbons.
The first step of the Krebs cycle involves the combination of Acetyl CoA (two carbons) with oxaloacetate (four carbons) to form citrate (six carbons). This reaction is catalyzed by the enzyme citrate synthase. Citrate then undergoes a series of reactions to release the two carbons introduced by Acetyl CoA as carbon dioxide.
Citrate is converted into its isomer, isocitrate, by the enzyme aconitase. This isomerization is crucial because the atomic arrangement in isocitrate is better suited for subsequent oxidation-reduction reactions. Next, isocitrate is converted to alpha-ketoglutarate by isocitrate dehydrogenase. This is an oxidative decarboxylation reaction, where hydrogen is removed (oxidizing isocitrate and forming NADH) and a carbon atom is lost as carbon dioxide, resulting in a five-carbon alpha-ketoglutarate.
The conversion of alpha-ketoglutarate to succinyl CoA is another oxidative decarboxylation reaction, catalyzed by alpha-ketoglutarate dehydrogenase. In this step, NADH and carbon dioxide are produced, and coenzyme A is utilized, leading to the formation of succinyl CoA.
Succinyl CoA is converted to succinate by succinyl CoA synthetase. This is a crucial step where the high energy stored in succinyl CoA is used to attach an inorganic phosphate to GDP, forming GTP. This is an example of substrate-level phosphorylation, and the coenzyme A is released, leaving a four-carbon succinate.
Succinate is converted to fumarate by succinate dehydrogenase. This enzyme removes hydrogen from succinate, which is accepted by FAD to form FADH2, as the energy change is less than what's needed for NAD. Fumarate is then hydrated to malate by the enzyme fumarase. Finally, malate is oxidized to oxaloacetate by malate dehydrogenase, reducing NAD to NADH. This oxaloacetate then combines with a new molecule of Acetyl CoA to restart the cycle.
For every molecule of Acetyl CoA entering the cycle, two molecules of carbon dioxide are released. Three molecules of NAD are reduced to NADH, and one molecule of FAD is reduced to FADH2. One molecule of GTP is also produced. The net reaction highlights the inputs and outputs. Most energy is produced indirectly via NADH and FADH2, which are utilized in the electron transport chain. One NADH yields approximately 2.5 ATPs, and one FADH2 yields about 1.5 ATPs. Including the direct GTP production (which converts to ATP), one Acetyl CoA unit generates roughly 10 ATPs. Since one glucose molecule produces two Acetyl CoA molecules, the Krebs cycle contributes about 20 ATPs per glucose molecule.