What is the Krebs citric acid cycle and how does it work in the body?

The Krebs citric acid cycle is a sequence of chemical reactions central to cellular respiration, breaking down components from carbs, fats, and proteins to release energy. It occurs in the mitochondria of eukaryotic cells, specifically in the mitochondrial matrix, where enzymes and substrates needed for the reactions are found.

The cycle starts when acetyl-CoA, a two-carbon molecule, joins with oxaloacetate, a four-carbon molecule, to form citrate, a six-carbon compound. Citrate rearranges into isocitrate, which then oxidizes and loses a carbon to become alpha-ketoglutarate, a five-carbon molecule, releasing NADH and carbon dioxide. Alpha-ketoglutarate oxidizes further, losing another carbon to form succinyl-CoA, a four-carbon molecule, producing more NADH and carbon dioxide.

Succinyl-CoA converts to succinate, making GTP (which can turn into ATP). Succinate oxidizes to fumarate, creating FADH2, and fumarate becomes malate with water. Malate then oxidizes to regenerate oxaloacetate, generating another NADH, letting the cycle repeat.

Each cycle turn produces three NADH, one FADH2, one GTP or ATP, and two carbon dioxide molecules. These electron carriers (NADH, FADH2) move to the electron transport chain, donating electrons to make large amounts of ATP, the cell’s main energy source. The cycle is key for energy production as it connects nutrient breakdown to the electron transport chain, where most ATP forms, efficiently fueling cellular activities.

The Krebs cycle also called the citric acid cycle or tricarboxylic acid TCA cycle functions as the central metabolic pathway for aerobic respiration. This intricate series of chemical reactions oxidizes acetyl CoA derived from carbohydrates fats and proteins to generate energy rich molecules while releasing carbon dioxide. The cycle was first identified by Hans Krebs in 1937 whose groundbreaking work elucidated how cells convert nutrients into usable energy earning him the Nobel Prize in Physiology or Medicine in 1953.

This cycle takes place within the mitochondrial matrix of eukaryotic cells. The mitochondria's inner compartment provides an ideal environment with all necessary enzymes coenzymes and substrates required for efficient operation. The close proximity of the Krebs cycle to the electron transport chain ETC allows for immediate transfer of high energy electrons to the ETC for ATP production.

The cycle begins when acetyl CoA a two carbon molecule combines with oxaloacetate a four carbon compound to form citrate a six carbon molecule. This reaction is catalyzed by citrate synthase. Citrate then undergoes isomerization to form isocitrate through the intermediate cis aconitate with aconitase facilitating this conversion. Isocitrate dehydrogenase catalyzes the oxidation and decarboxylation of isocitrate producing alpha ketoglutarate a five carbon molecule while releasing carbon dioxide and generating NADH.

Alpha ketoglutarate dehydrogenase complex then converts alpha ketoglutarate to succinyl CoA another four carbon molecule releasing another carbon dioxide molecule and producing NADH. Succinyl CoA synthetase catalyzes the conversion of succinyl CoA to succinate generating GTP or ATP through substrate level phosphorylation. Succinate dehydrogenase oxidizes succinate to fumarate producing FADH2 as a byproduct. Fumarase then hydrates fumarate to malate which is finally oxidized back to oxaloacetate by malate dehydrogenase producing another NADH molecule.

Each complete cycle generates three NADH molecules one FADH2 molecule one GTP molecule equivalent to ATP and two carbon dioxide molecules. These electron carriers transport high energy electrons to the ETC where their energy is used to create a proton gradient driving ATP synthesis. Since one glucose molecule produces two acetyl CoA molecules the cycle runs twice per glucose molecule yielding six NADH two FADH2 and two GTP molecules.

The Krebs cycle serves as a metabolic junction connecting various biochemical pathways. It provides precursors for amino acid synthesis such as alpha ketoglutarate and oxaloacetate supplies heme synthesis components via succinyl CoA and contributes to gluconeogenesis through oxaloacetate. This dual function as both an energy producer and metabolic integrator makes the cycle essential for cellular metabolism.

Regulation occurs at key steps with citrate synthase isocitrate dehydrogenase and alpha ketoglutarate dehydrogenase acting as control points. These enzymes respond to cellular energy levels through allosteric inhibition by ATP NADH and succinyl CoA ensuring the cycle matches the cell's energy demands. This precise regulation maintains metabolic balance between energy production and biosynthetic needs.

The Krebs cycle, also known as the citric acid cycle or tricarboxylic acid (TCA) cycle, stands as the cornerstone of cellular respiration, orchestrating the complete oxidation of acetyl-CoA derived from carbohydrates, fats, and proteins. This intricate metabolic pathway, comprising eight distinct enzymatic reactions, serves as the primary generator of high-energy electron carriers while simultaneously producing key metabolic intermediates for biosynthetic processes. The cycle's location within the mitochondrial matrix of eukaryotic cells underscores its critical role in aerobic energy production, as it directly feeds into the electron transport chain situated on the inner mitochondrial membrane.

The cycle commences with the condensation of acetyl-CoA, a two-carbon molecule formed from pyruvate decarboxylation or fatty acid β-oxidation, with oxaloacetate, a four-carbon compound, to form citrate. This initial step, catalyzed by the regulatory enzyme citrate synthase, represents a committed point in the cycle. Citrate then undergoes isomerization to isocitrate via aconitase, preparing it for oxidative decarboxylation by isocitrate dehydrogenase. This pivotal reaction releases the first molecule of CO₂ and generates NADH, while also illustrating the cycle's sensitivity to cellular energy status through allosteric regulation.

The subsequent transformation of α-ketoglutarate to succinyl-CoA, mediated by the multienzyme α-ketoglutarate dehydrogenase complex, mirrors the chemistry of pyruvate dehydrogenase while producing another NADH and releasing additional CO₂. This step's requirement for thiamine pyrophosphate (TPP), lipoic acid, and other cofactors highlights the cycle's dependence on vitamin-derived coenzymes. The energy-rich thioester bond in succinyl-CoA is then cleaved by succinyl-CoA synthetase, producing succinate and generating GTP (or ATP) through substrate-level phosphorylation.

Succinate dehydrogenase, which uniquely spans the mitochondrial inner membrane, converts succinate to fumarate while reducing FAD to FADH₂, directly channeling electrons into Complex II of the electron transport chain. The cycle concludes with malate dehydrogenase oxidizing malate back to oxaloacetate, producing the third NADH and completing the cycle. This seamless integration of energy production and biosynthetic precursor generation makes the Krebs cycle indispensable for cellular metabolism.

The Krebs citric acid cycle is a key set of reactions in how cells get energy from nutrients. It processes acetyl-CoA, which comes from breaking down carbs, fats, and proteins, to release stored energy.

It happens in the mitochondria of eukaryotic cells, specifically in the mitochondrial matrix. Bacteria, without mitochondria, run it in their cytoplasm instead.

The cycle starts when acetyl-CoA joins with oxaloacetate to make citrate, a six-carbon molecule. Then, citrate goes through rearrangements, loses some carbons as carbon dioxide, and passes electrons to NAD+ and FAD, turning them into NADH and FADH2. By the end, oxaloacetate is regenerated to start the cycle again with new acetyl-CoA.

Produced substances include carbon dioxide, NADH, FADH2, and a little ATP or GTP.

Its role in energy production is huge. The NADH and FADH2 move to the electron transport chain, where their electrons help make lots of ATP. Without this cycle, cells couldn’t get nearly as much energy from the food molecules they use.