The citric acid cycle, also known as the Krebs cycle, is a key metabolic pathway that breaks down nutrients to generate energy. It's the final common pathway for oxidation of carbohydrates, fats, and proteins, producing ATP and important metabolic intermediates.

This cycle involves a series of chemical reactions that oxidize acetyl-CoA, releasing energy in the form of NADH and FADH2. These electron carriers then fuel the electron transport chain, driving ATP production through oxidative phosphorylation.

The Citric Acid Cycle

Acetyl CoA in citric acid cycle

• Acetyl CoA high-energy molecule initiates citric acid cycle
  • Formed from oxidative decarboxylation of pyruvate, end product of glycolysis (glucose breakdown)
  • Consists of acetyl group (-COCH3) bound to coenzyme A (CoA), a sulfur-containing compound
• Acetyl CoA donates acetyl group to oxaloacetate, four-carbon molecule, forming citrate (six-carbon molecule)
  • Reaction catalyzed by enzyme citrate synthase
  • Formation of citrate irreversible step marks beginning of citric acid cycle (Krebs cycle)
• Coenzyme A (CoA) released can be recycled to form more acetyl CoA from pyruvate
  • Pyruvate dehydrogenase complex catalyzes oxidative decarboxylation of pyruvate to acetyl CoA
  • Requires several cofactors (thiamine pyrophosphate, lipoic acid, FAD, NAD+)

Oxidation and decarboxylation reactions

• Isocitrate dehydrogenase catalyzes oxidative decarboxylation of isocitrate forming α-ketoglutarate
  • Releases CO2 molecule reduces NAD+ to NADH (electron carrier)
  • Isocitrate formed from citrate by aconitase enzyme via cis-aconitate intermediate
• α-Ketoglutarate dehydrogenase complex catalyzes oxidative decarboxylation of α-ketoglutarate forming succinyl-CoA
  • Releases another CO2 molecule reduces NAD+ to NADH
  • Enzyme complex requires multiple cofactors (thiamine pyrophosphate, lipoic acid, FAD)
  • Succinyl-CoA high-energy compound used in substrate-level phosphorylation to generate GTP or ATP
• Succinate dehydrogenase catalyzes oxidation of succinate to fumarate
  • Reduces FAD to FADH2 used to generate ATP through electron transport chain
  • Succinate formed from succinyl-CoA by succinyl-CoA synthetase enzyme
• Malate dehydrogenase catalyzes oxidation of malate to oxaloacetate
  • Reduces NAD+ to NADH used to generate ATP through electron transport chain
  • Malate formed from fumarate by fumarase enzyme

Oxaloacetate regeneration and energy production

• Citric acid cycle regenerates oxaloacetate allowing cycle to continue
  • Oxaloacetate regenerated from malate by malate dehydrogenase in last step of cycle
  • Regenerated oxaloacetate accepts another acetyl group from acetyl CoA to start cycle again
• One turn of citric acid cycle produces:
  1. 3 molecules of NADH (from isocitrate dehydrogenase, α-ketoglutarate dehydrogenase, malate dehydrogenase)
  2. 1 molecule of FADH2 (from succinate dehydrogenase)
  3. 1 molecule of GTP or ATP (from substrate-level phosphorylation by succinyl-CoA synthetase)
• NADH and FADH2 produced during citric acid cycle used to generate ATP through electron transport chain and oxidative phosphorylation
  • Each NADH yields about 2.5 ATP while each FADH2 yields about 1.5 ATP
  • One turn of citric acid cycle generates approximately 10 ATP molecules indirectly through electron transport chain
  • Electron transport chain creates proton gradient across inner mitochondrial membrane drives ATP synthase to produce ATP

Cellular location and carbon dioxide production

• Citric acid cycle occurs in the matrix of mitochondria, the powerhouses of the cell
• Each turn of the cycle releases two carbon dioxide molecules, contributing to cellular respiration
• The cycle was elucidated by Hans Adolf Krebs, who received the Nobel Prize for his work on cellular respiration