Citric Acid Cycle Overview

Overview

This section explains the steps that convert pyruvate to acetyl CoA, describes how the citric acid cycle works, and contrasts circular and linear metabolic pathways.

Pyruvate Oxidation and Entry into the Citric Acid Cycle

• In aerobic conditions, pyruvate from glycolysis enters the mitochondria in eukaryotes.
• Pyruvate is converted into an acetyl group, which combines with coenzyme A (CoA) to form acetyl CoA.
• The conversion involves three steps: removal of CO₂, oxidation to form NADH, and transfer of the acetyl group to CoA.
• For each glucose, two pyruvate molecules are processed, forming two acetyl CoA and two NADH, releasing two CO₂.

Structure and Function of the Citric Acid Cycle

• The citric acid cycle (also called Krebs or TCA cycle) is a circular pathway located in the mitochondrial matrix.
• Acetyl CoA (2C) combines with oxaloacetate (4C) to form citrate (6C) at the start of the cycle.
• The cycle is a closed loop—its end product (oxaloacetate) is used in the initial step.
• The cycle is considered aerobic because the reduced cofactors (NADH, FADH₂) require oxygen to transfer their electrons.

Steps of the Citric Acid Cycle

• Step 1: Acetyl group joins oxaloacetate to form citrate; this step is irreversible and regulated by ATP levels.
• Step 2: Citrate is converted to its isomer, isocitrate.
• Step 3: Isocitrate is oxidized to α-ketoglutarate, producing NADH and CO₂; regulated by ATP/NADH.
• Step 4: α-ketoglutarate is oxidized to succinyl CoA, yielding another NADH and CO₂; feedback inhibited.
• Step 5: Succinyl CoA is converted to succinate, generating ATP or GTP via substrate-level phosphorylation.
• Step 6: Succinate is oxidized to fumarate, reducing FAD to FADH₂.
• Step 7: Fumarate is converted to malate after hydration.
• Step 8: Malate is oxidized to oxaloacetate, forming one more NADH.

Outputs and Importance of the Cycle

• For each acetyl CoA, the cycle produces 2 CO₂, 3 NADH, 1 FADH₂, and 1 ATP or GTP.
• All six carbons from glucose are eventually released as CO₂ after two turns per glucose.
• Reduced carriers (NADH, FADH₂) feed electrons to the electron transport chain for ATP production.
• Several intermediates serve as starting points for biosynthesis (cycle is amphibolic).

Key Terms & Definitions

• Acetyl CoA — a molecule formed from pyruvate and CoA, entering the citric acid cycle.
• Citric acid cycle/Krebs cycle/TCA cycle — a circular metabolic pathway that oxidizes acetyl CoA to CO₂ and produces NADH and FADH₂.
• Oxaloacetate — a four-carbon molecule that starts and ends the citric acid cycle.
• NADH, FADH₂ — reduced electron carriers that drive ATP production in the electron transport chain.
• Substrate-level phosphorylation — direct synthesis of ATP/GTP using energy from a high-energy substrate molecule.
• Amphibolic — describes pathways that are both catabolic (breakdown) and anabolic (biosynthesis).

Action Items / Next Steps

• Review animations of the citric acid cycle to strengthen understanding.
• Study the regulation points and products of each cycle step for exam preparation.