Biochemistry - Lesson 14: Citric Acid Cycle (TCA Cycle)
The tricarboxylic acid (TCA) cycle, also referred to as the citric acid cycle or Krebs cycle, is the hub of aerobic metabolism. Acetyl-CoA, produced from various substrates (primarily pyruvate, but also fatty acids and certain amino acids), enters this cycle in the mitochondrial matrix, where carbons are fully oxidized to CO₂. The cycle generates high-energy electrons carried by NADH and FADH₂, which feed into oxidative phosphorylation for ATP production, as well as a small amount of GTP directly. Notably, many cycle intermediates also serve as precursors for biosynthetic pathways, rendering the TCA cycle amphibolic.
Pyruvate Dehydrogenase Complex
Before entering the TCA cycle, pyruvate from glycolysis is decarboxylated by the pyruvate dehydrogenase (PDH) complex, yielding acetyl-CoA. This multi-enzyme complex uses thiamine pyrophosphate (TPP), lipoate, FAD, coenzyme A, and NAD⁺. PDH is regulated by phosphorylation and product inhibition (acetyl-CoA, NADH), linking glycolysis to aerobic metabolism.
Citric Acid Cycle Steps
In the TCA cycle, each acetyl group (2 carbons) condenses with oxaloacetate (4 carbons) to form citrate (6 carbons), followed by a series of oxidations and decarboxylations, regenerating oxaloacetate. The cycle’s net yield per turn:
- 3 NADH
- 1 FADH₂
- 1 GTP (often converted to ATP)
- 2 CO₂
Each turn of the cycle thus recycles oxaloacetate to accept the next acetyl group, fueling continuous oxidation as long as substrates and oxygen are available. Below is a table summarizing the major enzymes and reactions, highlighting where reducing equivalents (NADH, FADH₂) and CO₂ are generated.
Overall Pathway Flow
The diagram below shows pyruvate descending through the pyruvate dehydrogenase complex to acetyl-CoA, continuing downward until succinyl-CoA and eventually to oxaloacetate, then ascending from oxaloacetate back to citrate synthase.
(Acetyl-CoA Formation)"] PDH --> AC["Acetyl-CoA"] AC --> CS["Citrate Synthase"] CS --> CIT["Citrate"] CIT --> ISODH["Isocitrate Dehydrogenase"] ISODH --> AKG["α-Ketoglutarate"] AKG --> KGDH["α-Ketoglutarate Dehydrogenase"] KGDH --> SUCCoA["Succinyl-CoA"] SUCCoA --> Succ["Succinate"] Succ --> Fum["Fumarate"] Fum --> Mal["Malate"] Mal --> OAA["Oxaloacetate"] direction BT OAA --> CS
Regulation
The TCA cycle’s rate is chiefly governed by three enzymes:
- Citrate Synthase: Slowed by high ATP, NADH, citrate, and succinyl-CoA.
- Isocitrate Dehydrogenase: Stimulated by ADP, inhibited by NADH and ATP.
- α-Ketoglutarate Dehydrogenase: Inhibited by NADH, succinyl-CoA, ATP.
High-energy signals (ATP, NADH) decelerate the cycle, preventing excessive oxidation of substrates when energy is ample.
Amphibolic Nature
While primarily catabolic (oxidizing carbons for ATP production), the TCA cycle also provides intermediates for biosynthesis:
- Oxaloacetate for gluconeogenesis (via PEP) or aspartate family amino acids.
- α-Ketoglutarate for glutamate family amino acids.
- Succinyl-CoA for porphyrins and heme.
- Citrate for fatty acid synthesis (transported out of mitochondria as a source of acetyl-CoA).
Cells replenish these intermediates via anaplerotic reactions, such as pyruvate carboxylation to oxaloacetate, preserving cycle function when intermediates are siphoned off for anabolism.
Summary
The citric acid cycle fully oxidizes acetyl units to CO₂, yielding NADH, FADH₂, and GTP—hallmarks of aerobic energy production. Beyond ATP generation, it furnishes precursors for numerous biosynthetic pathways, exemplifying its amphibolic identity. Regulation responds to ATP and NADH levels and substrate availability, ensuring metabolic flux aligns with cellular demands. Mastering TCA cycle details underpins comprehension of broader metabolic integration, connecting carbohydrate, lipid, and amino acid catabolism to anabolism.
Suggested Reading:
Lehninger Principles of Biochemistry (chapters on the citric acid cycle and respiration)
Biochemistry by Berg, Tymoczko, and Stryer (sections detailing TCA cycle regulation and anaplerosis)
