What is the Krebs (Citric Acid) cycle?

The Krebs Cycle (Citric Acid Cycle)

The Krebs cycle, also known as the citric acid cycle or tricarboxylic acid (TCA) cycle, is a central metabolic pathway that performs the essential function of oxidizing nutrients to support cellular bioenergetics and providing intermediates for biosynthetic processes.

Core Components and Function

The Krebs cycle operates in the mitochondrial matrix of eukaryotic cells and serves as the final common pathway for the oxidation of carbohydrates, fatty acids, and amino acids 1. It functions through a series of enzymatic reactions that oxidize acetyl-CoA, generating energy in the form of ATP, NADH, and FADH₂.

Key features of the Krebs cycle include:

• Starting point: Acetyl-CoA enters the cycle by combining with oxaloacetate to form citrate, catalyzed by citrate synthase
• Oxidative reactions: Through a series of eight enzymatic reactions, the cycle oxidizes acetyl-CoA completely to CO₂
• Energy production: Each cycle produces:
  • 1 GTP (equivalent to 1 ATP)
  • 3 NADH (which can generate 9 ATP through oxidative phosphorylation)
  • 1 FADH₂ (which can generate 2 ATP through oxidative phosphorylation)
• Amphibolic pathway: Functions in both catabolic (breaking down nutrients) and anabolic (providing biosynthetic precursors) processes

Cycle Steps

1. Citrate formation: Acetyl-CoA (2C) + Oxaloacetate (4C) → Citrate (6C)
2. Isomerization: Citrate → Isocitrate
3. First oxidative decarboxylation: Isocitrate → α-Ketoglutarate + CO₂ + NADH
4. Second oxidative decarboxylation: α-Ketoglutarate → Succinyl-CoA + CO₂ + NADH
5. Substrate-level phosphorylation: Succinyl-CoA → Succinate + GTP/ATP
6. FAD reduction: Succinate → Fumarate + FADH₂
7. Hydration: Fumarate → Malate
8. Final oxidation: Malate → Oxaloacetate + NADH

Metabolic Significance

The Krebs cycle is crucial for cellular metabolism for several reasons:

• Energy production: It is a major source of reducing equivalents (NADH and FADH₂) for the electron transport chain, which drives ATP synthesis 1
• Metabolic integration: It serves as a hub connecting various metabolic pathways, including glycolysis, fatty acid oxidation, amino acid metabolism, and gluconeogenesis 1
• Biosynthetic precursor provision: Intermediates of the cycle serve as building blocks for amino acids, nucleotides, heme, and other biomolecules 1
• Anaplerotic reactions: The cycle can be replenished through reactions like pyruvate carboxylation to oxaloacetate, which is essential for maintaining cycle function when intermediates are withdrawn for biosynthesis 1

Regulation

The Krebs cycle is tightly regulated at multiple points:

• Citrate synthase: Inhibited by ATP, NADH, and succinyl-CoA
• Isocitrate dehydrogenase: Activated by ADP and Ca²⁺; inhibited by ATP and NADH
• α-Ketoglutarate dehydrogenase: Inhibited by NADH and succinyl-CoA; activated by Ca²⁺
• Substrate availability: The cycle activity depends on the availability of acetyl-CoA, NAD⁺, and oxygen

Clinical Relevance

Understanding the Krebs cycle is important for several clinical contexts:

• Metabolic disorders: Defects in TCA cycle enzymes can lead to various metabolic disorders with neurological manifestations
• Cancer metabolism: Cancer cells often exhibit altered TCA cycle activity, with accumulation of certain intermediates that can act as oncometabolites 2
• Immune cell function: The cycle is rewired in activated immune cells like macrophages and dendritic cells, with intermediates like citrate, succinate, and fumarate acting as signaling molecules that regulate inflammatory responses 2
• Mitochondrial diseases: Many mitochondrial disorders involve dysfunction of TCA cycle enzymes
• Nutritional support: In critically ill patients, understanding the energy provision from different substrates through the Krebs cycle is important for optimal nutritional support 1

Evolutionary Significance

The Krebs cycle represents a remarkable example of evolutionary optimization:

• Analysis shows it is the most efficient chemical solution for oxidizing acetate to produce reducing equivalents for ATP synthesis 3
• It has the minimum possible number of steps and maximum ATP yield compared to alternative theoretical pathways 3
• Its evolution appears to have been opportunistic, building upon existing pathways for amino acid biosynthesis 3

The Krebs cycle stands as a cornerstone of cellular metabolism, demonstrating both elegant chemical design and evolutionary optimization in supporting the energy and biosynthetic needs of cells.