From the Guidelines
The Krebs cycle, also known as the citric acid cycle or tricarboxylic acid (TCA) cycle, is a series of chemical reactions that occurs in the mitochondria of cells to generate energy through the oxidation of acetyl-CoA derived from carbohydrates, fats, and proteins. This cycle is a central metabolic pathway that connects carbohydrate, fat, and protein metabolism. It begins when acetyl-CoA combines with oxaloacetate to form citric acid, then proceeds through eight steps, regenerating oxaloacetate at the end. During these reactions, the cycle produces carbon dioxide as waste, generates high-energy electron carriers (NADH and FADH2) that feed into the electron transport chain to produce ATP, and creates precursors for amino acid synthesis. For each glucose molecule that enters cellular respiration, the Krebs cycle runs twice, producing six NADH, two FADH2, and two ATP molecules. The cycle is regulated by several enzymes and is inhibited when cellular energy levels are high. Understanding the Krebs cycle is fundamental to comprehending how cells convert food into usable energy and how metabolic disorders can arise when this process is disrupted, as seen in conditions such as diabetes where insulin deficiency affects the functioning of the Krebs cycle 1. Moreover, the Krebs cycle is also affected by certain drugs that can induce cardiac mitochondrial cardiotoxicity by inhibiting mitochondrial enzymes involved in the Krebs cycle 1. The importance of the Krebs cycle in energy metabolism is highlighted by its role in providing ATP in the absence of oxygen, offering a higher oxidative efficiency, and allowing an anaplerotic flux that provides Krebs-cycle intermediates and other compounds 1. In summary, the Krebs cycle is a vital metabolic pathway that plays a central role in energy production and is essential for maintaining proper cellular function.
From the Research
Overview of the Krebs Cycle
- The Krebs cycle, also known as the tricarboxylic acid (TCA) or citric acid cycle, is a central metabolic pathway that takes place in prokaryotic cells and in the mitochondria of eukaryotic cells 2.
- This cycle is crucial for energy production and anabolic processes, and its impairment is associated with several diseases, particularly those involving neurodegeneration 2.
Function and Regulation
- The Krebs cycle functions as a biosynthetic pathway, with intermediates leaving to be converted into various compounds such as glutamate, GABA, glutamine, and aspartate 3.
- The cycle requires regulation to maintain its function, with evidence suggesting that mitochondrial enzyme activity is regulated by activation/deactivation of protein kinases and phosphatases 2.
- Hormonal-like regulation by posttranscriptional events mediated by activable kinases and phosphatases may also play a role in regulating the Krebs cycle 2.
Evolutionary Origin
- The evolutionary origin of the Krebs cycle has been a topic of interest, with studies suggesting that it may have emerged from pathways for amino acid biosynthesis 4.
- One study proposed that the Krebs cycle originated from the prebiotic oxidation of α-hydroxy carboxylates, which led to the formation of α-oxo carboxylates that feature in the Krebs cycle and glyoxylate shunt 5.
- Another study analyzed the Krebs cycle as a problem of chemical design and demonstrated that the actual Krebs cycle is the best possible chemical design, with the least possible number of steps and the greatest ATP yielding 4.
Historical Context
- The Krebs cycle was discovered by Hans Krebs, who also discovered two other cycles, and his work has had a significant impact on our understanding of metabolic pathways 6.
- The centenary of Hans Krebs' birth provides an opportunity to reflect on the circumstances and experiments that led to the establishment of these metabolic pathways 6.