Citric Acid Cycle (Krebs Cycle) – The Powerhouse of Cellular Metabolism

-

Introduction

The Citric Acid Cycle, also known as the Krebs Cycle or TCA Cycle (Tricarboxylic Acid Cycle), is central to cellular respiration, where carbohydrates, fats, and proteins are fully oxidized to generate energy. This pathway takes place in the mitochondria and is the final common pathway for the oxidation of fuel molecules. The cycle converts acetyl-CoA derived from carbohydrates, fatty acids, and amino acids into carbon dioxide and generates high-energy molecules such as NADH, FADH2, and GTP.

Step-by-Step Breakdown of the Citric Acid Cycle

  1. Formation of Citrate
    The cycle begins when acetyl-CoA, a two-carbon molecule, combines with oxaloacetate (a four-carbon molecule) to form citrate, a six-carbon compound. This reaction is catalyzed by citrate synthase.
    Key Point: Acetyl-CoA, derived from pyruvate (from glycolysis) or from fatty acids and amino acids, enters the cycle here.

  2. Isomerization of Citrate to Isocitrate
    Citrate undergoes an isomerization reaction, catalyzed by aconitase, to form isocitrate. This involves a dehydration step followed by a rehydration step, effectively rearranging the structure to prepare for the first decarboxylation.

  3. First Decarboxylation and NADH Production
    Isocitrate is oxidized by isocitrate dehydrogenase to form α-ketoglutarate, a five-carbon molecule. During this reaction, one molecule of carbon dioxide is released, and NAD+ is reduced to NADH.
    Key Point: This is the first of two decarboxylation reactions, where CO₂ is released as a byproduct.

  4. Second Decarboxylation and NADH Production
    α-ketoglutarate undergoes another decarboxylation, catalyzed by the α-ketoglutarate dehydrogenase complex. This produces succinyl-CoA, a four-carbon molecule, and another molecule of NADH is generated. This step is very similar to the pyruvate dehydrogenase reaction that generates acetyl-CoA from pyruvate.

  5. GTP Generation
    Succinyl-CoA is converted to succinate by succinyl-CoA synthetase, producing GTP (which can be easily converted to ATP) through substrate-level phosphorylation. This is the only step in the cycle that directly generates a high-energy phosphate compound.

  6. Oxidation of Succinate
    Succinate is oxidized to fumarate by succinate dehydrogenase, an enzyme that is part of both the Citric Acid Cycle and the Electron Transport Chain (ETC). During this step, FAD is reduced to FADH2, which will later donate electrons to the ETC.
    Key Point: FADH₂ yields less ATP than NADH because it enters the ETC at a different point.

  7. Hydration of Fumarate
    Fumarate is converted into malate by fumarase, a simple hydration reaction that adds a molecule of water across the double bond of fumarate.

  8. Regeneration of Oxaloacetate
    Finally, malate is oxidized by malate dehydrogenase to regenerate oxaloacetate, which can combine with another acetyl-CoA molecule to continue the cycle. NAD+ is reduced to NADH in this step, marking the third NADH production in one turn of the cycle.

Key Outputs of the Citric Acid Cycle

  • NADH and FADH2: 3 NADH and 1 FADH2 are produced per turn of the cycle. These molecules carry electrons to the Electron Transport Chain for ATP production.
  • GTP/ATP: 1 GTP (or ATP depending on the cell type) is produced through substrate-level phosphorylation.
  • CO₂: 2 molecules of carbon dioxide are released as waste products.
  • Oxaloacetate: Regenerated for another cycle to accept new acetyl-CoA molecules.

Why is the Citric Acid Cycle Important?

  • Central Role in Metabolism: The cycle is the convergence point of carbohydrate, fat, and protein metabolism, as acetyl-CoA can be derived from multiple sources.
  • Energy Generation: While the cycle itself directly produces only a small amount of ATP (or GTP), it generates large amounts of NADH and FADH2, which are used to produce ATP through oxidative phosphorylation in the Electron Transport Chain.
  • Biosynthetic Role: Many of the intermediates in the cycle are precursors for amino acids, nucleotides, and other biosynthetic pathways.

Regulation of the Citric Acid Cycle

The Citric Acid Cycle is tightly regulated at three main steps:

  1. Citrate Synthase: Inhibited by high concentrations of ATP, NADH, and citrate. When the cell’s energy levels are high, this enzyme is inhibited to prevent excessive acetyl-CoA consumption.
  2. Isocitrate Dehydrogenase: A major regulatory enzyme, it is activated by ADP (signaling low energy levels) and inhibited by NADH and ATP.
  3. α-Ketoglutarate Dehydrogenase: Inhibited by its products NADH and succinyl-CoA, and also by high levels of ATP.

Clinical Relevance

Disruptions in the Citric Acid Cycle are associated with a range of metabolic disorders and diseases, such as mitochondrial diseases. One prominent example is fumarase deficiency, a rare genetic disorder that severely impairs the body's ability to produce energy, leading to developmental issues and neurological symptoms.

Additionally, the Citric Acid Cycle is central to cancer metabolism. Many cancer cells rely on a modified version of the Citric Acid Cycle to meet their energy and biosynthetic demands. In fact, mutations in enzymes such as isocitrate dehydrogenase have been linked to certain cancers, making these enzymes targets for cancer therapies.

Conclusion
The Citric Acid Cycle is a core part of cellular respiration, acting as a metabolic hub where energy production and biosynthesis meet. Its efficient conversion of acetyl-CoA into energy-rich molecules is vital for cellular function, and its intermediates are essential for various biosynthetic processes.

Comments

Post a Comment

Popular posts from this blog

Understanding Orthopedic Conditions: Common Ailments and Medications

-
Orthopedic surgeons are specialized doctors who diagnose, treat, and manage musculoskeletal system conditions. This includes bones, joints, muscles, tendons, and ligaments. Here’s a look at 15 common medical conditions that orthopedic surgeons frequently treat and the medications commonly used in their management. 1. Osteoarthritis Ibuprofen : Reduces inflammation and pain. Acetaminophen : Alleviates pain without anti-inflammatory effects. Naproxen : Decreases inflammation and pain. Celecoxib (Celebrex) : Targets COX-2 enzyme to reduce inflammation and pain. Duloxetine (Cymbalta) : An antidepressant also used to manage chronic pain. 2. Rheumatoid Arthritis Methotrexate : A DMARD that slows disease progression and reduces joint damage. Adalimumab (Humira) : A biologic that targets TNF-alpha to reduce inflammation. Sulfasalazine : A DMARD that decreases inflammation. Etanercept (Enbrel) : A biologic that blocks TNF, reducing inflammation and halting disease progression. Leflunomide (Arav...
Read more

Unraveling the Complement System: A Key Defender in the Immune Response

-
The human immune system is an intricate network designed to defend the body against pathogens such as bacteria, viruses, and fungi. Among its many components, the complement system stands out as a crucial part of innate immunity. This sophisticated system of proteins works together to identify, attack, and eliminate invaders, playing a significant role in maintaining our health. In this blog post, we will explore the complement system, its pathways, and its importance in the immune response. What is the Complement System? The complement system consists of a series of proteins that circulate in the blood and tissue fluids. These proteins, produced primarily by the liver, work in a cascade manner, meaning that the activation of one protein triggers the activation of the next. This system complements the work of antibodies and phagocytic cells in clearing pathogens from an organism. Key Functions of the Complement System Opsonization : Enhancing the ability of phagocytes to engulf pathoge...
Read more

Understanding the Kinin System: A Key Player in Inflammation and Pain

-
The human body is a complex network of systems working in harmony to maintain health and respond to injuries. Among these systems, the kinin system plays a pivotal role in inflammation, pain regulation, and blood pressure control. While it may not be as well-known as other bodily systems, the kinin system's functions are crucial to our body's response to injury and infection. What is the Kinin System? The kinin system is a biochemical cascade that produces peptides known as kinins. The most well-known kinins are bradykinin and kallidin. These peptides are produced through the action of enzymes called kallikreins, which cleave kininogen precursors to release active kinins. Key Components of the Kinin System Kallikreins : These are enzymes that exist in various tissues and fluids within the body. They are responsible for cleaving kininogens to release kinins. Kininogens : These are precursor proteins that circulate in the bloodstream. When cleaved by kallikreins, they release act...
Read more