Citric Acid Cycle

Overview – Citric Acid Cycle

• Other names 
  • Krebs cycle, tricarboxylic acid (TCA) cycle
• Function
  • generate high amounts of NADH/FADH₂ that act as fuel for ATP synthesis in the electron transport chain
• Pathway 
  • occurs in the mitochondria
  • requires O₂ to function
  • net equation
    • acetyl-CoA + 3 NAD⁺ + FAD + GDP + P_i → 2CO₂ + 3 NADH + FADH₂ + GTP + CoA
      • will theoretically yield 12 ATP (if ETC were 100% efficient)
      • both carbons of acetyl-CoA leave as CO₂ in two of the reactions
        • conversion of isocitrate to alpha ketoglutarate
        • conversion of alpha ketoglutarate to succinyl-CoA
  • Important enzymes
    • isocitrate dehydrogenase
      • stimulated by ↓ energy
        • ↑ ADP
      • inhibited by ↑ energy
        • ↑ ATP, NADH
    • α-ketoglutarate dehydrogenase complex 
      • requires the same cofactors as the pyruvate dehydrogenase complex
        • B₁, B₂, B₃, B₅, lipoic acid
        • in alcoholics, B₁ deficiency leads to Wernicke’s encephalopathy
          • triad of ataxia, confusion, ophthalmoplegia  
        • inhibited by ↑ energy
          • ↑ ATP, NADH
        • inhibited by ↑ intermediates in the cycle
          • ↑ succinyl-CoA
    • succinyl-CoA synthetase
      • generates GTP
    • succinate dehydrogenase
      • a member of both the citric acid cycle and the electron transport chain
  • important intermediates
    • citrate
      • functions to shuttle acetyl-CoA out of mitochondria for fatty acid synthesis
        • citrate shuttle
    • succinyl-CoA
      • building block for heme synthesis
    • fumarate
      • enters from the urea cycle
    • malate
      • functions as a gluconeogenic substrate
• Regulation
  • energy status control
    • NO hormonal control

Introduction

The citric acid cycle, also known as the Krebs cycle or the tricarboxylic acid (TCA) cycle, is a series of biochemical reactions that occur in the mitochondria of eukaryotic cells and the cytoplasm of prokaryotic cells. It is a crucial metabolic pathway that plays a central role in the aerobic respiration of all living organisms.

The citric acid cycle starts with the conversion of the two-carbon compound acetyl-CoA, which is derived from the breakdown of carbohydrates, fats, and proteins, into citrate, a six-carbon compound. Citrate is then converted into a series of intermediate compounds, including isocitrate, alpha-ketoglutarate, succinyl-CoA, succinate, fumarate, malate, and oxaloacetate, before being converted back into oxaloacetate, completing the cycle.

Types

There is only one type of Citric Acid Cycle, but there are different variations or modifications that can occur depending on the type of organism and the specific conditions in which the cycle is taking place.

Here are a few examples:

1. Anaerobic Citric Acid Cycle: Some bacteria, such as Acetobacterium woodii, use a modified version of the Citric Acid Cycle under anaerobic conditions. Instead of using oxygen as the final electron acceptor, they use other molecules such as fumarate or nitrate.
2. Glyoxylate Cycle: Plants and some bacteria have a modified version of the Citric Acid Cycle called the glyoxylate cycle. This cycle is used to convert stored lipids into carbohydrates, which can be used as an energy source. The glyoxylate cycle bypasses two steps of the Citric Acid Cycle and involves the synthesis of new enzymes.
3. Reverse Citric Acid Cycle: Some bacteria, such as Chlorobium, use a reversed version of the Citric Acid Cycle. In this cycle, carbon dioxide is fixed to produce organic compounds instead of being released. The Reverse Citric Acid Cycle is important for carbon fixation in some autotrophic bacteria.

Function

Its main function is to generate energy in the form of ATP (adenosine triphosphate) by breaking down acetyl-CoA, a molecule that is produced from the breakdown of carbohydrates, fats, and proteins.

The Citric Acid Cycle also serves several other important functions, including:

1. Production of NADH and FADH2: As acetyl-CoA is broken down, it generates electrons that are captured by NAD+ and FAD, producing NADH and FADH2, which are electron carriers that are used in the electron transport chain to generate ATP.
2. Regulation of cellular metabolism: The Citric Acid Cycle helps regulate the metabolic activity of the cell by controlling the levels of certain intermediates in the cycle, such as ATP, NADH, and citrate. This regulation ensures that the cell has enough energy and building blocks to carry out its functions.
3. Synthesis of biomolecules: The intermediates in the Citric Acid Cycle can be used to synthesize many important biomolecules, such as amino acids, nucleotides, and fatty acids. This makes the Citric Acid Cycle an important pathway for anabolic metabolism.

Overall, the Citric Acid Cycle plays a critical role in cellular metabolism by generating energy, regulating metabolic activity, and synthesizing important biomolecules.

Complications

1. Mitochondrial diseases: Mitochondrial diseases are a group of genetic disorders that affect the function of the mitochondria, which are the organelles that carry out the Citric Acid Cycle. These diseases can impair the production of energy and the synthesis of biomolecules, leading to a wide range of symptoms such as muscle weakness, fatigue, and neurological problems.
2. Inborn errors of metabolism: Inborn errors of metabolism are genetic disorders that affect the way the body processes certain nutrients, including those that are involved in the Citric Acid Cycle. For example, defects in the enzymes that catalyze the reactions in the Citric Acid Cycle can lead to the accumulation of toxic metabolites, causing damage to the cells and tissues.
3. Nutrient deficiencies: Nutrient deficiencies, such as a lack of vitamin B1 or iron, can impair the function of the Citric Acid Cycle by affecting the activity of the enzymes involved in the pathway. This can lead to a decrease in energy production and the accumulation of toxic metabolites.
4. Oxidative stress: Oxidative stress is a condition in which the levels of reactive oxygen species (ROS) in the cell exceed the capacity of the antioxidant defense systems. This can lead to damage to the mitochondria and the enzymes involved in the Citric Acid Cycle, impairing the production of energy and the synthesis of biomolecules.

Overall, the Citric Acid Cycle is a complex pathway that is subject to various complications and disorders that can affect its normal functioning. Understanding these complications is important for the diagnosis and treatment of metabolic disorders.

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