8.1 Citric acid cycle: steps and regulation
3 min read•august 7, 2024
The citric acid cycle is a crucial metabolic pathway that breaks down nutrients for energy. It involves a series of enzyme-catalyzed reactions, producing high-energy molecules like NADH and FADH2 that fuel production.
Regulation of the cycle is key to maintaining energy balance. Allosteric enzymes respond to cellular energy levels, adjusting cycle activity based on ATP, NADH, and substrate availability. This fine-tuning ensures efficient energy production.
Citric Acid Cycle Enzymes
Catalytic Roles and Reactions
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- catalyzes the condensation of and to form , marking the first step of the citric acid cycle
- isomerizes citrate to via the intermediate cis-aconitate, allowing for the continuation of the cycle
- oxidatively decarboxylates isocitrate to form α-ketoglutarate, generating NADH in the process and contributing to the cycle's energy production
- α-Ketoglutarate dehydrogenase catalyzes the oxidative decarboxylation of α-ketoglutarate to form , generating NADH and serving as a key regulatory point in the cycle
- catalyzes the substrate-level phosphorylation of GDP or ADP to form or ATP, respectively, while converting succinyl- to
Oxidation-Reduction Reactions and Electron Transport
- oxidizes succinate to , reducing to FADH2 and serving as a direct link between the citric acid cycle and the
- catalyzes the hydration of fumarate to form , preparing the substrate for the final step of the cycle
- oxidizes malate to oxaloacetate, regenerating the starting compound of the citric acid cycle and reducing to NADH, which can feed into the electron transport chain
Energy Molecules and Regulation
High-Energy Compounds and Electron Carriers
- Acetyl-CoA, a high-energy compound derived from the oxidation of carbohydrates, fats, and proteins, serves as the primary input for the citric acid cycle
- NADH, produced by several enzymes in the citric acid cycle (isocitrate dehydrogenase, α-ketoglutarate dehydrogenase, and malate dehydrogenase), transfers electrons to the electron transport chain for ATP production
- FADH2, generated by succinate dehydrogenase, also transfers electrons to the electron transport chain, contributing to the proton gradient and subsequent ATP synthesis
- ATP, the primary energy currency of the cell, is directly produced by succinyl-CoA synthetase through substrate-level phosphorylation and indirectly via the electron transport chain and
Allosteric Regulation and Metabolic Control
- of citric acid cycle enzymes allows for precise control of the cycle's activity in response to the cell's energy demands and substrate availability
- Citrate synthase is inhibited by high levels of ATP, acetyl-CoA, and NADH, ensuring that the cycle does not proceed when energy is abundant or when there is a build-up of intermediates
- Isocitrate dehydrogenase is allosterically stimulated by ADP and inhibited by ATP and NADH, fine-tuning the cycle's activity based on the cell's energy status
- α-Ketoglutarate dehydrogenase is inhibited by high levels of NADH and succinyl-CoA, preventing the excessive accumulation of these compounds and maintaining the cycle's balance
- The citric acid cycle's regulation is closely linked to that of glycolysis and the electron transport chain, allowing for the coordinated control of cellular energy production in response to varying conditions (glucose availability, oxygen levels)
Key Terms to Review (30)
Acetyl-CoA: Acetyl-CoA is a crucial metabolic intermediate that plays a central role in energy production, as it serves as a substrate for the citric acid cycle and is a key molecule in the synthesis and degradation of fatty acids. It acts as a link between carbohydrate metabolism, lipid metabolism, and the production of energy in the form of ATP, thus integrating various metabolic pathways.
Aconitase: Aconitase is an enzyme that plays a critical role in the citric acid cycle (Krebs cycle) by catalyzing the isomerization of citrate to isocitrate. This enzyme facilitates a key step in cellular respiration, helping convert energy stored in carbohydrates, fats, and proteins into usable energy in the form of ATP. Aconitase also serves as an important regulatory point within the cycle, influencing metabolic pathways based on cellular conditions.
Allosteric Regulation: Allosteric regulation refers to the process by which the activity of an enzyme is modified through the binding of an effector molecule at a site other than the active site, leading to a change in its conformation. This regulatory mechanism plays a vital role in metabolic pathways, allowing cells to adaptively modulate enzyme function and coordinate biochemical processes.
Alpha-ketoglutarate: Alpha-ketoglutarate is a key intermediate in the citric acid cycle, playing a critical role in cellular respiration and energy production. It is formed from isocitrate through oxidative decarboxylation, and it can also serve as a substrate for various biosynthetic pathways, including amino acid synthesis. This compound connects crucial metabolic processes, such as the conversion of carbohydrates, fats, and proteins into usable energy.
Alpha-ketoglutarate dehydrogenase: Alpha-ketoglutarate dehydrogenase is an important enzyme in the citric acid cycle that catalyzes the conversion of alpha-ketoglutarate to succinyl-CoA, while reducing NAD+ to NADH. This enzyme plays a critical role in energy metabolism and is part of a multi-enzyme complex that includes several cofactors, which are essential for its activity. Its regulation is crucial for maintaining metabolic balance and influencing energy production within the cell.
Anaplerotic reactions: Anaplerotic reactions are metabolic processes that replenish intermediates of the citric acid cycle (CAC), ensuring its continuous function. These reactions are vital because they maintain the balance of metabolic pathways and support energy production by replenishing oxaloacetate and other key intermediates that can be drawn off for biosynthesis or energy generation.
ATP: ATP, or adenosine triphosphate, is a nucleotide that serves as the primary energy carrier in all living cells. It plays a crucial role in cellular processes by providing the energy needed for various biochemical reactions, including metabolism, muscle contraction, and the synthesis of macromolecules.
Cataplerotic reactions: Cataplerotic reactions are metabolic processes that help replenish intermediates of the citric acid cycle (CAC) by utilizing various substrates. These reactions are essential for maintaining the cycle's function and overall metabolic balance, especially when certain intermediates are withdrawn for other biosynthetic pathways or energy production. By providing necessary components, cataplerotic reactions ensure the continued operation of the CAC, which plays a critical role in cellular respiration and energy metabolism.
Citrate: Citrate is a key intermediate in the citric acid cycle, also known as the Krebs cycle, formed from the condensation of acetyl-CoA and oxaloacetate. It plays a vital role in cellular respiration by participating in a series of enzymatic reactions that lead to energy production through the oxidation of acetyl-CoA. The regulation of citrate levels can influence the citric acid cycle and is interconnected with various metabolic pathways, highlighting its importance in energy metabolism.
Citrate synthase: Citrate synthase is an essential enzyme in the citric acid cycle, responsible for catalyzing the first step of this metabolic pathway by combining acetyl-CoA and oxaloacetate to form citrate. This reaction is crucial as it initiates the cycle that generates energy through the oxidation of acetyl-CoA, linking carbohydrate, fat, and protein metabolism.
CoA: Coenzyme A (CoA) is a coenzyme that plays a crucial role in the metabolism of fatty acids and the citric acid cycle. It is responsible for carrying acyl groups, enabling the transfer of acetyl and other acyl groups in various biochemical reactions. This makes CoA essential for energy production and the synthesis of various biomolecules.
Electron transport chain: The electron transport chain (ETC) is a series of protein complexes and other molecules located in the inner mitochondrial membrane that transfer electrons from electron donors to electron acceptors through redox reactions. This process is crucial for cellular respiration, as it generates a proton gradient that powers ATP synthesis and facilitates the conversion of energy stored in nutrients into usable forms for biological functions.
FAD: FAD, or flavin adenine dinucleotide, is a coenzyme involved in various metabolic reactions, particularly in the transfer of electrons in cellular respiration. It plays a crucial role as an electron carrier in the citric acid cycle and other metabolic pathways, helping to facilitate the production of ATP, which is vital for energy in biological systems.
Feedback inhibition: Feedback inhibition is a regulatory mechanism in metabolic pathways where the end product of a reaction inhibits an enzyme involved in its synthesis, thereby preventing the overproduction of that product. This process ensures metabolic balance and efficient use of resources within a cell, linking it to various aspects of metabolism, enzyme function, and cellular signaling.
Fumarase: Fumarase is an enzyme that plays a crucial role in the citric acid cycle, also known as the Krebs cycle, by catalyzing the reversible hydration of fumarate to malate. This reaction is essential for the continuation of the cycle, as it links the steps involving the conversion of substrates into energy-rich molecules. Fumarase is vital for cellular respiration and energy production in aerobic organisms, helping convert carbohydrates, fats, and proteins into usable energy.
Fumarate: Fumarate is a key intermediate in the citric acid cycle, also known as the Krebs cycle, which plays a crucial role in cellular respiration. This four-carbon compound is formed from the oxidation of succinate and subsequently converted into malate through hydration. Fumarate not only contributes to energy production but also has regulatory roles in various metabolic pathways, making it significant in understanding how the citric acid cycle operates.
Gluconeogenesis: Gluconeogenesis is the metabolic process through which organisms synthesize glucose from non-carbohydrate precursors, primarily occurring in the liver and to a lesser extent in the kidneys. This pathway is crucial for maintaining blood glucose levels during fasting, starvation, or intense exercise, highlighting its importance in overall glucose metabolism and energy homeostasis.
GTP: Guanosine triphosphate (GTP) is a nucleotide that serves as an energy source and a signaling molecule in various cellular processes. It plays a critical role in protein synthesis, signal transduction, and as a substrate in several metabolic pathways, including the citric acid cycle and nucleotide metabolism. GTP is similar to ATP but contains guanine instead of adenine, making it essential for specific reactions and functions within the cell.
Isocitrate: Isocitrate is a six-carbon dicarboxylic acid that plays a crucial role as an intermediate in the citric acid cycle, also known as the Krebs cycle. It is formed from citrate through the action of the enzyme aconitase and is subsequently converted to alpha-ketoglutarate, a key step in energy production within aerobic respiration. The regulation of isocitrate's conversion is vital for controlling the flow of metabolites through the citric acid cycle.
Isocitrate dehydrogenase: Isocitrate dehydrogenase is an enzyme that plays a crucial role in the citric acid cycle by catalyzing the conversion of isocitrate to alpha-ketoglutarate, accompanied by the reduction of NAD+ to NADH. This enzyme is a key regulatory point in the cycle and is involved in cellular respiration, linking energy production to various metabolic pathways.
Malate: Malate is a four-carbon dicarboxylic acid that plays a critical role in the citric acid cycle, acting as an intermediate between fumarate and oxaloacetate. It is produced during the conversion of fumarate to malate by the enzyme fumarase and is further oxidized to regenerate oxaloacetate, which is essential for the continuation of the cycle and energy production in cellular respiration.
Malate dehydrogenase: Malate dehydrogenase is an enzyme that catalyzes the reversible conversion of malate to oxaloacetate while reducing NAD+ to NADH in the citric acid cycle. This enzyme plays a crucial role in energy production and metabolic regulation by linking the cycle's intermediate steps to the electron transport chain through NADH generation.
NAD+: NAD+ (Nicotinamide adenine dinucleotide) is a coenzyme found in all living cells that plays a critical role in metabolism by acting as an electron carrier in redox reactions. It is involved in transferring electrons during cellular respiration, particularly in the citric acid cycle, and is essential for energy production in biological systems. The ability of NAD+ to accept electrons and be reduced to NADH makes it vital for many metabolic pathways, linking various biochemical processes.
Oxaloacetate: Oxaloacetate is a four-carbon dicarboxylic acid that plays a crucial role in metabolism, serving as an intermediate in both gluconeogenesis and the citric acid cycle. It is essential for the conversion of pyruvate to glucose and for the entry of acetyl-CoA into the citric acid cycle, linking carbohydrate and fat metabolism and acting as a key point for energy production in cells.
Oxidative phosphorylation: Oxidative phosphorylation is a metabolic process that produces ATP through the transfer of electrons from NADH and FADH2 to oxygen via the electron transport chain, coupled with the phosphorylation of ADP to ATP. This process is vital for cellular energy production, linking it to other metabolic pathways such as the citric acid cycle and contributing to the overall metabolism and energy balance in biological systems.
Precursors for amino acids: Precursors for amino acids are the simple organic compounds that serve as building blocks or starting materials in the biosynthesis of amino acids. These precursors are often derived from metabolic pathways, including glycolysis and the citric acid cycle, highlighting their significance in cellular metabolism and the production of proteins essential for life.
Succinate: Succinate is a four-carbon dicarboxylic acid that plays a crucial role as an intermediate in the citric acid cycle, also known as the Krebs cycle. This compound is formed from fumarate through the action of the enzyme succinate dehydrogenase and is then converted to malate, demonstrating its importance in cellular respiration and energy production.
Succinate dehydrogenase: Succinate dehydrogenase is an enzyme that plays a crucial role in the citric acid cycle by catalyzing the conversion of succinate to fumarate, coupled with the reduction of FAD to FADH2. This enzyme not only participates in the citric acid cycle but also functions as a part of the electron transport chain, linking the two processes together. Its activity is essential for energy production in aerobic organisms.
Succinyl-CoA: Succinyl-CoA is a key intermediate in the citric acid cycle (Krebs cycle) and is a thioester compound formed from the condensation of succinate and coenzyme A. It plays an essential role in energy metabolism, particularly in linking carbohydrate and fatty acid metabolism to energy production through the citric acid cycle.
Succinyl-coa synthetase: Succinyl-CoA synthetase is an enzyme that catalyzes the conversion of succinyl-CoA to succinate, while simultaneously producing GTP or ATP from GDP or ADP and inorganic phosphate. This reaction is a key step in the citric acid cycle, linking energy production with the metabolic breakdown of acetyl-CoA. The function of this enzyme plays a crucial role in energy metabolism and regulation within the cycle.