MCAT Biochemistry
The TCA cycle, also known as the Krebs cycle, is a series of chemical reactions necessary for aerobic metabolism and ATP synthesis. Occurring in the mitochondria, the cycle begins with the combination of 2-carbon acetyl-CoA and 4-carbon oxaloacetate to form 6-carbon citrate via the enzyme citrate synthase. From there, a series of enzymatic reactions continue, including the formation of isocitrate, α-ketoglutarate, succinyl-CoA, succinate, fumarate, malate, and ultimately returning to oxaloacetate, completing the cycle.
The TCA cycle produces 3 NADH, 1 FADH2, and 1 GTP or ATP from 1 acetyl-CoA. It is crucial to note that various factors regulate the cycle, including ATP and NADH levels. Specifically, high levels of ATP and NADH inhibit the cycle, slowing down energy production, while low fuel levels, indicated by higher ADP levels, stimulate the TCA cycle.
Lesson Outline
<ul> <li>TCA Cycle Introduction</li> <ul> <li>Also called the Krebs cycle</li> <li>A series of chemical reactions necessary for aerobic metabolism and ATP synthesis</li> <li>Takes place in the mitochondria</li> <li>1 glucose produces 2 pyruvate, 2 NADH, and 2 net ATP during glycolysis</li> </ul> <li>Step 1: Citrate Synthase</li> <ul> <li>2-carbon acetyl-CoA and 4-carbon oxaloacetate combine to make 6-carbon citrate</li> <li>ATP inhibits citrate synthase</li> <li>Citrate is the first intermediate produced during the TCA cycle</li> </ul> <li>Step 2: Aconitase</li> <ul> <li>6-carbon citrate isomerizes to 6-carbon isocitrate</li> </ul> <li>Step 3: Isocitrate Dehydrogenase</li> <ul> <li>6-carbon isocitrate oxidizes to 5-carbon alpha-ketoglutarate</li> <li>Rate-determining step produces 1 NADH and 1 carbon dioxide</li> <li>ATP inhibits isocitrate dehydrogenase, while ADP activates it</li> </ul> <li>Step 4: Alpha-Ketoglutarate Dehydrogenase</li> <ul> <li>Oxidizes 5-carbon alpha-ketoglutarate into 4-carbon succinyl CoA</li> <li>Produces 1 NADH and 1 carbon dioxide</li> <li>ATP, NADH, and succinyl CoA inhibit alpha-ketoglutarate dehydrogenase</li> </ul> <li>Step 5: Succinyl CoA Synthetase</li> <ul> <li>Transforms 4-carbon succinyl CoA into 4-carbon succinate</li> <li>Produces 1 GTP or ATP</li> </ul> <li>Step 6: Succinate Dehydrogenase</li> <ul> <li>Turns 4-carbon succinate into 4-carbon fumarate</li> <li>Produces 1 FADH2</li> </ul> <li>Step 7: Fumarase</li> <ul> <li>Hydrolyzes 4-carbon fumarate to 4-carbon malate</li> </ul> <li>Step 8: Malate Dehydrogenase</li> <ul> <li>Oxidizes 4-carbon malate to 4-carbon oxaloacetate</li> <li>Produces third and final NADH</li> </ul> <li>NADH inhibits TCA cycle reactions</li> </ul>
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FAQs
Glycolysis, the TCA cycle, and oxidative phosphorylation are interconnected metabolic pathways that produce ATP during aerobic metabolism. Glycolysis occurs in the cytoplasm, converting glucose to pyruvate and generating some ATP and NADH. The pyruvate enters mitochondria and is converted to acetyl-CoA, which enters the TCA (Krebs) cycle, where further ATP, NADH, and FADH2 are produced. These NADH and FADH2 molecules then enter oxidative phosphorylation (via the electron transport chain) in the inner mitochondrial membrane, where they facilitate the synthesis of a larger amount of ATP. Altogether, these processes allow for efficient ATP synthesis in cells with access to oxygen.
The TCA cycle is also referred to as the Krebs cycle after its discoverer, Sir Hans Adolf Krebs.
The primary function of the TCA cycle in aerobic metabolism is to produce high-energy molecules like NADH and FADH2 (reduced electron carriers) and a small amount of ATP. The TCA cycle begins with the condensation of acetyl-CoA with oxaloacetate, followed by a series of redox, decarboxylation, and substrate-level phosphorylation reactions. The high-energy molecules NADH and FADH2 generated during the TCA cycle donate their electrons to the electron transport chain, which drives the process of oxidative phosphorylation, ultimately resulting in the synthesis of a significant amount of ATP.
Substrates enter the TCA cycle primarily through the conversion of pyruvate, generated during glycolysis, into acetyl-CoA. This process is catalyzed by the pyruvate dehydrogenase complex within the mitochondria. Acetyl-CoA can also be generated from the β-oxidation of fatty acids and the deamination of certain amino acids. The TCA cycle is regulated at multiple key enzymatic steps, including the actions of citrate synthase, isocitrate dehydrogenase, and α-ketoglutarate dehydrogenase. Availability of substrates, energy demand, and allosteric regulation by intermediates and end products (such as ATP) contribute to the fine-tuning of the TCA cycle's activity.
