The citric acid cycle animation PDF

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The citric acid cycle This takes place in the mitochondrial matrix It takes acetyl CoA (2C) from other metabolic pathways and oxidised it to 2 carbon dioxide The cycle produces reducing agents and GTP, and regenerates oxaloacetate. The reducing agents are used in the electron transport chain to generate ATP. The intermediates are also used to synthesise chemicals that feed into other metabolic pathways including amino acid synthesis, fatty acid synthesis and gluconeogenesis. These are replaced by products of other pathways such as glycolysis and protein catabolism. Sources of acetyl CoA Glucose: -

Important during fed state and in the brain Breaks down glucose into two molecules of pyruvate (3C) Pyruvate enters mitochondrion and converted to acetyl CoA by pyruvate dehydrogenase complex Pyruvate dehydrogenase is regulated so it is active when acetyl CoA is needed and inhibited when acetyl CoA is supplied from other sources.

Fatty acids: -

Important during fasting state when glucose needs to be spared Fatty acid oxidation breaks fatty acid chains into acetyl CoA that enters the citric acid cycle It is regulated by regulating entry of fatty acids into mitochondrion Acetyl CoA from fatty acids inhibits pyruvate dehydrogenase which inhibits use of glucose as a fuel

Amino acids: -

Important during fed state if excess amino acids are eaten, and starvation to spare glucose. Some converted directly into acetyl CoA Some converted into pyruvate and then into acetyl CoA by pyruvate dehydrogenase.

Ketone bodies: -

Synthesised in liver during starvation to use as fuel for other tissues During starvation, liver oxidises large amounts of fatty acids to acetyl CoA Liver converts pairs of acetyl CoA into ketone bodies (4C) Ketone bodies are transported via blood to other tissues especially brain Ketone bodies then converted back to acetyl CoA and oxidised in the citric acid cycle, reducing need for glucose

The citric acid cycle is a cyclical pathway in which one substrate is regenerated (oxaloacetate) and one substrate is completely oxidised (acetyl CoA) 1) Acetyl CoA (2C) combines with oxaloacetate (4C) to form citrate (6C) by citrate synthase 2) Aconitase isomerizes citrate into isocitrate 3) Isocitrate dehydrogenase converts isocitrate (6C) into alpha-ketogluterate (5C) with CO2 formation and reduction of NAD to NADH. This is an important regulatory step. 4) Alpha-ketogluterate is converted into succinyl CoA (4C) by alpha-ketogluterate dehydrogenase with CO2 being lost and another reduction of NAD to NADH. This is a regulatory step. 5) Succinyl CoA is converted to succinate with substrate level phosphorylation of GDP to GTP (in some tissues ATP is phosphorylated) 6) Succinate dehydrogenase converts succinate to fumarate. Succinate dehydrogenase is embedded within the inner mitochondrial membrane. The FAD reduced is covalently attached to the enzyme, and its electrons feed directly into the electron transport chain. 7) Fumarate is converted into malate by fumarase. 8) Malate dehydrogenase regenerates oxaloacetate from malate, along with the reduction of another NAD.

Citric Acid Cycle Intermediates and Synthesis During citric acid cycle: -

Acetyl CoA is oxidised to 2 CO2, 3 NAD reduced 1 FAD reduced 1 GTP produced by substrate level phosphorylation NADH and FADH2 can be used to generate more ATP through oxidative phosphorylation in the electron transport chain

Oxaloacetate and Gluconeogenesis: -

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Malate can be used to synthesise glucose Malate can leave the mitochondrion and enter cytosol where gluconeogenesis occurs Cytosolic malate dehydrogenase converts malate to oxaloacetate and NAD is reduced Phosphoenolpyruvate carboxylase converts oxaloacetate to phosphoenolpyruvate, an intermediate of both glycolysis and gluconeogenesis.  GTP converted to GDP  CO2 produced Phosphoenolpyruvate can continue along gluconeogenesis pathway

Citrate and fatty acid synthesis: -

Citrate can be used to synthesise fatty acids Citrate can leave the mitochondrion and enter the cytosol where fatty acid synthesis occurs In the cytosol, citrate is converted to oxaloacetate, forming acetyl CoA in the process Cytosolic acetyl CoA is able to take part in fatty acid synthesis

Amino acid synthesis: Both alpha-ketogluterate and oxaloacetate can be converted into amino acids. Conversion of citric acid cycle intermediates to amino acids is used for amino acid synthesis, and also for breaking down other amino acids by removing their amine groups. -

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Alpha-ketoglutarate can be converted to glutamate by glutamate dehydrogenase in a reversible reaction. This reaction removes toxic ammonium ions from the cell. Alpha-ketoglutarate can also be converted to glutamate by several amino transferases. This reaction is part of breaking down amino acids, removing their amine groups and replacing with carbonyl groups, making them into keto-acids. Glutamate can be metabolised to form glutamine, proline, or arginine.

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Oxaloacetate can be converted to aspartate by aspartate transaminase in a reversible reaction, which also converts glutamate back to alpha-ketoglutarate. This reaction is important in disposing of waste nitrogen.

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Aspartate can be converted to asparagine

Replacing Citric Acid Cycle Intermediates The citric acid cycle produces energy (NADH, FADH2, GTP/ATP) by oxidising acetyl CoA. This requires oxaloacetate. Although oxaloacetate is regenerated, low amounts of oxaloacetate mean that acetyl CoA can only be oxidised at a very slow rate. Pyruvate can be carboxylated to form oxaloacetate, so that acetyl CoA can be oxidised at a faster rate and citric acid cycle activity is increased. Therefore, energy can be produced more quickly. Some amino acids can be converted to pyruvate, and most can be converted to other intermediates of the citric acid cycle.

As intermediates are used for biosynthesis, the rate of energy production by the cycle is decreased. Enzymes Regulation in the Citric Acid Cycle The enzymes of the citric acid cycle are regulated to respond to the ATP/ADP ratio and the NADH/NAD ratio producing energy as it is needed. The citric acid cycle is considered aerobic. The two most important regulated enzymes are isocitrate dehydrogenase and alpha-ketoglutarate dehydrogenase. The inhibition of any enzyme in the pathway affects the whole cycle: -

These enzymes are more active when concentrations of NAD or ADP are high, and NADH or ATP are low. In absence of oxygen, less NADH is converted back to NAD causing it to build up, and the citric acid cycle is inhibited. In muscle, these enzymes are also stimulated by Ca2+ which is released during muscle contractions i.e. when more energy is needed

Summary The citric acid cycle oxidises acetyl CoA, producing NADH and ATP It is more active when: -

There is a good supply of acetyl CoA to oxidise The Concentration of citric acid intermediates is high The cell is low in ATP (stimulates enzymes) The cells is low in NADH (stimulates enzymes) There is sufficient oxygen to turn the NADH back to NAD.

Aerobic metabolism: -

Citric acid cycle is aerobic and cannot continue without oxygen In the absence of oxygen, the NADH it produces accumulates, and several cycle enzymes are inhibited, inhibiting the whole cycle.

Fuel for electron transport chain: -

Produces NADH and FADH2 which is uses by the electron transport chain to produce ATP

Last stop for all metabolic fuels: -

Oxidises acetyl CoA from different metabolic fuels such as glucose, fatty acids, amino acids, ketone bodies

Precursor for biosynthesis: -

Intermediates can be used to synthesise different compounds including glucose, amino acids, fatty acids

Ammonia may interfere with the citric acid cycle: -

Ammonia is highly toxic especially to brain and nervous system Proposed mechanism of toxicity is due to the reversibility of the glutamate dehydrogenase enzyme When ammonia levels are too high, glutamate dehydrogenase catalyses formation of glutamate from alphaketoglutarate, depleting the citric acid cycle of its intermediates and decreasing the rate at which acetyl CoA is oxidised. This reduces the capacity of the cell to generate ATP.

Exercise: -

In skeletal muscle, pool of citric acid cycle intermediates increases More oxaloacetate is available to react with acetyl CoA and increases rate of citric acid cycle to produce NADH and FADH2, and ATP.

Provides GTP for gluconeogenesis: -

Reaction of succinyl CoA to succinate catalysed by succinyl CoA synthetase produces GTP

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In tissues that carry out gluconeogenesis (liver, kidneys) the reaction provides GTP needed to a reaction in the gluconeogenesis pathway catalysed by phosphoenolpyruvate carboxykinase. This reaction converts oxaloacetate into phosphoenolpyruvate....