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acetyl-CoA

Wednesday 2 June 2004

Definition: Acetyl-CoA is an important molecule in metabolism, used in many biochemical reactions.

Its main use is to convey the carbon atoms within the acetyl group to the citric acid cycle (Krebs cycle) to be oxidized for energy production.

Its is the base of the biosynthesis of fatty acids and cholesterol.

Acetyl-CoA is also an important component in the biogenic synthesis of the neurotransmitter acetylcholine. Choline, in combination with Acetyl-CoA, is catalyzed by the enzyme choline acetyltransferase to produce acetylcholine and a coenzyme a byproduct.

Structure

In chemical structure, acetyl-CoA is the thioester between coenzyme A (a thiol) and acetic acid (an acyl group carrier). Acetyl-CoA is produced during the second step of aerobic cellular respiration, pyruvate decarboxylation, which occurs in the matrix of the mitochondria. Acetyl-CoA then enters the citric acid cycle (Krebs cycle).

Metabolism

Acetyl-CoA is produced in mitochondria through the metabolism of fatty acids and the oxidation of pyruvate to acetyl-CoA.

When ATP is needed, this acetyl-CoA can enter the Krebs cycle to drive oxidative phosphorylation. When ATP supplies are abundant, the acetyl-CoA can be diverted to other purposes like energy storage in the form of fatty acids.

The biosynthesis of fatty acids from this acetyl-CoA cannot take place directly however, since it is produced inside mitochondria while fatty acid biosynthesis occurs in the cytosol.

There is not a mechanism that directly transports acetyl-CoA out of mitochondria. To be transported, the acetyl-CoA must be chemically converted to citric acid using a pathway called the tricarboxylate transport system.

Inside mitochondria, the enzyme citrate synthase joins acetyl-CoA with oxaloacetate to make citrate. This citrate is transported from the mitochondria to the cytosol, thus transporting the acetyl-CoA in the form of citrate. Once in the cytosol, the citrate is converted back to oxaloacetate, which is then reduced to malate.

Malate can be oxidized to pyruvate by the malic enzyme, with production of NADPH as well that can contribute to fatty acid biosynthesis. Pyruvate can be reimported back into the mitochondria.

Alternatively, malate can be transported itself back into the mitochondria and used to produce NADH once inside mitochondria.

Pyruvate dehydrogenase and pyruvate formate lyase reactions

The oxidative conversion of pyruvate into acetyl-CoA is referred to as the pyruvate dehydrogenase reaction. It is catalyzed by the pyruvate dehydrogenase complex.

Other conversions between pyruvate and acetyl-CoA are possible. For example, pyruvate formate lyase disproportionates pyruvate into acetyl-CoA and formic acid. The pyruvate formate lyase reaction does not involve any net oxidation or reduction.

Acetyl-CoA and fatty acid metabolism

In animals, acetyl-CoA is very central to the balance between carbohydrate metabolism and fat metabolism (fatty acid synthesis).

In normal circumstances, acetyl-CoA from fatty acid metabolism feeds into the citric acid cycle (Krebs cycle), contributing to the cell’s energy supply.

In the liver, when levels of circulating fatty acids are high, the production of acetyl-CoA from fat breakdown exceeds the cellular energy requirements. To make use of the energy available from the excess acetyl-CoA, ketone bodies are produced which can then circulate in the blood.

In some circumstances, this can lead to the presence of ketone bodies in the blood, a condition called ketosis. Benign dietary ketosis can safely occur in people following low-carbohydrate diets, which cause fats to be metabolised as a major source of energy. This is different from ketosis brought on as a result of starvation and ketoacidosis, a dangerous condition that can affect diabetics.

In plants, de novo fatty acid synthesis occurs in the plastids. Many seeds accumulate large reservoirs of seed oils to support germination and early growth of the seedling before it is a net photosynthetic organism. Fatty acids are incorporated into membrane lipids, the major component of most membranes.

Other reactions

Acetyl-CoA is the precursor to HMG-CoA, which, in animals, is a vital component in cholesterol and ketone synthesis. Furthermore, it contributes an acetyl group to choline to produce acetylcholine, in a reaction catalysed by choline acetyltransferase.

In plants and animals, cytosolic acetyl-CoA is synthesized by ATP citrate lyase. When glucose is abundant in the blood of animals, it is converted via glycolysis in the cytosol to pyruvate, and thence to acetyl-CoA in the mitochondrion. The excess of acetyl-CoA results in production of excess citrate, which is exported into the cytosol to give rise to cytosolic acetyl-CoA.

Acetyl-CoA can be carboxylated in the cytosol by acetyl-CoA carboxylase, giving rise to malonyl-CoA, a substrate required for synthesis of flavonoids and related polyketides, for elongation of fatty acids to produce waxes, cuticle, and seed oils in members of the Brassica family, and for malonation of proteins and other phytochemicals.

Two acetyl-CoA can be condensed to create acetoacetyl-CoA, the first step in the HMG-CoA/ mevalonic acid pathway leading to synthesis of isoprenoids. In plants, these include sesquiterpenes, brassinosteroids (hormones), and membrane sterols.

Synthesis of Cholesterol and other Steroids:

Acetyl CoA forms the basis from which the fairly complicated steroids are synthesized. Some steroids of importance include cholesterol, bile salts, sex hormones, aldosterone, and cortisol.

The major concern about cholesterol in the diet is muted somewhat by the knowledge that the liver can and does synthesize all of the cholesterol that the body needs.

Excess cholesterol, whether from food or synthesized by the liver, ends up in the blood stream where it builds up on the artery walls.

It has been determined that cholesterol levels can be controlled by lowering the amount of saturated fat and increasing the unsaturated fats.

Unsaturated fats seem to speed the rate at which cholesterol breaks down in the blood. Controlling fats and cholesterol in the diet can significantly affect the levels of these substances in the blood.

Acetyl-CoA and lipogenesis

Since carbohydrates are the major part of the diet, they must be immediately converted into energy, stored as glycogen, or converted into fats. The introduction has already presented the facts about the necessity of storing energy as fat. A total of 55% of the carbohydrates are involved in the synthesis of fats.

The total energy content of the diet must be balanced with the energy requirements of the human body. If excess foods (calories) are ingested beyond the body’s energy needs, the excess foods (energy) are converted into fat. If insufficient calories are ingested, the energy deficit is made up by oxidizing fat reserves. These simple facts provide the key to weight control although it is probably more easily understood than carried out in practice.

Excessive deposits of lipids lead to an obese condition. Extensive blood capillary networks in these deposits mean that they are quite active metabolically. Obesity puts a strain on the heart by causing it to pump blood through extra capillaries. Generally, obesity results from overeating, but a few people have malfunctioning endocrine glands.

Lipid metabolism is in a constant state of dynamic equilibrium. This means that some lipids are constantly being oxidized to meet energy needs, while others are being synthesized and stored. In rats, the average life-time of a single lipid molecule ranges from 2 to 10 days. A similar figure probably applies to human lipid metabolism.

The sequence of reactions involved in the formation of lipids is known as Lipogenesis. Lipogenesis is not simply the reverse of the fatty acid spiral, but does start with acetyl CoA and does build up by the addition of two carbons units. The synthesis occurs in the cytoplasm in contrast to the degradation (oxidation) which occurs in the mitochondria. Many of the enzymes for the fatty acid synthesis are organized into a multienzyme complex called fatty acid synthetase.

The major points in the overall lipogenesis reactions are:

1) ATP is required
2) The reactions are reductions (addition of H+ and use of NADPH) which are the reverse of the oxidations in the fatty acid spiral.

Acetyl-CoA, starvation and insuline deficiency: Synthesis of ketone bodies

When the body is deprived of food whether by voluntary or involuntary fasting, starvation is the net result. During starvation, glycogen reserves are rapidly depleted and the body begins to metabolize reserves of fat (lipolysis) and protein.

The entry of acetyl-CoA into the citric acid cycle depends on the availability of oxaloacetic acid for the formation of citric acid. In starvation or uncontrolled diabetes situations, oxaloacetic acid is used to synthesize glucose and is then not available for use with acetyl-CoA.

Under these conditions, acetyl-CoA is diverted from the citric acid cycle to the formation of acetoacetic and 3-hydroxybutanoic acids. In three steps, two acetyl-CoA react to make acetoacetic acid. The acetoacetic acid may be changed into either acetone or 3-hydroxybutanoic acid. All three compounds are collectively known as ketone bodies even though one is not a ketone.

The odor of acetone may be detected on the breath of a person with excess ketone bodies in the blood. The overall accumulation of ketone bodies in blood and urine is known as ketosis. The acids also upset buffers in the blood to cause acidosis.

Both acetoacetic acid and 3-hydroxybutanoic acid can be used by the heart, kidneys, and brain for metabolism to produce energy.

The heart and kidneys actually prefer these to glucose. In contrast, the brain prefers glucose, but will adapt if necessary in starvation or diabetic conditions.