Acetyl-CoA
From Wikipedia, the free encyclopedia
Acetyl-CoA is a very important molecule in metabolism since it is used in many biochemical reactions. Its main task is conveying the carbon atoms within the acetyl group to the citric acid cycle to be oxidized for energy production. Chemically it is the thioester between coenzyme A (an acyl group carrier) and acetic acid. Acetyl-CoA is produced during the second step of aerobic cellular respiration, pyruvic acid breakdown, which occurs in the matrix of the mitochondria. Acetyl Co-A then enters the Krebs Cycle.
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[edit] Functions
[edit] Pyruvate dehydrogenase reaction
The conversion of pyruvate into acetyl-CoA is referred to as the pyruvate dehydrogenase reaction. It is catalyzed by an enzyme-complex called pyruvate dehydrogenase.
The enzyme consists of 60 subunits:
- 24 pyruvate dehydrogenase,
- 24 dihydrolipoyl transacetylase, and
- 12 dihydrolipoyl dehydrogenase (commonly denoted E1, E2, and E3 respectively).
The E1 subunits use TPP (thiamin pyrophosphate), the E2 subunits use lipoate and coenzyme A, and the E3 subunits use FAD and NAD+ as coenzymes.
The reaction of this complex follows three steps:
- Initially, pyruvate is bound by pyruvate dehydrogenase (E1) subunits and attacked at C2 by the zwitterionic form (negative charge about C2 fo the thiazolium ring) of thiamin pyrophosphate, also bound by the enzyme. This tetrahedral intermediate undergoes decarboxylation resulting in an acyl anion equivalent (see cyanohydrin or aldehyde-dithiane umpolung chemistry, as well as benzoin condensation). This anion attacks the S1 of the oxidized lipoate species in an SN2-like mechanism that displaces the S2 thiol as a sulfide or sulfhydryl moiety. Subsequent breakdown of the thiazole-hemithioacetal species ejects the TPP cofactor and generates an S1 thioester about the lipoate moiety.
- At this point, the lipoate-thioester functionality is translocated into the lipoate transacetylase (E2) active site, where it undergoes a transacylation with coenzyme A, generating dihydrolipoate and acetyl-CoA which subsequently enters the citric acid cycle.
- The dihydrolipoate moiety then migrates to the dihydrolipoyl dehydrogenase (E3) active site where it undergoes FAD-mediated oxidation (identical in chemistry to disulfide isomerase) which returns lipoate to its resting state and generates FADH2, which is further oxidized by the bound nicotinamide cofactor producing NADH2 and regenerated flavin.
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[edit] Fatty acid metabolism
In animals, acetyl-CoA is very central to the balance between carbohydrate metabolism and fat metabolism. Normally, acetyl-CoA from fatty acid metabolism feeds into the citric acid 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 an excess of ketone bodies in the blood, a condition known as ketoacidosis. This can occur in diabetes, starvation or in people following low-carbohydrate diets, all of which can cause fats to be metabolised as a major source of energy.
In plants, de novo fatty acid synthesis occurs in the plastids. Many seeds accumulate large resevoirs 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.
[edit] Other reactions
It 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, cytosolic acetyl-CoA is synthesized by ATP citrate lyase [1].
Acetyl-CoA can be carboxylated in the cytosol by acetyl-CoA carboxylase, giving rise to malonyl-CoA, a substrate required for synthesis of flavonones and related polyketides, for elongation of fatty acids to produce waxes, cuticle, seed oils in members of the Brassica family, and for malonation of proteins and other phytochemicals [2].
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.
