20.9: Thioesters: Biological Carboxylic Acid Derivatives
- Page ID
Introduction to thioesters and Coenzyme A
In the metabolism of lipids (fats and oils), thioesters are the principal form of activated carboxylate groups. They are employed as acyl carriers, assisting with the transfer of acyl groups such as fatty acids from one acyl X substrate to another.
The ‘acyl X group’ in a thioester is a thiol. The most important thiol compound used to make thioesters is called coenzyme A, which has the following structure:
Coenzyme A is often abbreviated HSCoA, in order to emphasize that it is the thiol sulfur that provides the critical thioester linkage to acyl groups. When fuel (carbohydrate and fat) is broken down in your body, it is eventually converted to a simple two-carbon unit called acetyl CoA, which is essentially a thioester derivative of acetic acid:
Activation of fatty acids by coenzyme A: a thioesterification reaction
In the biologically active form of fatty acids, the carboxylate groups have been converted to thioesters using coenzyme A. For example, the activated form of the C16 fatty acid palmitate is:
Let’s take a look at how this activation takes place, in a reaction catalyzed by an enzyme called acyl CoA synthetase. You already know that carboxylates are not themselves good substrates for acyl substitution reactions, and must be activated. Thus, you might predict that the first step of this reaction requires ATP to make a high-energy acyl phosphate intermediate. In fact, the activated carboxylate in this case is an acyl-AMP, formed in the same way as the acyl-AMP intermediate in the asparagine synthetase reaction.
The activated acyl-AMP intermediate is then attacked by the thiol sulfur of coenzyme A, and the AMP group is expelled to form the fatty acyl CoA.
Transfer of fatty acyl groups to glycerol: a thioester to ester substitution
The -SCoA thioester form of the fatty acid is a good substrate for a number of metabolic transformations. This is the form of fatty acid, for example, that is oxidized and broken down for energy in the mitochondria of your cells. Fatty acyl CoA also serves as substrate for the construction of triacylglycerol, which is the fat molecule that your body uses to store energy in fat cells. Recall that triacylglycerol is composed of a glycerol ‘backbone’ connected to three fatty acid groups through ester linkages.
The reaction in which a fatty acid acyl group is linked to glycerol represents the conversion of a thioester (fatty acyl CoA) to an ester. First, however, a transthioesterification reaction occurs. A transthioesterification is merely the conversion of one thioester to another. In the case of monoacylglycerolacyltransferase, the fatty acyl group first trades its thioester link to coenzyme A for another thioester link to a cysteine residue in the active site of the enzyme. It is a common strategy for enzymes to first form a covalent link to one substrate before catalyzing the principle chemical reaction.
The fatty acyl group is now ready to be transferred to glycerol, trading its thioester linkage to the cysteine for a new ester linkage to one of the alcohol groups on glycerol. The attacking nucelophile in this reaction is of course the alcohol oxygen of monoacylglycerol.
Because esters are more stable than thioesters, this is an energetically downhill reaction.
In the previous section we saw one example of a transthioesterification. Another important transthioesterification reaction involves acetyl CoA, the activated form of acetic acid and the basic two-carbon building block for fats and oils. Before it can be incorporated into a growing fatty acid molecule, acetyl CoA must first be linked to a so-called ‘acyl carrier protein’ (ACP). The acetyl group is linked to the acyl carrier protein via a thiol group on a carrier molecule that is covalently attached to the protein.
Notice that the structure of this carrier group (called phosphopantetheine) is identical to the region of coenzyme A (structure shown earlier in this section) near the thiol group. Once attached to the ACP, the two-carbon acetyl group condenses with another acyl group (which is also attached to its own ACP), and the fatty acid chain begins to grow.
Finally, a transthioesterification is the final step in one of the most important and well-studied reactions in animal metabolism: the conversion of pyruvate to acetyl CoA by a cluster of enzymes called the pyruvate dehydrogenase complex.
The overall reaction looks simple, but is actually quite complex and involves several intermediate species. The final step in the process is a transthioesterification, involving a dithiol molecule called lipoamide:
We will look more closely at the complete biochemical transformation catalyzed by the pyruvate dehydrogenase complex in section 16.12B.
Hydrolysis of thioesters
The acyl group of a thioester can be transferred to a water molecule in a hydrolysis reaction, resulting in a carboxylate. An example of thioester hydrolysis is the conversion of (S)-citryl CoA to citrate in the citric acid cycle (also known as the Krebs cycle).
Reactivity of thioesters and acyl phosphates
Thioesters are reactive among the biologically relevant acyl groups. However, thioesters are not as reactive as an acid chlorides or acid anhydrides.
Relative reactivity of biologically relevant acyl groups
Contributors and Attributions
Dr. Dietmar Kennepohl FCIC (Professor of Chemistry, Athabasca University)
Prof. Steven Farmer (Sonoma State University)
Organic Chemistry With a Biological Emphasis by Tim Soderberg (University of Minnesota, Morris)