21.8 Chemistry of Thioesters and Acyl Phosphates: Biological Carboxylic Acid Derivatives

Thioesters and acyl phosphates are key players in cellular metabolism. These molecules, like Acetyl-CoA, have a unique structure that makes them more reactive than other carboxylic acid derivatives. This reactivity is crucial for their roles in important biological processes.

Nucleophilic acyl substitution reactions involving thioesters are vital in biology. For example, N-acetylglucosamine, a component of cell surface glycoproteins and chitin, is formed when glucosamine reacts with acetyl-CoA. This showcases how thioesters participate in building essential biological molecules.

Thioesters and Acyl Phosphates

Structure and function of thioesters

• Contain a sulfur atom instead of the oxygen atom in the ester functional group
• General structure: R-C(=O)-S-R', where R and R' are alkyl or aryl groups
• Acetyl Coenzyme A (Acetyl-CoA) is a crucial molecule in cellular metabolism
  • Consists of an acetyl group (CH3-C(=O)-) bound to Coenzyme A (CoA) through a thioester bond
  • Plays a central role in the citric acid cycle, fatty acid synthesis, and other metabolic pathways
• Thioesters are more reactive than oxygen esters due to the weaker C-S bond compared to the C-O bond
  • The weaker C-S bond makes the carbonyl carbon more electrophilic and susceptible to nucleophilic attack
  • Allows thioesters to participate readily in various biological reactions (citric acid cycle, fatty acid synthesis)

Reactivity of acyl CoA vs carboxylic acids

• Acyl CoA compounds (thioesters) are more reactive than carboxylic acids and other carboxylic acid derivatives
• Reactivity order of carboxylic acid derivatives (most reactive to least reactive):
  1. Acyl chlorides (R-C(=O)-Cl)
  2. Anhydrides (R-C(=O)-O-C(=O)-R)
  3. Thioesters (R-C(=O)-S-R')
  4. Esters (R-C(=O)-O-R')
  5. Amides (R-C(=O)-NH2)
  6. Carboxylic acids (R-C(=O)-OH)
• The high reactivity of acyl CoA compounds enables them to participate readily in biological reactions
  • Citric acid cycle
  • Fatty acid synthesis
• Carboxylic acids are less reactive due to the stronger C-O bond and the stabilizing effect of the hydroxyl group

Nucleophilic acyl substitution in biology

• Involves the replacement of the leaving group in a carboxylic acid derivative by a nucleophile
  • The nucleophile attacks the electrophilic carbonyl carbon, displacing the leaving group and forming a new bond
• N-Acetylglucosamine (GlcNAc) is formed by the nucleophilic acyl substitution reaction between glucosamine (a nucleophilic amine) and acetyl-CoA (a thioester)
  1. The amine group of glucosamine attacks the electrophilic carbonyl carbon of acetyl-CoA
  2. Coenzyme A (the leaving group) is displaced
  3. An amide bond is formed
  • The resulting product is N-acetylglucosamine, with the acetyl group (CH3-C(=O)-) attached to the amine group of glucosamine
• GlcNAc is an important component of cell surface glycoproteins and chitin
  • Chitin is a structural polysaccharide found in the exoskeletons of arthropods (insects, crustaceans) and cell walls of fungi
• Other examples of biologically important molecules formed by nucleophilic acyl substitution reactions:
  • Acetylcholine (a neurotransmitter)
  • Acetylated proteins (involved in gene regulation and cellular signaling)
  • Fatty acid synthesis builds long-chain fatty acids from acetyl-CoA units

Biological Reactions and Catalysis

• Acylation: The process of adding an acyl group to a molecule, often catalyzed by enzymes in metabolic pathways
• Hydrolysis: The breakdown of molecules through reaction with water, common in the metabolism of thioesters and acyl phosphates
• Enzyme catalysis: Proteins that accelerate chemical reactions in biological systems, often involved in the formation and breakdown of thioesters and acyl phosphates
• Metabolic pathways: Series of chemical reactions in cells that maintain life, frequently involving thioesters and acyl phosphates as intermediates or energy carriers