thioester

Meaning: A thioester is a carboxylic acid derivative in which sulfur replaces the ester oxygen. In metabolism the sulfur comes from a thiol such as coenzyme A, acyl carrier protein, or a cysteine side chain. Thioesters count as "high-energy" because hydrolysis is strongly exergonic. Sulfur's larger 3p orbital overlaps poorly with the carbonyl carbon, so there is less resonance stabilization than in an oxygen ester, and the carbonyl carbon is more electrophilic. The products, a carboxylate and a thiol, are more stable. This makes thioesters good acyl-transfer groups.

Equation: R–CO–S–R′ + H₂O → R–COO⁻ + R′–SH + H⁺, with ΔG°′ ≈ −31 kJ/mol for acetyl-CoA. R is the acyl carbon chain, R′ is the group on sulfur (such as CoA), and ΔG°′ is the standard free energy change at pH 7 (J/mol).

On the MCAT: You need to recognize acetyl-CoA, succinyl-CoA, and fatty acyl-CoA as thioesters. In the citric acid cycle, cleaving succinyl-CoA to succinate drives GTP or ATP formation by substrate-level phosphorylation. Fatty acid activation uses ATP to build the acyl-CoA thioester. Glyceraldehyde-3-phosphate dehydrogenase forms a cysteine thioester intermediate whose energy is then used to add phosphate. Questions ask which bond is cleaved or whether a coupled step is favorable.

Common confusion: Students say the energy comes from breaking the C–S bond itself. Breaking a bond costs energy. The release comes from the net hydrolysis, because the products are more stable than the thioester. A thioester (R–CO–S–R′) is also not a thioether (R–S–R′).