Thioesterase is an enzyme that catalyzes various chemical reactions within living organisms. Its primary function involves breaking a specific chemical linkage known as a thioester bond. Thioesterases are widespread across different life forms, from bacteria to humans, highlighting their importance in biological processes. This enzyme family is categorized under hydrolases, which break down compounds by adding water.
The Basic Mechanism of Thioesterases
A thioester bond is a chemical linkage between a carbonyl group (carbon double-bonded to oxygen) and a sulfur atom, often found in molecules like acyl-Coenzyme A (acyl-CoA) or acyl carrier protein (acyl-ACP). This sulfur-carbon connection stores chemical energy that can be released when the bond is broken. Thioesterases catalyze the breaking of this bond through a process called hydrolysis, involving the addition of a water molecule.
During this hydrolysis, the thioesterase enzyme positions the thioester substrate and a water molecule within its active site. The water molecule acts as a nucleophile, attacking the carbonyl carbon of the thioester, leading to a temporary intermediate structure. This intermediate then collapses, expelling the thiol group (containing sulfur) and forming a carboxylic acid. This action releases a fatty acid or another acyl group from a larger molecule, making it available for further metabolic steps.
Key Biological Roles
Thioesterases are involved in numerous biological pathways, performing varied and specific functions.
In fatty acid synthesis, thioesterases are responsible for the final step, where they release the newly formed fatty acid chain from the acyl carrier protein (ACP) complex. This release allows the fatty acid to be utilized or modified by the cell. Tailoring the specificity of these enzymes can even influence the length of the fatty acid produced.
Thioesterases also participate in the production of polyketides, which are a diverse group of natural products, including many antibiotics and immunosuppressants. In this process, thioesterase domains are often found at the end of polyketide synthase (PKS) assembly lines, where they cleave the polyketide chain from the enzyme. Some polyketide synthases also have type II thioesterases that remove aberrant intermediates.
Beyond synthesis, thioesterases contribute to lipid and steroid metabolism by regulating the intracellular levels of fatty acyl-CoAs. They hydrolyze acyl-CoAs into free fatty acids and coenzyme A, which influences the balance between fatty acid synthesis and breakdown. This regulation affects cellular energy metabolism and overall lipid balance. For example, acyl-CoA thioesterase 11 (ACOT11) cleaves long-chain fatty acyl-CoAs, promoting their storage in lipid droplets.
Thioesterases play a role in protein modification and degradation. Ubiquitin carboxyl-terminal hydrolases (UCHs), a type of thioesterase, remove ubiquitin from proteins. Ubiquitin is a small protein attached to other proteins, often marking them for degradation. By removing ubiquitin, thioesterases help regulate protein levels and prevent their premature breakdown.
Thioesterases in Health and Biotechnology
Dysregulation of thioesterase activity can have implications for human health. An imbalance in certain acyl-CoA thioesterases (ACOTs) has been linked to metabolic disorders such as obesity, diabetes, and nonalcoholic fatty liver disease. Specific ACOTs, such as ACOT8 and ACOT7, have shown increased expression in certain cancers, suggesting a role in cancer development by altering free fatty acid metabolism.
These enzymes represent potential targets for drug development. Inhibiting specific bacterial thioesterases, particularly those involved in fatty acid or polyketide synthesis, could lead to the creation of new antibiotics. For example, the thioesterase domain of the mycobacterial polyketide synthase Pks13 is a target for compounds aimed at disrupting mycolic acid biosynthesis in bacteria. Modulating human thioesterases, such as those implicated in cancer or metabolic disorders, offers avenues for therapeutic intervention.
In biotechnology, thioesterases are explored for various industrial applications. Their ability to cleave fatty acids makes them valuable for producing specific chemicals, biofuels, and other compounds. Plant acyl thioesterases are also of interest for the sustainable production of fatty acids and their derivatives for industrial uses.