Beta-ketoacyl-ACP synthase III

Beta-ketoacyl-ACP synthase III (KAS III), also known as 3-oxoacyl-[acyl-carrier-protein] synthase III, is an enzyme that plays a crucial role in the fatty acid synthesis pathway, specifically in the initiation step of the synthesis process. This enzyme is responsible for the condensation of malonyl-ACP with acetyl-CoA, leading to the formation of a 3-ketoacyl-ACP compound. This reaction is pivotal in the elongation cycle of fatty acid synthesis, setting the foundation for the production of long-chain fatty acids.

Function

Beta-ketoacyl-ACP synthase III is one of the three types of KAS enzymes found in nature. Unlike KAS I and II, which are involved in the elongation steps of fatty acid synthesis, KAS III is unique in its role in initiating the process. It catalyzes the Claisen condensation between acetyl-CoA and malonyl-ACP, a reaction that is essential for the biosynthesis of fatty acids. This enzyme is highly specific for its substrates, particularly acetyl-CoA, distinguishing it from other KAS enzymes that have broader substrate specificities.

Structure

The structure of KAS III is characterized by a thiolase fold, which is common among enzymes involved in acyl-CoA metabolism. This fold provides the enzyme with the necessary structural framework to facilitate the binding of its substrates and the subsequent catalytic reaction. The active site of KAS III contains a cysteine residue that plays a critical role in the enzyme's catalytic mechanism, acting as a nucleophile in the condensation reaction.

Catalytic Mechanism

The catalytic mechanism of beta-ketoacyl-ACP synthase III involves several key steps. Initially, the enzyme binds to acetyl-CoA and malonyl-ACP, positioning them for the condensation reaction. The cysteine residue in the active site attacks the carbonyl carbon of acetyl-CoA, forming a carbon-carbon bond with the release of CoA. Subsequently, the enzyme facilitates the decarboxylation of malonyl-ACP, leading to the formation of a 3-ketoacyl-ACP product. This product then undergoes further processing in the fatty acid synthesis pathway.

Biological Significance

KAS III is essential for the biosynthesis of fatty acids, which are fundamental components of cell membranes and serve as important energy sources. The enzyme's specificity and role in initiating fatty acid synthesis make it a potential target for the development of antibacterial and antifungal agents. Inhibitors of KAS III could disrupt the fatty acid synthesis pathway in pathogens, leading to their death.

Inhibition

Several compounds have been identified as inhibitors of beta-ketoacyl-ACP synthase III, including cerulenin and thiolactomycin. These inhibitors bind to the active site of the enzyme, preventing it from catalyzing the condensation reaction. The development of specific KAS III inhibitors is of interest in the field of drug discovery, particularly for the treatment of infectious diseases caused by bacteria and fungi that rely on fatty acid synthesis for survival.

See Also

• Fatty acid synthesis
• Acyl carrier protein
• Enzyme
• Catalysis
• Antibacterial