Ketosynthase

Ketosynthase

Ketosynthase (KS) is a crucial enzyme involved in the biosynthesis of polyketides and fatty acids. It plays a pivotal role in the polyketide synthase (PKS) and fatty acid synthase (FAS) systems, catalyzing the condensation reactions that extend the carbon chain of the growing polyketide or fatty acid molecule.

Structure

Ketosynthases are typically large, multi-domain proteins that form part of a larger enzyme complex. The active site of ketosynthase contains a cysteine residue that forms a thioester bond with the acyl carrier protein (ACP)-bound substrate. This active site is highly conserved across different species and is essential for the enzyme's catalytic activity.

Mechanism

The ketosynthase enzyme catalyzes the decarboxylative condensation of an acyl-CoA or acyl-ACP with a malonyl-CoA or malonyl-ACP. This reaction involves the following steps:

1. Binding of the Acyl Substrate: The acyl group is transferred from the ACP to the active site cysteine of the ketosynthase. 2. Decarboxylation: The malonyl group undergoes decarboxylation to form an enolate ion. 3. Condensation: The enolate ion attacks the thioester-linked acyl group, forming a new carbon-carbon bond and extending the carbon chain by two carbons. 4. Release of the Product: The extended acyl chain is transferred back to the ACP, allowing the cycle to repeat.

Biological Function

Ketosynthases are integral to the production of a wide variety of natural products, including antibiotics, immunosuppressants, and anticancer agents. In fatty acid biosynthesis, ketosynthases are responsible for the elongation of the fatty acid chain, a process that is essential for the production of cellular membranes and energy storage molecules.

Types of Ketosynthases

There are several types of ketosynthases, each with specific roles in different biosynthetic pathways:

• Type I Ketosynthase: Found in modular polyketide synthases, these are part of large, multifunctional proteins.
• Type II Ketosynthase: Found in iterative polyketide synthases, these are discrete enzymes that work in conjunction with other proteins.
• Type III Ketosynthase: Also known as chalcone synthases, these are involved in the biosynthesis of flavonoids and other secondary metabolites.

Clinical Significance

Inhibitors of ketosynthase have been explored as potential antibiotics and anticancer agents. For example, the antibiotic thiolactomycin targets the ketosynthase domain of bacterial fatty acid synthase, inhibiting bacterial growth.

Also see

• Polyketide synthase
• Fatty acid synthase
• Acyl carrier protein
• Enzyme catalysis
• Biosynthesis