Polyketide Synthetase

Polyketide synthases (PKSs) are a group of enzymes responsible for the biosynthesis of polyketides, a diverse class of natural products with significant pharmaceutical importance. These enzymes catalyze the assembly of polyketide chains through the successive condensation of simple carboxylic acid units. 

Types of Polyketide Synthases

1. Type I PKSs:
   • Modular PKSs: Found in microorganisms like bacteria, these are large, multifunctional enzymes with a modular architecture. Each module is responsible for one cycle of chain elongation and contains multiple catalytic domains.
   • Iterative PKSs: Found in fungi, these enzymes use a single module iteratively to elongate the polyketide chain.
2. Type II PKSs:
   • These are multienzyme complexes primarily found in bacteria, particularly actinomycetes. Each enzyme typically performs a single function, and the complex works together to build the polyketide.
3. Type III PKSs:
   • Also known as chalcone synthase-like PKSs, these are simpler homodimeric enzymes found in plants and some bacteria. They produce polyketides through the iterative addition of extender units without modular organization.

Structure and Function

Modular PKSs (Type I):

• Loading Module: Initiates the synthesis by attaching a starter unit (e.g., acetyl-CoA) to the enzyme.
• Extension Modules: Each module contains a set of domains that add and process an extender unit (e.g., malonyl-CoA):
  • Acyltransferase (AT): Selects and transfers the extender unit to the acyl carrier protein (ACP).
  • Ketosynthase (KS): Catalyzes the condensation reaction that extends the polyketide chain.
  • Acyl Carrier Protein (ACP): Carries the growing polyketide chain as a thioester.
  • Optional Domains: May include ketoreductase (KR), dehydratase (DH), and enoyl reductase (ER) to modify the β-carbon position of the polyketide.
• Thioesterase (TE) Domain: Releases the completed polyketide from the enzyme, often cyclizing it.

Iterative PKSs (Type I):

• These function similarly to modular PKSs but use the same set of catalytic domains repeatedly to elongate the chain.

Type II PKSs:

• These involve multiple discrete enzymes that work in a coordinated manner. Key components include:
  • KSα and KSβ: Core enzymes for chain elongation.
  • ACP: Carries the growing chain.
  • Cyclases, aromatases, and ketoreductases: Modify the chain during and after elongation.

Type III PKSs:

• These enzymes directly use the acyl-CoA substrates to perform condensation reactions, producing polyketides with simpler structures compared to Type I and II.

Mechanism

1. Chain Initiation:
   • The starter unit is attached to the PKS by the loading module or domain.
2. Chain Elongation:
   • Extender units are added in a stepwise fashion. Each cycle involves condensation, reduction, dehydration, and reduction reactions, depending on the enzyme’s domain composition.
3. Chain Termination:
   • The completed polyketide chain is released from the enzyme, often by a thioesterase domain, which can also cyclize the product to form rings.

Genetic and Synthetic Biology Applications

• Genetic Engineering: By manipulating the genes encoding PKSs, scientists can create new polyketides with desirable properties. This is achieved by swapping, adding, or deleting specific modules or domains.
• Synthetic Biology: Advanced techniques allow the design and construction of synthetic PKS pathways to produce novel compounds or increase yields of existing ones.

Pharmaceutical Importance

Polyketides produced by PKSs have a wide range of therapeutic applications, including:

• Antibiotics: Erythromycin, tetracycline
• Anticancer Agents: Doxorubicin
• Immunosuppressants: Tacrolimus
• Cholesterol-Lowering Agents: Lovastatin

Polyketide synthases are essential for the biosynthesis of complex and bioactive natural products. Understanding their structure, function, and the mechanisms they employ provides valuable insights into natural product biosynthesis and opens up avenues for novel drug discovery and development through biotechnological and synthetic biology approaches.