Polyketides are secondary metabolites from bacteria, fungi, plants, and animals. Secondary metabolites seem to be unnecessary for an organism’s ontogeny, but appear to have applications such as defence and intercellular communication. Polyketides are derived from the polymerization of acetyl and propionyl subunits in a similar process to fatty acid synthesis. They also serve as building blocks for a broad range of natural products or are derivatized.

Polyketides are structurally a very diverse family of natural products with an extremely broad range of biological activities and pharmacological properties. Polyketide antibiotics, antifungals, cytostatics, anticholesterolemics, antiparasitics, coccidiostatics, animal growth promotants and natural insecticides are in commercial use.

Examples

• Macrolides
  • Picromycin, the first isolated macrolide (1950).
  • The antibiotics erythromycin B, clarithromycin, and azithromycin.
  • The immunosuppressant tacrolimus (FK506).
• Polyene antibiotics
  • Amphotericin.
• Tetracyclines
  • The tetracycline family of antibiotics.
• Others
  • Discodermolide

Biosynthesis

The biosynthesis of polyketides shares striking similarities with the fatty acid biosynthesis. Polyketides are synthesized by one or more specialized polyketide-synthase (PKS) enzyme. The PKS genes for a certain polyketide are usually organized in one operon in bacteria and in gene clusters in eukaryotes. The type I polyketide-synthases are large, highly modular proteins, while type II polyketide-synthases are aggregates of monofunctional proteins.

Each type I polyketide-synthase module consists of several domains with defined functions, separated by short spacer regions. The order of modules and domains of a complete polyketide-synthase is as follows (in the order N-terminus to C-terminus):

• Starting or loading module: AT-ACP-
• Elongation or extending modules: -KS-AT-^*-ACP-
• Termination or releasing module: -TE

Domains:

• AT: Acyl-transferase
• ACP: Acyl-carrier-protein with an SH group on the cofactor, a serine-attached 4'PP (4'-phospho-pantethein)
• KS: Keto-synthase with an SH group on a cysteine side-chain
• KR: Keto-reductase
• DH: Dehydratase
• ER: Enoyl-reductase
• TE: Thio-esterase

The polyketide chain and the starter groups are bound with their carboxy group to the SH groups of the ACP and the KS domain through a thioester linkage: R-C(=O)OH + HS-protein <=> R-C(=O)S-protein + H₂O. The growing chain is handed over from one SH group to the next by trans-acylations and is releases at the end by hydrolysis or by cyclization (alcoholysis or aminolysis).

Starting stage:

• The starter group, usually acetyl-CoA or malonyl-CoA, is loaded onto the ACP domain of the starter module catalyzed by the starter module's AT domain.

Elongation stages:

• The polyketide chain is handed over from the ACP domain of the previous module to the KS domain of the current module, catalyzed by the KS domain.
• The elongation group, usually malonyl-CoA or methyl-malonyl-CoA, is loaded onto the current ACP domain catalyzed by the current AT domain.
• The ACP-bound elongation group reacts in a Claisen condensation with the KS-bound polyketide chain under CO₂ evolution, leaving a free KS domain and an ACP-bound elongated polyketide chain. The reaction takes place at the KS_n-bound end of the chain, so that the chain moves out one position and the elangation group becomes the new bound group.
• Optionally, the new fragment of the polyketide chain can be altered stepwise by additional domains. The KR (keto-reductase) domain reduces the β-keto group to a β-hydroxy group, the DH (dehydratase) domain splits off H₂O, resulting in the α-β-unsaturated alkene, and the ER (enoyl-reductase) domain reduces the α-β-double-bond to a single-bond.
• This cycle is repeated for each elongation module.

Termination stage:

• The TE (thio-esterase) domain hydrolyzes the completed polyketide chain from the ACP-domain of the previous module.

See also

• Esterase

Plant toxin insecticides | Biochemistry | Molecular biology | Enzymes | Polyketide antibiotics

Polyketide | Polykétide