Polyketide synthase

Polyketide synthases (PKSs) are a family of multi-domain enzymes or enzyme complexes that produce polyketides, a large class of secondary metabolites, in bacteria, fungi, plants, and a few animal lineages. The biosyntheses of polyketides share striking similarities with fatty acid biosynthesis.

The PKS genes for a certain polyketide are usually organized in one operon in bacteria and in gene clusters in eukaryotes.

Classification
PKSs can be classified into three groups:
 * Type I polyketide synthases are large, highly modular proteins.
 * Type II polyketide synthases are aggregates of monofunctional proteins.
 * Type III polyketide synthases do not use ACP domains.

Type I PKSs are further subdivided:
 * Iterative PKSs reuse domains in a cyclic fashion.
 * Modular PKSs contain a sequence of separate modules and do not repeat domains.

Iterative PKSs (IPKSs) can be still further subdivided:
 * NR-PKSs &mdash; non-reducing PKSs, the products of which are true polyketides
 * PR-PKSs &mdash; partially reducing PKSs
 * FR-PKSs &mdash; fully reducing PKSs, the products of which are fatty acid derivatives

Modules and domains


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-[DH-ER-KR]-ACP-
 * Termination or releasing module: -TE

Domains:


 * AT: Acyltransferase
 * ACP: Acyl carrier protein with an SH group on the cofactor, a serine-attached 4'-phosphopantetheine
 * KS: Keto-synthase with an SH group on a cysteine side-chain
 * KR: Ketoreductase
 * DH: Dehydratase
 * ER: Enoylreductase
 * MT: Methyltransferase O- or C- (α or β)
 * SH: Sulfhydrolase
 * TE: Thioesterase

The polyketide chain and the starter groups are bound with their carboxy functional 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.

Stages
The growing chain is handed over from one thiol group to the next by trans-acylations and is released 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 methylmalonyl-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 KSn-bound end of the chain, so that the chain moves out one position and the elongation group becomes the new bound group.
 * Optionally, the 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. It is important to note that these modification domains actually affect the previous addition to the chain (i.e. the group added in the previous module), not the component recruited to the ACP domain of the module containing the modification domain.
 * 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.

Pharmacological Relevance
Polyketide synthases are an important source of naturally occurring small molecules used for chemotherapy. For example, many of the commonly used antibiotics, such as tetracyclin, and macrolides are produced by polyketide synthases. Other industrially important polyketides are rapamycin (immunosuppressant), erythromycin (antibiotic), lovastatin (anticholesterol drug), and epothilone B (anticancer drug).

Ecological Significance
Only about 1% of all known organic molecules are natural products, yet it has been recognized that that almost two thirds of all drugs currently in use are at least in part derived from a natural source. This bias is commonly explained with the argument that natural products have co-evolved in the environment for long time periods and have therefore been pre-selected for active structures. Polyketide synthase products include lipids with antibiotic, antifungal, antitumor, and predator-defense properties; however, many of the polyketide synthase pathways that bacteria, fungi and plants commonly use have not yet been characterized. Methods for the detection of novel polyketide synthase pathways in the environment have therefore been developed. Molecular evidence supports the notion that many novel polyketides remain to be discovered from bacterial sources.