Polyketide synthase

Polyketide synthases, also known as PKSs, are a family of enzymes or enzyme complexes that produce polyketides, a large class of secondary metabolites, in bacteria, fungi, plants, and animals. 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:
* 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. (See below.)

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.

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
* 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.

tages

The growing chain is handed over from one SH group to the next by trans-acylationsand 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 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 elangation 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.

See also

* Doxorubicin

External links

*


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