engleski

In silico recombination using the Avermectin gene-cluster for the development of novel antiparasitics

Parasites are a major problem both for meat production and in fish farming. Avermectin and its derivatives have proved very successful antiparasitics, but there is a constant demand for new compounds. The most important traditional path to new compounds is by screening for secondary metabolites. The diminishing returns from this approach have stimulated the development of alternative approaches in recent years. Avermectin, which is produced by Streptomyces avermitilis, is a polyketide that is synthesised by a modular polyketide synthase (PKS). Such PKSs function on a "building block" basis so that it is possible to obtain derivatives in a rational way by carrying out defined genetic manipulation on individual modules. Unfortunately, this usually results in dramatic decreases of yield making industrial production impossible. We have suggested an alternative approach using homologous recombination between different clusters. This will select recombinants between closely related modules without unnatural junctions and may, thus, result in higher yields. We have developed a generic computer program package CompGen that contains programs to predict recombination sites. The package also predicts the primary linear polyketide chain products of recombinant clusters. The package was used to examine potential recombinants between the avermectin gene cluster and other PKS clusters. The compounds were classified in terms of their similarity to avermectin to identify candidates for novel antiparasitics.

Polyketides; homologous recombination; modules

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