Computational identification and analysis of orphan assembly-line polyketide synthases

Area of Science:

• Biochemistry
• Bioinformatics
• Natural Product Discovery

Background:

• DNA sequence data is rapidly expanding, presenting opportunities to discover novel assembly-line polyketide synthases (PKSs).
• PKSs are crucial for producing biologically active natural products, including many antibiotics.
• Identifying and characterizing PKSs is essential for natural product drug discovery.

Purpose of the Study:

• To develop an automated method for extracting and cataloging multimodular PKS sequences from the NCBI database.
• To create a non-redundant catalog of assembly-line PKSs for future research.
• To demonstrate the utility of the catalog for identifying novel PKSs and potential antibiotic products.

Main Methods:

• Automated data extraction and consolidation of PKS sequences from the NCBI database.
• In silico analysis of identified PKS sequences, including engineering an orphan PKS for antibiotic analog production.
• Comparative sequence analysis to identify relationships among known and orphan PKSs.

Main Results:

• A catalog of 885 distinct assembly-line PKSs, including hybrid PKS/non-ribosomal peptide synthetases, was generated.
• The majority of identified PKSs were orphans, lacking known polyketide products.
• An orphan PKS was identified for potential engineering into an albocycline analog, and a novel metazoan PKS family was discovered.

Conclusions:

• The developed automated method and PKS catalog serve as a valuable community resource.
• This resource facilitates the discovery of new PKS families and their associated antibiotic products.
• The study highlights the potential for discovering novel bioactive compounds through PKS mining.