APPLICATIONS OF TECHNOLOGY:
- Drug development
- Chemical Engineering
- Saves time in developing novel or drop-in molecules using type I PKS
- Easily identify polyketide synthase (PKS) modules based either on amino acid sequence or on the chemical structure of the cognate polyketide intermediate
- More reliable construction of functional PKS chimeras
Type I modular polyketide synthases (PKS) have a unique modular structure in which the product of each module is determined by the catalytic domains that comprise each module. This modular nature suggests that their biosynthetic power can be harnessed for combinatorial biosynthesis. Previous work has demonstrated that it is possible to construct functional chimeric PKSs by exchanging catalytic domains between heterologous PKS modules. However, limitations in the theoretical understanding of the complex protein-protein interactions that govern the fold and function of natural and engineered PKSs mean that identifying strategies to reliably design functional PKS chimeras remains an open research problem.
Researchers at Berkeley Lab have developed a computational platform, known as ClusterCAD, that facilitates the informed design of chimeric type I modular PKSs in order to achieve the microbial production of novel drug analogs and industrially relevant small molecules. These type I modular PKS clusters are contained in the ClusterCAD database and are linked to the corresponding MiBiG database and NCBI Nucleotide database entries. It provides chemical structures with stereochemistry for the intermediates generated by each PKS module, as well as sequence- and structure-based search tools that allow users to identify modules based either on amino acid sequence or on the chemical structure of the cognate polyketide intermediate. This facilitates the process behind chimeric PKS design, as the nature of protein-protein interactions are very complex.
ClusterCAD provides the first database of PKS biosynthetic clusters that contains predicted chemical structures for the polyketide intermediates generated by each module, as well as the predicted relatively solvent accessibility and secondary structure of each subunit. With search tools to query the database for modules based on either amino acid sequence, or on the chemical structure of the cognate polyketide intermediate, ClusterCAD provides the first computational platform developed for computer-aided design of chimeric PKSs.
- Clara H Eng
- Tyler W H Backman
- Constance B Bailey
- Christophe Magnan
- Hector Garcia Martin
- Leonard Katz
- Pierre Baldi
- Jay D Keasling
FOR MORE INFORMATION:
ClusterCAD: a computational platform for type I modular polyketide synthase design. Eng, C.H.*, Backman, T.W.H.*, Bailey, C.B., Magnan, C., Martin, H.G., Katz, L., Baldi, P., Keasling, J.D., Nucleic Acids Research, 2017 Oct.,https://doi.org/10.1093/nar/gkx893
JBEI ClusterCAD web page: https://clustercad.jbei.org/
OPPORTUNITIES: Available/Open Source