Engineered biosynthesis of regioselectively modified aromatic polyketides using bimodular polyketide synthases.
Yi Tang1, Taek Soon Lee, Chaitan Khosla
1Department of Chemical Engineering, Stanford University, Stanford, California, USA.
Plos Biology
|February 18, 2004
Summary
Engineered bacterial polyketide synthases (PKSs) enable the creation of novel aromatic polyketides using non-acetate primers. This breakthrough allows for the design of new antibiotics with enhanced activity against cancer and diabetes targets.
Area of Science:
- Biochemistry and Molecular Biology
- Natural Product Biosynthesis
- Synthetic Biology
Background:
- Bacterial aromatic polyketides, like tetracycline, are vital natural products synthesized by polyketide synthases (PKSs).
- Most polyketide backbones originate from malonyl-CoA units, but some, like R1128, use non-acetate primers.
- Understanding non-acetate priming is key to developing polyketides with improved pharmacological profiles.
Purpose of the Study:
- To develop a general method for the engineered biosynthesis of regioselectively modified aromatic polyketides.
- To investigate the mechanism of non-acetate priming in PKSs.
- To create novel anthraquinone antibiotics with tailored properties.
Main Methods:
- Coexpression of the R1128 initiation module with actinorhodin and tetracenomycin minimal PKS modules.
- Engineering hybrid PKSs by combining different initiation and minimal PKS modules.
- Utilizing tailoring enzymes (ketoreductases, cyclases) to process unnatural polyketides.
Main Results:
- Novel hexaketides and octaketides were synthesized using propionyl and isobutyryl primer units.
- Tailoring enzymes efficiently processed these unnatural polyketide structures.
- Engineered hybrid PKSs produced new anthraquinone antibiotics with predictable modifications.
Conclusions:
- Bimodular aromatic PKSs provide a general mechanism for non-acetate priming of polyketide backbones.
- Minimal PKSs control chain length by atom count, not elongation cycles.
- Auxiliary PKS enzymes recognize specific functional groups, enabling targeted modifications for novel drug discovery.
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