Polyketide Bioderivatization Using the Promiscuous Acyltransferase KirCII

Area of Science:

• Biochemistry
• Synthetic Biology
• Natural Product Synthesis

Background:

• Acyltransferases (ATs) are crucial enzymes in polyketide biosynthesis, dictating precursor selection and influencing structural diversity.
• The discrete AT KirCII, from the kirromycin antibiotic pathway, has previously shown the ability to incorporate non-malonate extender units.
• Understanding AT promiscuity is key to expanding the chemical space of natural products.

Purpose of the Study:

• To leverage the promiscuity of the KirCII acyltransferase for the generation of novel kirromycin analogs.
• To explore the utility of modified kirromycins in synthetic biology and drug discovery.
• To demonstrate the application of click chemistry for further functionalization of newly synthesized compounds.

Main Methods:

• In vivo generation of modified kirromycins using the promiscuous KirCII AT.
• Incorporation of allyl and propargyl extender units into the kirromycin scaffold.
• Utilizing propargyl-modified kirromycins as substrates for click chemistry reactions.

Main Results:

• Successfully synthesized novel kirromycin derivatives containing allyl and propargyl side chains in vivo.
• Demonstrated the successful application of click chemistry for further derivatization of propargyl-containing kirromycins.
• Expanded the structural diversity of kirromycin antibiotics through enzymatic promiscuity and subsequent chemical modification.

Conclusions:

• The promiscuity of KirCII can be exploited to generate diverse kirromycin analogs with unique side chains.
• Allyl and propargyl modifications provide versatile handles for further synthetic elaboration via click chemistry.
• This approach offers a powerful strategy for the discovery of new bioactive natural product derivatives.