Engineering the acyltransferase substrate specificity of assembly line polyketide synthases

Area of Science:

• Biochemistry
• Natural Product Synthesis
• Drug Discovery

Background:

• Polyketide natural products exhibit diverse therapeutic applications, including antibiotics and anti-cancer agents.
• Modular polyketide synthases produce these molecules through an assembly-line process.
• Acyltransferase (AT) domains within these synthases control the selection of building blocks, significantly influencing structural diversity.

Purpose of the Study:

• To review recent advancements in engineering acyltransferase (AT) domains for polyketide natural product synthesis.
• To explore strategies for generating novel, therapeutically active compounds by modifying AT domains.
• To propose new engineering approaches based on current knowledge of AT domains.

Main Methods:

• Analysis of AT sequence and structural data.
• Investigation of mechanistic insights into AT domain function.
• Methods for producing diverse extender units for polyketide synthesis.
• Review of previous AT domain engineering attempts.

Main Results:

• Recent developments provide tools for successful AT domain engineering.
• Understanding AT mechanisms and structural data is crucial for targeted modifications.
• Diverse extender unit pools enhance the potential for novel polyketide structures.

Conclusions:

• Engineering AT domains is a promising strategy for creating novel polyketide natural products.
• Combining sequence, structural, and mechanistic data can guide successful engineering efforts.
• This approach holds potential for producing biologically active 'unnatural' natural products with therapeutic value.