Decision making by modular polyketide synthases and implications for genetic engineering

Covering: up to 2025Modular polyketide synthases (PKSs) are often described as molecular-scale assembly lines - a moniker that implies a high-degree of coordinated and regulated activity. Belying this characterization, all of these systems must navigate a number of critical biosynthetic 'choices' in order to faithfully produce one or a limited number of products. Such alternative options occur at all stages of the assembly process, including building block selection, chain extension, intersubunit transfer, modification by in-trans acting enzymes, and chain termination. Here we discuss research over many decades that has shed substantial light on the detailed and often stunningly complex molecular mechanisms that underpin PKS biosynthetic fidelity. These insights have inspired increasingly effective efforts to intervene at these decision points by genetic engineering to redirect the pathways towards alternative outcomes and their associated novel products.