Engineered polyketide synthases with non-natural substrate specificities

Many polyketides are biosynthesized in a modular fashion by the selection and condensation of small molecule building blocks, catalyzed by polyketide synthases. Chimeric synthases can be constructed in an attempt to produce analogues. Yet, the scope and utility of such combinatorial approaches is limited by the inherent substrate specificity and poor functional modularity of many biosynthetic components. Here, we show that polyketide synthases are more tolerant towards non-natural building blocks than has been previously recognized. Such promiscuity forms a platform for constructing new synthases with substrate specificities orthogonal to those found in Nature. Our synthetic biology approach expands the synthetic capabilities of polyketide biosynthetic machinery.