Chapter 11: Precursor-directed Biosynthesis and Semi-synthesis of Natural Products

Natural products and their derivatives make up a large percentage of all pharmaceuticals on the market. While many purely biological or chemical routes to these molecules do exist, each has certain limitations, depending on the target. More often, a semi-synthetic approach is taken, wherein the natural product is isolated from its native producer and subsequently derivatized chemically. However, as our collective knowledge of biosynthetic pathways grows, other opportunities for structural modification present themselves. One such method, termed precursor-directed biosynthesis, involves the incorporation of chemically synthesized substrates for enzymatic transformations. Other pathway-engineering approaches involve the mutagenesis of enzymes for rapid production of chemically intractable moieties. Herein, we explore the different combinations of biology and chemistry for different natural product classes. These include polyketides, non-ribosomal and ribosomal peptides, terpenes, alkaloids and glycosides. We do this by highlighting important and recent advances in the field of natural product combinatorial biosynthesis.