Chapter 3: Polyketide Natural Products

The first major class of natural products examined for biosynthetic chemical logic and enzymatic machinery are polyketides. They are formed by a series of thio-Claisen C–C bond-forming chain elongations while tethered as acyl thioesters to 8–10 kDa acyl carrier protein domains/subunits. Carbanionic intermediates from malonyl-, methylmalonyl-, and acetyl-thioester building blocks dominate polyketide chain elongation logic. Among the major categories of mature scaffolds are fused aromatic scaffolds, in molecules such as tetracycline and daunomycin; large ring macrolactones, as in erythromycin, tylosin, and ivermectin; polyenes, such as nystatin; and polyethers with tetrahydrofuran and tetrahydropyran ring-containing ionophores, such as monensin and lasalocid. Decalin-containing scaffolds, as in the statin inhibitors of cholesterol biosynthesis, are taken up in Chapter 14 on pericyclases. The polyketide frameworks can also be coupled during biosynthesis to peptide groups in polyketide–nonribosomal peptide hybrids, such as rapamycin, or polyketide–isoprene hybrids, such as hyperforin.