Biosynthetic mechanism for polyketide-derived mycotoxin fumonisins and antimycotic HSAF

Polyketides are a large group of natural products produced by microorganisms and plants. Polyketides exhibit a staggering range of medicinally important activities, including antibiotic, anticancer, antifungal, antiparasitic, and immunosuppressive properties. They are biopolymers of acetate and other short carboxylates and are biosynthesized by multifunctional enzymes called polyketide synthases (PKS). Based on protein architecture, PKSs are classified into three basic types: Types I, II, and III. Some PKSs also form hybrids with nonribosomal peptide synthetases (NRPS) that synthesize short peptide polymers via the condensation of both proteinogenic and non-proteinogenic amino acid building blocks. Both substrate usage and protein architecture lend themselves to the vast diversity of polyketide and polyketide/non-ribosomal peptide natural products. Biosynthetic aspects of the mycotoxin fumonisins and the antimycotic HSAF will be discussed in this dissertation. Fumonisins are a group of myctoxins produced by several agriculturally important fungi, including Fusarium verticillioides, which is a common fungal contaminant of corn and maize-derived products worldwide. Elevated fumonisin levels in corn have become an area of concern since ingestion of fumonisin-contaminated corn has been associated with livestock loss and human health risks, including esophageal cancer and neural tube defects. Fum6p, which represents the first characterized example of a fusion P450 with a known physiological function, has been investigated for the role it plays in the hydroxylation of the fumonisin backbone. In contrast, the antimycotic HSAF (heat stable antifungal factor) exhibits potent inhibitory activities against a wide range of fungal species, including the life-threatening human pathogen, Aspergillus fumigatus, and shows a novel mode of action by disrupting the biosynthesis of sphingolipids. Sterol desaturase (SD) that catalyzes the 3-hydroxylation of the polycyclic tetramate macrolactam HSAF from Lysobacter enzymogenes C3 will be discussed. The global regulatory functions of CLP and GNAT in the control of HSAF biosynthesis and resistance to chloramphenicol via unusual acylations are also described