Total Biosynthesis and Engineering of Cinatrins: Inhibitors of Phospholipase A2 and Squalene Synthase

An alkyl citrate biosynthetic gene cluster (ctr) was identified from 47 members of the fungal family of Hypoxylaceae by genome mining. The Hypomontagnella monticulosa MUCL 54604 ctr cluster was deployed for the total biosynthesis of the known specialised metabolites CJ-13,982 and cinatrins C1 and C3. The required 2- and 4- oxygenations were catalysed by an alpha-ketoglutarate-dependent non-heme iron dioxygenase that is homologous to known oxygenases including MfR1 and MfR2 from the squalestatin biosynthetic pathway. Combinatorial biosynthesis, and in vitro experiments including the oxygenases MfR1 and MfR2, were used for the synthesis of new natural products with bioactivity against phospholipase A2 and squalene synthase.