Pseudopterosin Biosynthesis: Unravelling a Decades Old Problem in Animal Specialized Metabolism

Abstract

Soft corals are prolific producers of terpenoids, such as pseudopterosins. The exact biosynthetic pathway of these anti-inflammatory diterpene glycosides has eluded the scientific community for decades. Using a forward genetic approach, we have identified, cloned, and expressed the key genes involved in pseudopterosin biosynthesis. We characterized a unique class of multifunctional cytochrome P450 enzymes that catalyze a cascade reaction that produces a nearly mature natural product using a single enzyme. This clarifies the previously proposed biosynthetic pathways to pseudopterosin A and its relatives. The mechanism of the oxidative cascade was probed using in vivo feeding studies in Saccharomyces cerevisiae expressing heterologous coral genes. The cascade produces the pseudopterosin aglycone 7,8-dihydroxyerogorgiaene via elisabethatrienol and its epimer, starting from elisabethatriene. This discovery demonstrates the potential to produce this valuable class of natural products using fermentation.