Marine Natural Products Lab

Kerr Research Group

Pseudopterosins

 

The pseudopterosins are a family of diterpene glycosides isolated from the gorgonian Pseudopterogorgia elisabethae. To date, 26 derivatives have been identified (PsA – PsZ) and in most cases, pseudopterosins represent 2-5% of the crude extract. The pseudopterosins are anti-inflammatory and analgesic agents with potencies superior to that of existing drugs such as indomethacin in mouse ear models. They are not active against PLA2, cyclooxygenase and cytokine release or as regulators of adhesion molecules. Evidence suggests the pseudopterosins block eicosanoid release rather than biosynthesis in murine macrophages. Recent data from the Jacobs laboratory (UCSB) indicates that pseudopterosins inhibit inflammation by a novel mechanism suggesting that these metabolites represent a novel class of anti-inflammatory agent. Importantly, one of the pseudopterosins has a substantial commercial market as an additive in personal care products and a simple derivative of pseudopterosin A, methopterosin, has successfully completed a Phase II clinical trial as a topical anti-inflammatory agent.
 
 
 
 
We have a long-standing interest in the biosynthesis of these marine metabolites. We have elucidated the biosynthetic origin of pseudopterosins from geranylgeranyl diphosphate through a series of radiolabeling experiments as well as detailed NMR-directed investigations (Coleman and Kerr 2000, Kohl and Kerr 2003, Ferns and Kerr 2005a, Ferns and Kerr 2005b, Kerr et al. 2006). One of the key steps in the production of the pseudopterosins (and all terpenes) is the cyclization of the appropriate polyprenyl diphosphate. Knowledge of the structure of the cyclase product involved in pseudopterosin biosynthesis provided us with an assay to purify the enzyme responsible for this transformation. This enzyme (elisabethatriene synthase) has been purified to homogeneity (Kohl and Kerr 2004, Brueck and Kerr 2006). A biosynthetic question that is currently under investigation is whether pseudopterosins are produced by the invertebrate host or an associated microbe.