Planta Med 2012; 78 - IL19
DOI: 10.1055/s-0032-1320206

Integrating disciplines in the natural products sciences: The story of Curacin A

WH Gerwick 1, 2, E Hamel 3, JD White 4, L Gerwick 1, DH Sherman 5, JL Smith 5
  • 1Scripps Institution of Oceanography, University of California San Diego, La Jolla, CA 92037
  • 2Skaggs School of Pharmacy and Pharmaceutical Sciences, UC San Diego, La Jolla, CA 92037
  • 3Screening Technologies Branch, Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, Frederick National Laboratory for Cancer Research, National Cancer Institute, Frederick, Maryland 21702
  • 4Department of Chemistry, Oregon State University, Corvallis, OR 97331
  • 5Life Sciences Institute and Department of Biological Chemistry, University of Michigan, Ann Arbor, MI 48109

In 1993 we made collections of a filamentous marine cyanobacterium, originally identified as Lyngbya majuscula, from near the CARMABI research station in Curaçao. Subsequent study of these reddish hair-like bacteria and their fascinating natural products has engaged my laboratory and numerous collaborative partners and students for nearly 20 years. This was stimulated by potent cancer cell toxicity in the crude extract, and subsequently, we isolated and determined the structure of a novel active metabolite given the name 'curacin A'. Ensuing studies have probed the pharmacology of this new antimitotic agent and have used synthetic and semi-synthetic approaches to determine structure-activity features. Additionally, the biosynthetic origin of curacin A was mapped from isotope feeding studies, and genetic methods were used to locate and characterize the biosynthetic gene cluster. This latter milestone, published in the Journal of Natural Products in 2004 (67, 1356–1367), has spawned numerous investigations of the mechanistic biochemistry of curacin A formation, including a novel means for initial loading the Polyketide Synthase pathway with acetate, a new reaction manifold for cyclopropyl ring formation that includes cryptic chlorination, and a unique method of offloading from the megasynthase that results in terminal alkene formation. X-ray crystallographic approaches have been used to gain deep insights into the biochemical mechanisms of several of these biosynthetic enzymes. These efforts recently led to a genome sequencing project of the producing strain which gave further insights of the pathway as well as other features of its life history, including the fact that it does not fix atmospheric nitrogen. The genome sequencing project also helped recognize that the producing cyanobacterium constituted a new genus which we named Moorea in recognition of the pioneering efforts of Richard E. Moore in this area of marine natural products research.