BIOSYNTHESIS OF ECTEINASCIDIN 743

Johns Hopkins University, Baltimore MD

Investigators

Abstract

While the biosynthesis of natural products from marine invertebrates has been studied using classical feeding techniques, the field has been largely bypassed by molecular-biological approaches to biosynthesis, including cloning and expression of genes and gene clusters. Application of these techniques to marine compounds would be advantageous because development of many promising marine pharmaceuticals has been stymied by a problem of supply, which could be largely circumvented by heterologous expression of biosynthetic genes. In this study, the biosynthesis of ecteinascidin-743 (Et-743), a potent cytotoxin in phase B clinical trials, will be examined as a model system for the application of molecular biology to complex marine systems. A biosynthetic hypothesis will be explored, and the possibility that the compound is produced by a bacterium living in symbiotic association with its ascidian host will be probed. Once genes are cloned, their heterologous expression will be attempted in a strategy aimed at the eventual fermentative production of Et-743 in bacteria