BIOSYNTHETIC OPTIMIZATION OF BRYOSTATINES IN AQUACULTURE

BIOCHEMICAL AND BIOSYNTHESIS INFORMATION WILL BE USED TO FORMULATE AN OPTIMAL DIET FOR THE AQUACULTURAL PRODUCTION OF THE NATURAL PRODUCT DRUG BRYOSTATIN 1 BY THE MARINE BRYOZOAN BUGULA NERITINA. PHASE I WILL: 1) DEVELOP METHODS FOR WHOLE ANIMAL BIOSYNTHESIS EXPERIMENTS; 2) DETERMINE WHICH STEROLS AND FATTY ACIDS ARE PRODUCED DE NOVO BY THE BRYOZOAN AND WHICH MUST BE OBTAINED FROM THE DIET; AND 3) ESTABLISH THE BASIC BIOSYNTHETIC PATHWAY FOR BRYOSTATIN PRODUCTION. PHASE II WILL FURTHER DEFINE THE BRYOSTATIN BIOSYNTHESIS; IDENTIFIED LIMITING BIOSYNTHETIC AND LIPID BUILDING BLOCKS WILL THEN BE INCORPORATED INTO ENRICHED ARTIFICIAL DIETS AND EVALUATED FOR THEIR POTENTIAL TO INCRASE BRYOSTATIN 1 YEILD IN AQUACULTURE SYSTEMS ALREADY UNDER DEVELOPMENT BY CALBIOMARINE. BRYOSTATIN 1 IS PRESENTLY IN CLINICAL DEVELOPMENT AS AN ANTILEUKEMIC AGENT. DEVELOPMENT OF A RELIABLE SOURCE OF THE DRUG IS NECESSARY TO MEET THE PROJECTED CLINICAL AND MARKET DEMAND. SUCCESSFUL COMPLETION OF THIS PROJECT WILL ENABLE INCREASED AQUACULTURE YIELDS OF THIS HIGH-VALUE PHARMACEUTICAL, POSSIBLY REDUCING PRODUCTION COSTS BY ONE OR MORE ORDERS OF MAGNITUDE. BIOSYNTHETIC METHODS FOR OPTIMIZATION OF AQUACULTURE FEEDS FOR HIGH-YIELD PRODUCTION OF NATURAL PRODUCTS, ONCE DEVELOPED, CAN ALSO BE APPLIED TO OTHER MARINE INVERTEBRATE DRUGS PRESENTLY IN THE PHARMACEUTICAL PIPELINE.