COMMERCIAL PRODUCTION OF OKADAIC ACID FROM PROROCENTRUM

THE OCEANS HAVE SUPPLIED SUBSTANCES WHICH ARE PHARMACOLOGICALLY ACTIVE AND USEFUL IN MEDICINE AND RESEARCH. ONE OF THE MOST INTERESTING COMPOUNDS IS THE POLYETHER OKADAIC ACID WHICH IS PRODUCED BY MARINE DINOFLAGELLATE ALGAE (DINOPHYSIS AND PROROCENTRUM SPP.). OKADAIC ACID IS INVOLVED IN CAUSING TWO SEAFOOD-BORNE, CHEMICALLY-INDUCED HUMAN DISEASES, DIARRHETIC SHELLFISH POISONING AND CIGUATERA. IN CONTRAST, HOWEVER, THIS MONOCARBOXYLIC ACID IS A POWERFUL MOLECULAR PROBE WITH TREMENDOUS COMMERCIAL POTENTIAL. AT LOW CONCENTRATIONS (1 X 10-7 M), OKADAIC ACID CAUSED A PROLONGED TONIC CONTRACTION IN HUMAN UMBILICAL ARTERIES AND IN GUINEA PIG ISOLATED VENTRICAL MUSCLES. THESE EFFECTS COULD BE INDUCED EVEN DURING SEVERE CA2+ DEFICIENCY AND THIS TYPE OF AGENT HAS NOT BEEN PREVIOUSLY REPORTED. SUBSEQUENT STUDIES HAVE ESTABLISHED OKADAIC ACID AS A SPECIFIC INHIBITOR OF PROTEIN PHOSPHATASE 1 AND PROTEIN PHOSPHATASE 2A, TWO OF THE FOUR MAJOR PROTEIN PHOSPHATASE ENZYMES IN THE CYTOSOL OF MAMMALIAN CELLS THAT DEPHOSPHORYLATE SERINE AND THREONINE RESIDUES. OKADAIC ACID IS ALSO A POTENT NON-PHORBOL ESTER-TYPE TUMOR PROMOTER ON MOUSE SKIN. THUS, OKADAIC ACID IS WELL ESTABLISHED IN THE FIELD OF BIOMEDICAL RESEARCH. THE AMIS OF PHASE I OF THIS RESEARCH WILL BE TO DETERMINE FEASIBILITY OF OBTAINING COMMERCIAL QUANTITIES OF OKADAIC ACID FROM CULTURES OF PROROCENTRUM HOFFMANNAINUM. WE WILL CONBINE STUDIES OF INNOVATIVE CULTURING TECHNIQUES AND PHYSIOLOGICAL MANIPULATION IN ORDER TO OPTIMIZE AND ECONOMIZE OKADAIC ACID PRODUCTION IN THIS SPECIES.