PRODUCTION OF ML-236B, AND INHIBITOR OF 3-HYDROXY-3-METHYLGLUTARYL COA REDUCTASE, BY PENICILLIUM-CITRINUM - IMPROVEMENTS OF STRAIN AND CULTURE CONDITIONS

In order to increase the yield of ML-236B, an intermediate for pravastatin Na an inhibitor of cholesterol synthesis) production, the improvements of an ML-236B producing strain of Penicillium citrinum, the medium composition, and the culture conditions were studied. A mutant strain S-5808, which produces ML-236B 20 times more than the original strain does in flask culture, was isolated. As the cells of S-5808 required a large amount of the carbon source substrate to produce a lot of ML-236B, a fed-batch culture method was developed. The continuous feeding of carbon source (glycerol or mixture of glycerol and maltose) was very effective for the increase of ML-236B production. ML-236B in the culture broth became oily with lowering of pH during cultivation, adhered to the cell surface, decreased the carbon source consumption and finally stopped the ML-236B production at a late period of fermentation. The addition of a polypropylene glycol type surfactant enhanced the ML-236B productivity. The addition of the surfactant released oily ML-236B from the cell surface, therefore oxygen uptake, carbon source consumption, and ML-236B production continued throughout the fermentation.