DYNAMICS OF L-VALINE IN RELATION TO THE PRODUCTION OF CYCLOSPORINE-A BY TOLYPOCLADIUM-INFLATUM

We report the kinetics of endogenous L-valine in the fungus Tolypocladium inflatum, in an effort to understand the enhancing effect of externally supplemented L-valine on the production of the immunosuppressant cyclosporin A (CyA) in chemically defined medium. In a batch laboratory stirred reactor cultivation, the concentration of intracellular L-valine increased by up to four times between the end of the exponential phase and the beginning of the stationary phase when the medium was supplemented externally with 4 g/l L-valine. The final CyA titre under these conditions was 710 mg/l compared to only 130 mg/l attained without L-valine supplementation. In contrast to substantial growth-associated production of CyA in unsupplemented culture, the formation of the immunosuppressant was prolonged during the stationary phase in L-valine-supplemented medium. As a result, the conversion yield of CyA on L-valine remained constant during the stationary phase at 0.27 g CyA/g L-valine.