Pravastatin

Product Technology and high-productive strain producing Pravastatin

Strain-producer Streptomyces carbofilus

Productivity 8.0 G/L of Pravastatin out of 11.0 G/L of Compactin load (70% conversion).

Cycle time 120-144 hours (depends on mutant)

Analysis HPLC

Standard Pravastatin of LKT laboratories cat# P6801

Remarks Initial conversion of the strain of Streptomyces carbofilus was about 20% with initial concentration of Compactin 100 mg/L.

Using combined (chemical and physical) induced mutagenesis methods 2 years later first mutant that converted 40%-60% of 3 G/L of Compactin (t.i. 1.2-2.0 G/L of Pravastatin yield respectively) in shaken flasks was obtained.

Keeping on working at the technology improvement, yield of 3.3 G/L (80 %) of Pravastatin out of 4 G/L in 3L fermentor was obtained. In last experiments productivity up to 5.0 G/L of Pravastatin out of 7.0 G/L of Compactin load was achieved (70% conversion).

Yield 60%

Purity Not less than 98.5%

Remarks Pravastatin is a known 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA ) reductase inhibitor, widely used for the treatment of arteriosclerosis. Pravastatin is conventionally synthesized by a two-step fermentation procedure. Firstly Compactin is produced by Penicillium citrinum followed by the hydroxylation by Streptomyces carbophilus into Pravastatin.

Initial conversion level in Streptomyces carbophilus strain when in 1996 year we started working at it was about 30%, t.i. only 30% of Compactin was reverted into Pravastatin. Our expertise in random mutagenesis by ultraviolet radiation and chemical mutagens, screening and rational selection gave us opportunity to obtain fourteen months later first mutants with conversion rate of 45%. Up to now we have obtained mutants transforming about 70-75% of Compactin into Pravastatin in 3L fermentor. At the same time we increased initial concentration of Compactin to be added from 2 G/L up to 4-5 G/L. We are keeping working at it and aim to achieve increase both in conversion rate and initial Compactin concentration.