University of Manchester (UK) researchers, together with industrial partner
DSM, have developed a single-step fermentative method for the production
of leading cholesterol-lowering drug, pravastatin, which will
facilitate industrial-scale statin drug production.
In a study published in Proceedings of the National Academy of Sciences,
the researchers have devised a single-step fermentative method for the
industrial production of the active drug pravastatin that previously
involved a costly dual-step fermentation and biotransformation process.
Reprogramming
the antibiotics-producing fungus Penicillium chrysogenum, with
discovery and engineering of a cytochrome P450 enzyme involved in the
hydroxylation of the precursor compactin, enabled high level
fermentation of the correct form of pravastatin to facilitate efficient
industrial-scale statin drug production.
Key steps leading to the
successful outcome included the identification and deletion of a fungal
gene responsible for degradation of compactin, in addition to evolution
of the P450 to enable it to catalyse the desired stereoselective
hydroxylation step required for high level pravastatin production.
Statins
are successful, widely used drugs that decrease the risk of coronary
heart disease and strokes by lowering cholesterol levels. The
development of this group of drugs has been one of the major
breakthroughs in human healthcare over the last two decades.
Statins
have their origins in the discovery of a fungal natural product
(compactin), which was shown to have good cholesterol lowering
properties. Since compactin itself was not stable enough for clinical
use, derivatives were created and other molecules with a similar mode of
action were prepared to provide useful drugs.
Professor Andrew Munro based at the Manchester Institute of Biotechnology
at The University of Manchester said: “This research marks a
significant breakthrough and forms the basis of a patented process for
the efficient production of this blockbuster drug. These results are
the first example of harnessing the potential of a previously improved
industrial production strain which can be used in the rapid development
of other novel production strains for unrelated chemicals.
“The
data also highlight how protein engineering can be exploited in
synthetic biology applications towards industrial scale production of
valuable pharmaceuticals.”
The paper ‘Single-step fermentative production of the cholesterol-lowering drug pravastatin via reprogramming of Penicillium chrysogenum’, was published in Proceedings of the National Academy of Sciences.