Abstract
The fungus Aspergillus (A.) terreus has dominated the biological production of the “blockbuster” drugs known as statins. The statins are a class of drugs that inhibit HMG-CoA reductase and lead to lower cholesterol production. The statins were initially discovered in fungi and for many years fungi were the sole source for the statins. At present, novel chemically synthesised statins are produced as inspired by the naturally occurring statin molecules. The isolation of the natural statins, compactin, mevastatin and lovastatin from A. terreus represents one of the great achievements of industrial microbiology. Here we review the discovery of statins, along with strategies that have been applied to scale up their production by A. terreus strains. The strategies encompass many of the techniques available in industrial microbiology and include the optimization of media and fermentation conditions, the improvement of strains through classical mutagenesis, induced genetic manipulation and the use of statistical design.
Highlights
Statins are polyketide compounds that are produced by some fungi during their secondary metabolism [1]
The Japanese microbiologist Dr Akira Endo pioneered the discovery of statins from the filamentous fungi Penicillium (P.) citrinum and later from A. terreus in the 1970s
It is noteworthy that ring-opened forms of lovastatin and simvastatin inhibit the growth of A. terreus [30], though the production of lovastatin does not pose a problem to A. terreus since it is released outside the cell as the active beta hydroxyl form, possibly as a defense mechanism during a secondary metabolism [38]
Summary
Statins are polyketide compounds that are produced by some fungi during their secondary metabolism [1]. The statins act as competitive inhibitors, inhibiting HMG-CoA reductase, a rate limiting step of cholesterol biosynthesis. Statins block the conversion of HMG-CoA to mevalonic acid in the mevalonate pathway [1,2,3]. In this metabolic pathway, mevalonate is converted into a number of hydrophobic molecules, sterol isoprenoids and nonsterol isoprenoids [4]. The statins reduce total cholesterol level in serum, especially the low-density lipoprotein levels and are used to treat hypercholesterolemia [5,6]. Statins reduce the LDL-cholesterol levels and protect against atherosclerotic plaque growth via their antithrombotic and anti-inflammatory effects [9,10,11]. Statins may further be used in cases of hypertension, osteoporotic fractures, ventricular arrhythmia and prevention of Alzheimer’s disease and Parkinson’s disease [12,13,14,15]
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