Lovastatin fermentation

Subsequently, a second, closely related molecule—lovastatin—was discovered by scientists at Merck in the United States in another fungal fermentation broth and by Sankyo in Japan. Lovastatin, marketed as Mevacor in the United States, proved both safe and efficacious for the intended nse and was the first statin to be approved for human use. Several others, some mentioned above, followed. The history of discovery and development of HMGR inhibitors has been pnUed together by Jonathan Tobert, who led the lovastatin and simvastatin clinical development effort at Merck. ... 

Whereas several anh-cholestemic dmgs such as lovastatin and pravastatin are produced wholly by fermentation, the side chain of several others such as fluvastatin... 

The high-value HMG-CoA reductase inhibitor Simvastatin (8) is marketed by Merck under the name Zocor. The active ingredient is obtained from a fermentation approach. It is very similar in structure to lovastatin, which has fallen from the top-sellers list. Lovastatin (9) is also a cholesterol-reducing drug that is isolated from Aspergillus terreus.51-60 It is still obtained by fermentation,61 and with the current advances in molecular biology,62 64 chemical approaches are not able to compete in a cost-effective manner.65-67 The usage of lipases allows for the manipulation of the butyric acid sidechain to access other HMG-CoA reductase inhibitors such as simvastatin.68 A number of routes to various portions of lovastatin have been reported.69... 

Pravastatin (10) is another HMG-CoA reductase for the inhibition of cholesterol biosynthesis it is marketed by Sanyo and Bristol Myers Squibb under the trade names Mevalotin and Pravachol.87 It has a close structural relationship to lovastatin and simvastatin. It is produced by a two-step sequence. First, mevastatin (11), also known as ML-236B or compactin, is prepared by fermentation of Penicillium citrinum ss it is then enzymatically hydroxylated to produce 11 (Scheme 31.7).88-101... 

Rhabdomyolysis in a stable renal transplant recipient was attributed to the presence of red yeast rice (Monascus purpureas) in a herbal mixture (84). The condition resolved when he stopped taking the product. Rice fermented with red yeast contains several tjrpes of mevinic acids, including monacolin-K, which is identical to lovastatin. The authors postulated that the interaction of ciclosporin with these compounds through cjdochrome P450 had resulted in the adverse effect. Transplant recipients must be cautioned against using herbal products to lower their lipid concentrations, in order to prevent such complications. 

Fermentation has produced natural products such as antibiotics and the cholesterollowering agents pravastatin and lovastatin. Modification of fermentation products has led to semisynthetic compounds such as simvastatin (see Figure 1.2), penicillins, and cephalosporins. With increased capability in genetic engineering,... 

This high-value 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor (4) is obtained from a fermentation. It is very similar in structure to lovastatin (see Section 3.2.9). A number of routes to various portions of the compound have been reported [3]. However, fermentation is used to provide the core structure and the dimethylbutyric acid side chain is enforced by coupling [8-10], although chemical methylation to form the quaternary dimethylated center has been achieved on synthetic intermediates [11,12]. 

The fermentation products of Monascus, especially those produced by solid-state fermentation of rice, have been used as food and health remedies for over 1000 years in China. Monascus rice products (MRPs) are currently being used as health foods in the United States and many Asian countries such as Japan, Taiwan, China, Korea, Thailand, the Philippines, and Indonesia. Many studies have shown that Monascus spp. produce commercially viable metabolites, including food colorants, cholesterol-lowering agents, and antibiotics. The most important bioactive compound isolated from Monascus is monacolin K, which is identical to the potent cholesterol-lowering, antiatherosclerotic drug lovastatin, a 3-hydroxy-3-methylglutaryl... 

A promising natural product, compactin, was discovered in a screen of compounds from a fermentation broth from Fenicillium citrinum in a search for antibacterial agents. In some, but not all, animal studies, compactin was found to inhibit HMG-CoA reductase and to lower serum cholesterol levels. In 1982, a new HMG-CoA reductase inhibitor was discovered in a fermentation broth from Aspergillus cereus. This compound, now called lovastatin, was found to be structurally very similar to compactin, bearing one additional methyl group. 

There have been numerous approaches to the totai synthesis of lovastatin (8-10) however, lovastatin is produced commercially via a multi-stage fermentation process which originates from cultures of a strain of Aspergillus terreus. The complete details of the isolation and identification of lovastatin from the fermentation media have been described (1). Synthetic approaches have been reviewed (11). 

Prior to the discovery of monacoUn K, Endo isolated a compound called mevas-tatin from grain ferment. This is the parent compound of most modem cholesterol drags. Some of its derivatives can be used more favorably, but mevastatin is still a useful medicine. In 1980 Lovastatin (or mevinolin), a mevastatin-related compound isolated form of the fungus Aspergillus terreus (Fig. 3.27), had been shown to be identical to monacolin K. This discovery was not particularly useful for some time. 

All are antibiotics except for lovastatin and cyclosporin. Imipenem (thienamycin) is also a fermentation product, but it is more conveniently manufactui by... 

Red yeast rice contains the HMG-CoA reductase inhibitor lovastatin, which forms naturally when the rice yeast is fermented. Hence, its LDL cholesterol-lowering properties for the relatively low concentrations of lovastatin (around 5-10 mg when the rice is taken as 2 g bd) appear greater than can be accounted by the statin. In a study that lasted more than 12 weeks in 43 subjects who were intolerant of conventional statins, red yeast rice was compared with pravastatin 20 mg bd, the numbers who withdrew because of recurrence of myalgia were one and two respectively with the rice formulation and pravastatin [33. ... 

Lovastatin can be prepared by a fermentation process in the presence of a specific microorganism. Lovastatin can be converted to simvistatin. Hydrolysis of the ester followed by reclosure of the lactone gives the diol. The less-hindered alcohol can be selectively protected using the bulky t-butyldimethylchlorosilane. The free alcohol can be esterified by the acid chloride in the presences of dimethylaminopyridine acylation catalyst. The silyl ether can be selectively removed by treatment with tetrabutyl ammonium fluoride. The fluoride anion reacts at the silicon without hydrolyzing the lactone or ester. 

Gbewonyo, K., G. Hunt, and B. C. Buckland (1992). Interactions of cell morphology and transport processes in the lovastatin fermentation. Bioprocess. Eng., 8, 1-7. 

This study demonstrated that the Pu-Erh tea contained lovastatin in a low, but yet detectable amount. The aqueous extract of Pu-Erh tea (PET) inhibited cholesterol biosynthesis in cultured human hepatoma cells (Hep G2). PET did not affect post-mevalonate events in the cholesterol pathway, since the incorporation of labeled mevalonate into cholesterol was not affected. Direct evidence to support the occurrence of lovastatin in PET was based on extensive purification and identification of lovastatin in its lactone form by mass spectrometry. To enrich lovastatin, PET was solvent extracted to recover lovastatin in lactone form. The content of lovastatin in Pu-Erh tea varied greatly among different batches. The situation is not unexpected, since the preparation procedure of Pu-Erh tea involves natural fermentation. The growth of Aspergillus and production of lovastatin in Pu-Erh tea during the fermentation and storage is not under control. 

In conclusion, uptake of Pu-Erh tea lowers plasma cholesterol and triacylglycerol in cholesterol-fed hamsters. The lipid lowering effects of Pu-Erh tea is likely caused by a combination of lovastatin and tea polyphenols. As a naturally fermented tea with lower EGCG and other catechins, Pu-Erh tea still exhibits strong antioxidant activities to scavenge DPPH radical and inhibit LDL oxidation in vitro and ex vivo. This study suggests that Pu-Erh tea drinking may reduce the risk factors in atherosclerosis-related ischemic heart disease. 

The discovery of these early statins paved the way for the worldwide development of other drugs based on the statin chemical structure (Figure 8.2). Sankyo and Merck directed their later efforts at manufacturing synthetic analogs. Many different statins are currently available for therapeutic use, but lovastatin and mevastatin remain the only fermentation-derived statins. The lovastatin biosynthetic pathway in A. terreus is well understood. This pathway was the first example of a polyketide synthetic pathway in which two fungal type I polyketide synthases work in combination to produce a product (Hendrickson et al., 1999 Kennedy et al., 1999). Since then several statins, including simvastatin, pravastatin, fluvastatin and atorvastatin, have been approved in many countries and are currently used by millions. 

Mevastatin (compactin) and lovastatin (mevinolin) are fungal fermentation products naturally produced by certain higher fungi. Mevastatin was first isolated by Akira Endo and co-workers in the 1970s from Penicillium citri-num Lovastatin is produced by Pleurotus ostreatus (oyster mushroom) and closely related to Pleurotus spp. as well as to Monascus purpureus (Chinese red yeast rice). Both mevastatin and lovastatin have a powerful inhibitory effect on HMG-CoA reductase. Discovered in the 1970s, they were taken into clinical development as potential dmgs... 

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