Aspergillus terreus, lovastatin from

It was discovered by the Merck Sharp Dohme Research Laboratories that a strain of Aspergillus terreus obtained from a soil sample produced the cholesterol lowering fungal metabolite lovastatin (initially named mevinolin). Details of the isolation, structural characterization and biochemicai properties of iovastatin have been summarized by Alberts et al. (1). Lovastatin is identicai to monacoiin K isoiated independently from Monascus ruber by Endo (2). 

Lovastatin and mevastatin Lovastatin, (lS,3R,7S,8S,8aR)-l,2,3,7,8,8a-hexahydro-3, 7-dimethyl-8-[-[2R,4R]-[tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl]ethyl]-l-naphthyl (S)-2-methylbutyrate (20.2.7) is isolated from Monascus rubber [17] mA Aspergillus terreus [18], as is mevastatin (lS,3R,7S,8S,8aR)-l,2,3,7,8, 8a-hexahydro-7-metliyl-8-[-(2R,4R)-[tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl]ethyl]-l-naphthyl (S)-2-metliylbutyrate (20.2.8), which is isolated from Penicillium citrinum [19, 20] as well as from Penicillium brevicom-pactum [21]. 

Lovastatin and mevastatin are new-generation drugs that were introduced into medicine for treating hyperlipocholesterolemia, and they are unique compounds. Lovastatin is isolated from Aspergillus terreus mushrooms. Mevastatin is a chemically analogous compound that differs only in the absence of a methyl group at C3 of the naphthaline system, and it is isolated from Penicillium citrinum mushrooms. 

Some plant-derived drugs come from lower organisms, such as fungi (e.g., the antihyperlipidemic agent lovastatin from Aspergillus terreus and the immunosuppressant cyclosporin from Beauveria nivea) whereas others are obtained from higher plants (see Table 5.3 and Table 5.4). 

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... 

Lovastatin (fungal metabolite from Aspergillus terreus)... 

Lovastatin was the first statin to be developed, and was isolated from the fungus Aspergillus terreus. It was launched in 1987 by Merck, Sharpe and Dohme (USA), and is a two-fold more potent methyl-homologue of mevastatin (Fig. 4.3). 

For several years, lovastatin represented the commerically most successful drug from nature. Named mevinolin, it was discovered as a metabolite from Aspergillus terreus cultures at the US company Merck by a target-directed screening for inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, a key enzyme of cholesterol biosynthesis [32]. Cholesterol, which in humans more than one-half of the total body cholesterol is derived from its de novo biosynthesis in the liver, is the major component of atherosclerotic plaques built up as fatty deposits on the inner walls of arteries, thus contributing to arteriosclerosis and coronary heart diseases [33]. 

Many attempts have been made to find cholesterol biosynthesis inhibitors for development as hypocholesterolemic agents. Microbial secondary metabolites have been used as valuable natural sources in the development of novel cholesterol biosynthesis inhibitors. Mevastatin and lovastatin were isolated from the fungi, Penicillium citrinum and Aspergillus terreus, respectively, as potent inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase which is involved in the rate-limiting step of cholesterol synthesis in mammals. These findings have led to the development of statins , which are drugs of choice in the treatment of hypercholesterolemia. 

In 1976, mevastatin (ML-236B, 6-demethylmevinolin) (2) was first reported as a potent competitive inhibitor of HMG-CoA reductase from the culture of Penicillium citrinum [23,24], which is identical with compactin, an antifungal compound isolated from P. brevicompactum [25,26]. Lovastatin (mevinolin, monacolin K) (3) has been isolated from the cultures of Aspergillus terreus [27] and Monascus ruber [28,29], separately. 

Lovastatin is an inhibitor of the enzyme (35)-hydrooxymethylglutaryl-CoA (HMG-CoA) reductase tliat catalyzes the reduction of HMG-CoA to mevalonate, a key step in cholesterol biosynthesis. Tliis activity confers on lovastatin its medically important anti-hyperchoilesterolemic activity and other potentially important uses. It is a secondary metabolite from the filamentous fungus Aspergillus terreus and has been shown to be derived from acetate via a polyketide pathway. 

Statins are the secondary metaboKtes of a number of different filamentous fungi. Their medical importance and commercial value stem from their ability to inhibit the enzyme (3S)-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase. Since this enzyme catalyzes a key step in the endogenous cholesterol biosynthetic pathway, statins have become the widely used an-tihypercholesterolemic drugs. Along with some synthetic statins, the most prominent examples are lovastatin, mainly from Aspergillus terreus, and mevastatin produced by Penicillium citrinum, which was the first statin to be discovered [92, 93]. 

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. 

Lovastatin, Mevacor (isolated from a strain of Aspergillus terreus). 

Biological Diels-Alder reactions are known but uncommon. One example occurs in the biosynthesis of the cholesterol-lowering drug lovastatin (Chapter 1 Introduction) isolated from the bacterium Aspergillus terreus. The key step is the Diels-Alder reaction of a triene in which the diene and dienophile components are within the same molecule. Following this intramolecular Diels-Alder reaction, several subsequent transformations yield lovastatin. 

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