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      Response surface methodology for optimization of production of lovastatin by solid state fermentation

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          Abstract

          Lovastatin, an inhibitor of HMG-CoA reductase, was produced by solid state fermentation (SSF) using a strain of Aspergillus terreus UV 1718. Different solid substrates and various combinations thereof were evaluated for lovastatin production. Wheat bran supported the maximum production (1458 ± 46 µg g -1 DFM) of lovastatin. Response surface methodology (RSM) was applied to optimize the medium constituents. A 2 4 full-factorial central composite design (CCD) was chosen to explain the combined effects of the four medium constituents, viz. moisture content, particle size of the substrate, di -potassium hydrogen phosphate and trace ion solution concentration. Maximum lovastatin production of 2969 µg g -1 DFM was predicted by the quadratic model which was verified experimentally to be 3004 ± 25 μg g -1 DFM. Further RSM optimized medium supplemented with mycological, peptone supported highest yield of 3723.4±49 µg g -1 DFM. Yield of lovastatin increased to 2.5 fold as with compared to un-optimized media.

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          Mevinolin: a highly potent competitive inhibitor of hydroxymethylglutaryl-coenzyme A reductase and a cholesterol-lowering agent.

          O Hensens, J Hirshfield, K Hoogsteen … (1980)
          Mevinolin, a fungal metabolite, was isolated from cultures of Aspergillus terreus. The structure and absolute configuration of mevinolini and its open acid form, mevinolinic acid, were determined by a combination of physical techniques. Mevinolin was shown to be 1,2,6,7,8,8a-hexahydro-beta, delta-dihydroxy-2,6-dimethyl-8-(2-methyl-1-oxobutoxy)-1-naphthalene-hepatanoic acid delta-lactone. Mevinolin in the hydroxy-acid form, mevinolinic acid, is a potent competitive inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A reductase [mevalonate: NADP+ oxidoreductase (CoA-acylating), EC 1.1.1.34]; its Ki of 0.6 nM can be compared to 1.4 nM for the hydroxy acid form of the previously described related inhibitor, ML-236B (compactin, 6-demethylmevinolin). In the rat, orally administered sodium mevinolinate was an active inhibitor of cholesterol synthesis in an acute assay (50% inhibitory dose = 46 microgram/kg). Furthermore, it was shown that mevinolin was an orally active cholesterol-lowering agent in the dog. Treatment of dogs for 3 weeks with mevinolin at 8 mg/kg per day resulted in a 29.3 +/- 2.5% lowering of plasma cholesterol.
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            Biosynthesis and biotechnological production of statins by filamentous fungi and application of these cholesterol-lowering drugs.

            M. Manzoni, M Rollini (2002)
            Hypercholesterolemia is considered an important risk factor in coronary artery disease. Thus the possibility of controlling de novo synthesis of endogenous cholesterol, which is nearly two-thirds of total body cholesterol, represents an effective way of lowering plasma cholesterol levels. Statins, fungal secondary metabolites, selectively inhibit hydroxymethyl glutaryl-coenzyme A (HMG-CoA) reductase, the first enzyme in cholesterol biosynthesis. The mechanism involved in controlling plasma cholesterol levels is the reversible inhibition of HMG-CoA reductase by statins, related to the structural similarity of the acid form of the statins to HMG-CoA, the natural substrate of the enzymatic reaction. Currently there are five statins in clinical use. Lovastatin and pravastatin (mevastatin derived) are natural statins of fungal origin, while symvastatin is a semi-synthetic lovastatin derivative. Atorvastatin and fluvastatin are fully synthetic statins, derived from mevalonate and pyridine, respectively. In addition to the principal natural statins, several related compounds, monacolins and dihydromonacolins, isolated fungal intermediate metabolites, have also been characterized. All natural statins possess a common polyketide portion, a hydroxy-hexahydro naphthalene ring system, to which different side chains are linked. The biosynthetic pathway involved in statin production, starting from acetate units linked to each other in head-to-tail fashion to form polyketide chains, has been elucidated by both early biogenetic investigations and recent advances in gene studies. Natural statins can be obtained from different genera and species of filamentous fungi. Lovastatin is mainly produced by Aspergillus terreus strains, and mevastatin by Penicillium citrinum. Pravastatin can be obtained by the biotransformation of mevastatin by Streptomyces carbophilus and simvastatin by a semi-synthetic process, involving the chemical modification of the lovastatin side chain. The hypocholesterolemic effect of statins lies in the reduction of the very low-density lipoproteins (VLDL) and LDL involved in the translocation of cholesterol, and in the increase in the high-density lipoproteins (HDL), with a subsequent reduction of the LDL- to HDL-cholesterol ratio, the best predictor of atherogenic risk. The use of statins can lead to a reduction in coronary events related to hypercholesterolemia, but the relationship between benefit and risk, and any possible interaction with other drugs, must be taken into account.
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              Production of the secondary metabolites gamma-aminobutyric acid and monacolin K by Monascus.

              YUAN SU, Tzu-Lung Lin, Shu-ming Pan … (2002)
              gamma-Aminobutyric acid (GABA), a hypotensive agent, and monacolin K, a cholesterol-lowering drug, can be produced by Monascus spp. Under optimal culture conditions, the products of fermentation using Monascus spp. may serve as a multi-functional dietary supplement and can prevent heart disease. In this study, Monascus purpureus CCRC 31615, the strain with the highest amount of monacolin K, was identified from 16 strains using solid fermentation. Its GABA productivity was particularly high. Addition of sodium nitrate during solid-state fermentation of M. purpureus CCRC 31615 improved the productivity of monacolin K and GABA to 378 mg/kg and 1,267.6 mg/kg, respectively. GABA productivity increased further to 1,493.6 mg/kg when dipotassium hydrophosphate was added to the medium.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Braz J Microbiol
                Journal ID (iso-abbrev): Braz. J. Microbiol
                Journal ID (publisher-id): bjm
                Journal ID (pmc): bjm
                Title: Brazilian Journal of Microbiology
                Publisher: Sociedade Brasileira de Microbiologia
                ISSN (Print): 1517-8382
                ISSN (Electronic): 1678-4405
                Publication date (Print): Jan-Mar 2010
                Publication date (Electronic): 1 March 2010
                Volume: 41
                Issue: 1
                Pages: 164-172
                Affiliations
                Food Engineering and Technology Department, Institute of Chemical Technology, University of Mumbai ,Matunga east, Mumbai–400 019, India
                Author notes
                * Corresponding Author. Mailing address:Food Engineering and Technology Department, Institute of Chemical Technology, University of Mumbai, Matunga, Mumbai–400 019, India.; Tel: +91–022–24145616; Fax: +91–022–24145614.; Email: rekha@ 123456udct.org
                Article
                Publisher ID: S1517-838220100001000024
                DOI: 10.1590/S1517-838220100001000024
                PMC ID: 3768617
                PubMed ID: 24031477
                SO-VID: 3b333ff5-dd13-4023-b940-c97fe445c207
                Copyright © © Sociedade Brasileira de Microbiologia
                License:

                All the content of the journal, except where otherwise noted, is licensed under a Creative Commons License

                History
                Date received : 17 July 2008
                Date revision received : 10 February 2009
                Date accepted : 22 July 2009
                Categories
                Subject: Industrial Microbiology
                Subject: Research Paper

                Keywords: lovastatin,response surface methodology,solid state fermentation,aspergillus terreus
                Data availability:
                Keywords: lovastatin, response surface methodology, solid state fermentation, aspergillus terreus

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