Fermentation optimization for the production of lovastatin by Aspergillus terreus: use of response surface methodology
01 Oct 2004-Journal of Chemical Technology & Biotechnology (John Wiley & Sons, Ltd)-Vol. 79, Iss: 10, pp 1119-1126
TL;DR: A Box-Behnken experimental design was used to investigate the effects of five factors (oxygen content in the gas phase, concentrations of C, N and P, and fermentation time) on the concentrations of biomass and lovastatin produced in batch cultures of Aspergillus terreus as discussed by the authors.
Abstract: A Box-Behnken experimental design was used to investigate the effects of five factors—ie oxygen content in the gas phase; concentrations of C, N and P; and fermentation time—on the concentrations of biomass and lovastatin produced in batch cultures of Aspergillus terreus. The values of the various factors in the experiment ranged widely, as follows: 20-80% (v/v) oxygen in the aeration gas; 8-48 g dm −3 C-concentration; 0.2-0.6 g dm −3 N-concentration; 0.5-2.5 g dm −3 phosphate-concentration; and 7-11 days fermentation time. No previous work has used statistical analysis in documenting the interactions between oxygen supply and nutrient concentrations in lovastatin production. The Box-Behnken design identified the oxygen content in the gas phase as the principal factor influencing the production of lovastatin. Both a limitation and excess of oxygen reduced lovastatin titers. A medium containing 48 g dm −3 C supplied as lactose, 0.46 g dm −3 N supplied as soybean meal, and 0.79 g dm −3 phosphate supplied as KH2PO4, was shown to support high titers (∼230 mg dm −3 )o f lovastatin in a7 -day fermentation in oxygen-rich conditions (80% v/v oxygen in the aeration gas). Under these conditions, the culture medium had excess carbon but limiting amounts of nitrogen. The optimized fermentation conditions raised the lovastatin titer by four-fold compared with the worst-case scenario within the range of factors investigated. 2004 Society of Chemical Industry
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TL;DR: Environmental and economic benefits that biotechnology can offer in manufacturing, monitoring and waste management are highlighted and the following benefits include: greatly reduced dependence on nonrenewable fuels and other resources; reduced potential for pollution of industrial processes and products.
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TL;DR: Advances in the biochemistry and genetics of lovastatin have allowed the development of new methods for the production of simvastatin, the second leading statin in the market, which is a Lovastatin semisynthetic derivative.
Abstract: Statins are a group of extremely successful drugs that lower cholesterol levels in blood; decreasing the risk of heath attack or stroke. In recent years, statins have also been reported to have other biological activities and numerous potential therapeutic uses. Natural statins are lovastatin and compactin, while pravastatin is derived from the latter by biotransformation. Simvastatin, the second leading statin in the market, is a lovastatin semisynthetic derivative. Lovastatin is mainly produced by Aspergillus terreus strains, and compactin by Penicillium citrinum. Lovastatin and compactin are produced industrially by liquid submerged fermentation, but can also be produced by the emerging technology of solid-state fermentation, that displays some advantages. Advances in the biochemistry and genetics of lovastatin have allowed the development of new methods for the production of simvastatin. This lovastatin derivative can be efficiently synthesized from monacolin J (lovastatin without the side chain) by a process that uses the Aspergillus terreus enzyme acyltransferase LovD. In a different approach, A. terreus was engineered, using combinational biosynthesis on gene lovF, so that the resulting hybrid polyketide synthase is able to in vivo synthesize 2,2-dimethylbutyrate (the side chain of simvastatin). The resulting transformant strains can produce simvastatin (instead of lovastatin) by direct fermentation.
171 citations
Cites background from "Fermentation optimization for the p..."
...Some studies have used response surface methodology to identify the impact of the medium composition on lovastatin production (Lai et al. 2003; Casas-López et al. 2004)....
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...terreus batch fermentation and most of the literature deals with this species (Novak et al. 1997; Manzoni et al. 1998; Kumar et al. 2000; Casas-López et al. 2004; Rodríguez Porcel et al. 2007; Bizukojc and Ledakowicz 2008)....
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...However, commercial production of lovastatin is based on A. terreus batch fermentation and most of the literature deals with this species (Novak et al. 1997; Manzoni et al. 1998; Kumar et al. 2000; Casas-López et al. 2004; Rodríguez Porcel et al. 2007; Bizukojc and Ledakowicz 2008)....
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TL;DR: Both an upper limit on agitation intensity and a high level of dissolved oxygen are essential for attaining high titers of lovastatin in fungal pellet morphology and broth rheology.
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TL;DR: This review aims at analyzing and classifying the most recent advances and the several novel approaches to the design, development, control and modeling of photobioreactors.
Abstract: Over the past ten years a great deal of literature has focused on the biotechnological potential of microalgal commercial applications, mainly in the field of biofuel production. However, the biofuel production is not yet competitive, mainly due to the incidence of the photobioreactor technology on the process cost. Besides, major advances in classic photobioreactor design, several novel configurations have been proposed in the last 20 years to improve their performance expressed in terms of light absorption, biomass productivity, light to biomass yield and photosynthetic efficiency. This review aims at analyzing and classifying the most recent advances and the several novel approaches to the design, development, control and modeling of photobioreactors. The diverse approaches are grouped considering irradiance strategies, multiphase hydrodynamics, mass transfer mechanisms, modeling approaches and control strategies. Some innovative applications of the photobioreactor technology are also reported. © 2013 Society of Chemical Industry
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References
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TL;DR: Plackett–Burman screening, factorial designs, and second-order response surface methodology (RSM) for medium optimization were employed for lovastatin production by a high-producing mutant of Aspergillus terreus, and the method used was effective in screening for nutritional requirements in a limited number of experiments.
114 citations
TL;DR: Submerged cultivation of a high yielding strain of Aspergillus terreus DRCC 122 for the production of lovastatin in the batch process had limited success, but a cost effective repeated fed-batch process with maltodextrin and corn steep liquor feed as carbon and nitrogen sources, respectively, showed a significant increase in Lovastatin yield.
96 citations
TL;DR: Medium optimization experiments with the best isolate indicated that lactose, rapeseed meal and KNO3 were the best carbon, organic nitrogen and inorganic nitrogen sources, respectively.
Abstract: Of 68 Aspergillus terreus, three produced lovastatin with equivalent or better yield than strain ATCC 20542 originally described for lovastatin production. Medium optimization experiments with the best isolate (TUB F-514) indicated that lactose, rapeseed meal and KNO3 were the best carbon, organic nitrogen and inorganic nitrogen sources, respectively. In shake-flasks with optimized medium containing 4 % (w/v) lactose, 400 μg lovastatin/ml was produced, with a yield of 10 mg/g lactose. In solid substrate fermentation on extracted sweet sorghum pulp supplemented with cheese whey 1500 μg lovastatin/g dry weight was produced with a yield of 37.5 mg/g lactose. © Rapid Science Ltd. 1998
91 citations
TL;DR: Several Monascus and Aspergillus strains were screened for statins production and Lovastatin, monacolin J, pravastatin and mevastatin were produced, with higher yields from the A. terreus strains than from Monascus species.
Abstract: Several Monascus and Aspergillus strains were screened for statins production. Lovastatin, monacolin J, pravastatin and mevastatin were produced, with higher yields from the A. terreus strains than from Monascus species. Of all the strains investigated M. paxii AM12M, an isolated spontaneous mutant, yielded 127 mg lovastatin/l and 53 mg pravastatin/l at 21 days, and 18 mg pravastatin/l at 16 days employing a whole soybean flour medium; A. terreus BST yielded 230 mg lovastatin/l and 118 mg pravastatin/l at 14 days employing a defatted soybean flour medium. Statins recovery showed that pravastatin was, in both strains, mostly found in both the mycelium and the culture filtrate, while lovastatin remained closely associated (83%) to the A. terreus mycelium or was mainly released into the culture filtrate (64%) of M. paxii culture.
91 citations
TL;DR: Recovery yield showed that 83% lovastatin was associated with the mycelium and 17% was free in the culture filtrate as well as similar yields of monacolin J were detected for both strains.
Abstract: Lovastatin, mevastatin, pravastatin and monacolin J were produced using Aspergillus terreus strains. Mevastatin (170 mg/l) was obtained at 14 days from the A1 strain, lovastatin (256 mg/l) at 21 days from the A2 strain and pravastatin (270-300 mg/l) at 14 days from both the A1 and A2 strains grown on defatted soybean flour. Similar yields of monacolin J (5-10 mg/l) were detected for both strains. Fermentation carried out by adding glycerol to A1 7-d old cultures gave 244 mg lovastatin/l at 14 days employing whole soybean flour. A new extraction procedure was applied to an A2 19-d old culture on the mycelium and the culture filtrate separately. Recovery yield showed that 83% lovastatin was associated with the mycelium and 17% was free in the culture filtrate. © Rapid Science Ltd. 1998
82 citations