scispace - formally typeset

Journal ArticleDOI

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

AbstractA 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

Topics: Aspergillus terreus (53%), Fermentation (53%), Lovastatin (51%)

...read more

Content maybe subject to copyright    Report

Citations
More filters

Journal ArticleDOI
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.
Abstract: This review outlines the current and emerging applications of biotechnology, particularly in the production and processing of chemicals, for sustainable development. Biotechnology is "the application of scientific and engineering principles to the processing of materials by biological agents". Some of the defining technologies of modern biotechnology include genetic engineering; culture of recombinant microorganisms, cells of animals and plants; metabolic engineering; hybridoma technology; bioelectronics; nanobiotechnology; protein engineering; transgenic animals and plants; tissue and organ engineering; immunological assays; genomics and proteomics; bioseparations and bioreactor technologies. Environmental and economic benefits that biotechnology can offer in manufacturing, monitoring and waste management are highlighted. These benefits include the following: greatly reduced dependence on nonrenewable fuels and other resources; reduced potential for pollution of industrial processes and products; ability to safely destroy accumulated pollutants for remediation of the environment; improved economics of production; and sustainable production of existing and novel products.

612 citations


Journal ArticleDOI
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.

160 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)....

    [...]

  • ...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)....

    [...]

  • ...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)....

    [...]


Journal ArticleDOI
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.
Abstract: Pellet growth of Aspergillus terreus ATCC 20542 in submerged batch fermentations in stirred bioreactors was used to examine the effects of agitation (impeller tip speed u(t) of 1.01-2.71 ms(-1)) and aeration regimens (air or an oxygen-enriched mixture containing 80% oxygen and 20% nitrogen by volume) on the fungal pellet morphology, broth rheology and lovastatin production. The agitation speed and aeration methods used did not affect the biomass production profiles, but significantly influenced pellet morphology, broth rheology and the lovastatin titers. Pellets of approximately 1200 microm initial diameter were reduced to a final stable size of approximately 900 microm when the agitation intensity was >/=600 rpm (u(t)>/=2.03 ms(-1)). A stable pellet diameter of approximately 2500 microm could be attained in less intensely agitated cultures. These large fluffy pellets produced high lovastatin titers when aerated with oxygen-enriched gas but not with air. Much smaller pellets obtained under highly agitated conditions did not attain high lovastatin productivity even in an oxygen-enriched atmosphere. This suggests that both an upper limit on agitation intensity and a high level of dissolved oxygen are essential for attaining high titers of lovastatin. Pellet size in the bioreactor correlated equally well with the specific energy dissipation rate and the energy dissipation circulation function. The latter took into account the frequency of passage of the pellets through the high shear regions of the impellers. Pellets that gave high lovastatin titers produced highly shear thinning cultivation broths.

158 citations


Journal ArticleDOI
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

121 citations


Journal ArticleDOI
TL;DR: A new approach to form pellets has been developed using only potato dextrose broth, soybean peptone, and calcium carbonate allowing for pellet size to be controlled by adjusting inoculum size and the concentrations of potato deXTrose broth.
Abstract: The effects of inoculum and medium composition (i.e. potato dextrose broth as carbon source, soybean peptone, calcium carbonate, and metal ions) on pellet formation of Rhizopus oryzae ATCC 20344 have been studied. Metal ions were found to have a significant negative effect on pellet formation while soybean peptone had a positive effect. In addition, potato dextrose broth and calcium carbonate were beneficial to R. oryzae for growing small, smooth pellets during the culture. The study also demonstrated that an inoculum size of less than 1.5 × 10 9 spores/L had no significant influence on pellet formation although it had large impacts on pellet growth. Thus, a new approach to form pellets has been developed using only potato dextrose broth, soybean peptone, and calcium carbonate allowing for pellet size to be controlled by adjusting inoculum size and the concentrations of potato dextrose broth, soybean peptone, and calcium carbonate in the medium.

96 citations


References
More filters

Journal ArticleDOI
Abstract: A class of incomplete three level factorial designs useful for estimating the coefficients in a second degree graduating polynomial are described. The designs either meet, or approximately meet, the criterion of rotatability and for the most part can be orthogonally blocked. A fully worked example is included.

2,909 citations


Journal ArticleDOI
TL;DR: It was shown that mevinolin was an orally active cholesterol-lowering agent in the dog and orally administered sodium mevinolinate was an active inhibitor of cholesterol synthesis in an acute assay.
Abstract: 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.

1,465 citations



Journal ArticleDOI
TL;DR: The experiments reported in this paper demonstrate that MG236A and ML-236B inhibit specifically 3-hydroxy-3-methylglutaryl (HMG)CoA reductase (EC 1 .I .1.34), the rate-limiting enzyme in cholesterol synthetic pathway, without affecting the rest of the enzymes involved in this pathway, and that the inhibition is competitive with respect to the substrate HMG-CoA.
Abstract: Fungal metabolites, ML236A and ML236B (Bg.l), have been isolated from cultures of Penicillium citinum as potent inhibitors of cholesterol synthesis in vitro in this laboratory [l] . These metabolites (LD5e for mice > 2 g, per OS) cause a marked decrease in serum cholesterol levels in rats [l] , and in hens and dogs (Kitano, Tsujita and Endo, in preparation). The experiments reported in this paper demonstrate that MG236A and ML-236B inhibit specifically 3-hydroxy-3-methylglutaryl (HMG)CoA reductase (EC 1 .I .1.34), the rate-limiting enzyme in cholesterol synthetic pathway, without affecting the rest of the enzymes involved in this pathway, and that the inhibition is competitive with respect to the substrate HMG-CoA.

672 citations


Journal ArticleDOI
TL;DR: This review deals with polyketides produced by the filamentous fungusMonascus which include: 1) a group of yellow, orange and red pigments, 2) agroup of antihypercholesterolemic agents including mevinolin and related compounds and 3) the newly discovered metabolite ankalactone.
Abstract: This review deals with polyketides produced by the filamentous fungusMonascus which include: 1) a group of yellow, orange and red pigments, 2) a group of antihypercholesterolemic agents including mevinolin and related compounds and 3) the newly discovered metabolite ankalactone. Biosynthesis, methods of production, isolation and biological activities of these secondary metabolites are discussed.

343 citations