Kinetic Modelling of Lovastatin Biosynthesis by Aspergillus Terreus Cultivated on Lactose and Glycerol as Carbon Sources

Abstract

A kinetic model to describe lovastatin biosynthesis by Aspergillus terreus ATCC 20542 in a batch culture with the simultaneous use of lactose and glycerol as carbon sources was developed. In order to do this the kinetics of the process was first studied. Then, the model consisting of five ordinary differential equations to balance lactose, glycerol, organic nitrogen, lovastatin and biomass was proposed. A set of batch experiments with a varying lactose to glycerol ratio was used to finally establish the form of this model and find its parameters. The parameters were either directly determined from the experimental data (maximum biomass specific growth rate, yield coefficients) or identified with the use of the optimisation software. In the next step the model was verified with the use of the independent sets of data obtained from the bioreactor cultivations. In the end the parameters of the model were thoroughly discussed with regard to their biological sense. The fit of the model to the experimental data proved to be satisfactory and gave a new insight to develop various strategies of cultivation of A. terreus with the use of two substrates.

Bioprocess Engineering Aspects of the Cultivation of a Lovastatin Producer Aspergillus terreus

“…All in all, it is unlikely to find in literature the exponential growth curve for A. terreus. A linear biomass growth observed also by Bizukojc and Ledakowicz [8][9][10] and Pawlak and Bizukojc [57] seems to be untypical. Lack of typical exponential phase may make it difficult to model A. terreus growth as the existence of this phase is often assumed in the kinetic models, including the ones described above.…”

“…Lack of typical exponential phase may make it difficult to model A. terreus growth as the existence of this phase is often assumed in the kinetic models, including the ones described above. A closer look to this phenomenon was made by Pawlak and Bizukojc [57]. They thoroughly studied the very early stages of A. terreus growth in the shake flask culture and found that the exponential growth phase lasted not longer than 12 h since the inoculation with the 24-h preculture (Fig.…”

“…It can be without any doubts applied to A. terreus. Organic nitrogen-free media for feeding in fed-batch bioreactors are the most optimum for lovastatin production by A. terreus 17 Bizukojc and Ledakowicz [10] Too intensive aeration of the culture leads to the intensive formation of (+)-geodin, instead of lovastatin; pH control with carbonates is required for better lovastatin titres 18 Gupta et al [31] The optimum dilution rate is found for lovastatin production in a continuous bioreactor with free and immobilized biomass 19 Jia et al [34] Type of carbon source influences the properties (diameter and structure) of A. terreus pellets during lovastatin biosynthesis 20 Bizukojc and Ledakowicz [11] Lovastatin and (+)-geodin formation depends on the fraction of actively growing filaments in A. terreus pellets (the quantitative correlation given); first work on the intrastructure of A. terreus pellets 21 Gonciarz et al [29] Mineral microparticles (morphological engineering technique) should be added to the preculture in order to increase lovastatin titre; talc powder is better than aluminium oxide microparticles 22 Pawlak et al [59] Lovastatin formation strongly depends on the scale of bioreactor 23 Pawlak and Bizukojc [57] Unstructured kinetic model for A. terreus growth and lovastatin formation on two carbon substrates (lactose and glycerol) 24 Pawlak and Bizukojc [58] Apart from feeding profile, also the level of redox potential and utilization rate of inorganic carbon influence lovastatin formation in the fed-batch bioreactor 25 Gonciarz and Bizukojc [28] Addition of talc microparticles enhances lovastatin formation in the shake flask culture even by 50 %…”

“…This model was later extended by Pawlak and Bizukojc [57] for a two carbon substrates system. Most symbols used in it are the same as above.…”

“…The equations of this model, expressed as above, in the forms of specific rates σ LAC , σ GLC , σ N , π LOV and μ, were as follows: It is important to notice here that in this model, several limitation Contois terms were eliminated. It was done for the sake of better robustness of this model [57].…”