Journal of Biotechnology 130 (2007) 422–435 A macrokinetic modelling of the biosynthesis of lovastatin by Aspergillus terreus Marcin Bizukojc ∗ , Stanislaw Ledakowicz Department of Bioprocess Engineering, Technical University of Lodz, ul. Wolczanska 213/215, 90-924 Lodz, Poland Received 20 December 2006; received in revised form 20 April 2007; accepted 7 May 2007 Abstract In this work a simple kinetic model to describe the biosynthesis of lovastatin by Aspergillus terreus ATCC 20542 was proposed. Several series of experiments were conducted at different media compositions. The concentrations of C- and N-sources were changed over a wide range and so were the initial biomass concentrations. From these runs the relationships ruling the substrates uptake, biomass and product formation were learnt. Lovastatin biosynthesis appeared to be partly growth associated. The inhibitive effect of organic nitrogen on lovastatin biosynthesis was found and lactose appeared to be an important limiting substrate in the formation of lovastatin. The parameters of the model were evaluated on the basis of the kinetic data obtained in the separate experiments made in triplicate at two chosen media compositions. Other results obtained at different media compositions were independent of the ones mentioned above and used for the veriﬁcation of the model. The validity of the model was also examined for the lactose-fed fed-batch run. Finally, a sensitivity analysis of the model parameters was performed. The formulated model, although relatively simpliﬁed, described the experimental data quite well and could be regarded as the background for further attempts to mathematically describe the process of lovastatin biosynthesis. © 2007 Elsevier B.V. All rights reserved. Keywords: Lovastatin; Mevinolinic acid; Aspergillus terreus; Modelling; Kinetics 1. Introduction Lovastatin, belonging to statins, is a widely used antihy- percholesterolemia drug. The main producers of statins are Penicillium citrinum, Monascus ruber and Aspergillus terreus (Manzoni and Rollini, 2002; Endo, 2004). Lovastatin is a natu- ral product originated from A. terreus (Monaghan et al., 1980). This secondary metabolite is extensively excreted from fungal cells into a medium in the form of -hydroxy acid–mevinolinic acid (Casas Lopez et al., 2003). There are many papers concerning the biosynthesis of lovas- tatin. Some of them deal with the biochemical mechanism ruling this process. From the biochemical point of view the biosynthe- sis of mevinolinic acid is performed at two stages. The ﬁrst stage is catalysed by the nonaketide synthase (EC 2.3.1.161), which belongs to type I polyketide synthases and catalyses the nine-step formation of the polyketide (Shen, 2003). This PKS ∗ Corresponding author. Tel.: +48 42 631 37 04; fax: +48 42 636 56 63. E-mail address: marcin.bizukojc@p.lodz.pl (M. Bizukojc). stage leads to the lovastatin precursor 4a,5-dihydromonacoline L(Sutherland et al., 2001): AcCoA + 8malonyl-CoA + 11NADPH + 10H + + S-adenosyl-l-methionine EC 2.3.1.161 -------→4a, 5-dihydromonacoline L + 9CoA + 8CO 2 +11NADP + S-adenosyl-l-homocysteine + 6H 2 O In the post-PKS stage several oxidation steps with the participa- tion of molecular oxygen lead to mevinolinic acid (Sutherland et al., 2001). Other papers concern the inﬂuence of media composition on the process of mevinolinic acid production. The optimum car- bon source was widely sought by many authors (Sitaram Kumar et al., 2000; Casas Lopez et al., 2003; Lai et al., 2003). Also a variety of nitrogen-sources were tested with regard to the opti- misation of mevinolinic acid biosynthesis (Hajjaj et al., 2001; Casas Lopez et al., 2003; Lai et al., 2003). Casas Lopez et al. (2005) and Lai et al. (2005) investigated the inﬂuence of dissolved oxygen in the medium on the process 0168-1656/$ – see front matter © 2007 Elsevier B.V. All rights reserved. doi:10.1016/j.jbiotec.2007.05.007