Carbon sources and nitrogen sources
Carbon and nitrogen sources are essential for microbial growth. It has a great influence on the synthesis of lovastatin. A. terreus is the native strain that produces lovastatin. Therefore, most people focus on optimizing carbon and nitrogen sources using A. terreus ATCC 20542. Ansari et al.(Ansari, Jalili et al. 2018) showed that 64 g/L syrup carbohydrates, 15 g/L yeast extract can lead to the lovastatin titer of 105.6 mg/L using A. terreus ATCC 20542. Batch cultures were performed in a 2.5-L working volume bioreactor and led to the lovastatin titer of 241.1 mg/L during 12 days A. terreus ATCC 20542. Rollini et al.(Rollini and Manzoni 2006) showed soybean peptone generally allowed the best lovastatin yields to be achieved (250–280 mg/L) by A. terreusATCC 20542, particularly in the presence of soybean and peanut flours. Vegetable oil as sole carbon source and supplemental carbon source has effects on the fermentation of lovastatin by A. terreus . Sripalakit et al.(Sripalakit and Saraphanchotiwitthaya 2020) showed that all selected vegetable oils increased yields by at least two-fold. Especially, when 1% w/v coconut oil was added, the highest yield was 87.18 g/L using A. terreus ATCC 20542, approximately 11-fold compared to the oil-free control group. Hajjaj et al.(Hajjaj, Niederberger et al. 2001) found that a threefold-higher specific productivity was found with the defined medium on glucose and glutamate, compared to growth on complex medium with glucose, peptonized milk, and yeast extract using A. terreus Thom ATCC 74135. Oliveira et al.(Oliveira, Paulo et al. 2021) showed that 60 g/L soluble starch, 15 g/L soybean flour led to producing 100.86 mg/L lovastatin using A. terreus URM 5579. Kaur et al.(Kaur, Kaur et al. 2010) optimized the culture-medium parameters of A. terreus GD13. They found it can lead to the maximal lovastatin titer of 1342 mg/L when the initial C:N ratio in the culture medium was 37:1, which was 7-fold compared to the titer obtained under unoptimized conditions. Submerged fermentation of agricultural waste for fermentation substrate to produce statins can not only protect the environment, but also recycle resources. Srinivasan et al. (Srinivasan, Thangavelu et al. 2022) usedA. terreus KPR 12 to ferment the sago processing wastewater, getting 429.98 mg/L lovastatin. Medium optimization for other strains has also been reported. Atli et al. (Atli, Yamaç et al. 2013) found 30 g/L glucose, 10 g/L yeast extract can lead to 114.82 mg/L lovastatin using P. ostreatus OBCC 1031.
Carbon sources, nitrogen sources also have a great influence on the synthesis of compactin. Chakravarti et al.(Chakravarti and Sahai 2002) optimized the medium for compactin production by P. citrinum NCIM 768, lead to the maximum titer increased to 490 mg/L. Ahmad et al.(Ahmad, Panda et al. 2010) showed that glycerol, peptone, yeast extract improved the titer of compactin to 589.3 mg/L usingP.citrinum MTCC 1256. Syed et al.(Syed and Rajasimman 2015) optimized medium on the production of compactin by A. terreus , lead to the titer of compactin increased to 701 mg/L. Jekkel et al.(Kónya, Jekkel et al. 1998) showed that 7.0% glucose, 1.0% yeast extract led to the titer of compactin to 390-410 mg/mL using P. citrinum MTCC 1256.
Inorganic salts
Inorganic salts are not only nutrients for microbial growth, but also can participate in the building blocks of microbial cells and enzymes. Therefore, inorganic salts have a certain effect on the biosynthesis of lovastatin. Rahim et al.(Abd Rahim, Lim et al. 2019) showed that the yield of lovastatin increased by 282% to 25.52 mg/L when the medium have KH2PO4, MgSO4·7H2O, NaCl and ZnSO4·7H2O using A. terreus ATCC 20542. Jia et al.(Jia, Zhang et al. 2009) showed that Fe2+, Ca2+, Zn2+, Mg2+ and Mn2+ can promote lovastatin synthesis and cell growth. In the presence of 2mM and 5mM Zn2+, the highest titer was 49.2±1.4 mg gDCW-1, a 14.4-fold increased using A. terreusATCC 20542. Sayyad et al.(Sayyad, Panda et al. 2007) optimized M. purpureus MTCC 369 to produce lovastatin. In the medium containing 3.86 g/L NH4Cl, 1.73 g/L KH2PO4, 0.86 g/L MgSO4·7H2O and 0.19 g/L MnSO4·H2O, the maximum titer of lovastatin increased to 351 mg/L.
2.1.2 Dissolved Oxygen (DO)
The dissolved oxygen in Submerged fermentation medium has great influence on the synthesis of statins. Gonciarz et al.(Gonciarz and Bizukojc 2014) added 10μm of talc particles in the medium to decreases fungal pellet size to increase the oxygen saturation of the broth, which lead to lovastatin titer increased by 3.5-fold to exceed then 120 mg/L. The optimal continuous feed batch increased to 250 mg/L(Gonciarz, Kowalska et al. 2016). Lai group(Lai, Tsai et al. 2005) found that the 5-L fermenter increased lovastatin titer by 38% when the dissolved oxygen (DO) was controlled at 20%. When the medium temperature was reduced from 28 ℃ to 23 ℃, the titer of lovastatin was further increased by 25%, reaching 572 mg/L. Ansari et. al(Ansari, Jalili et al. 2019) showed that the highest titer of lovastatin (443 mg/L) were obtained at air bubbles diameter of 0.18 cm. The main reason is that the diameter of the bubble directly affects the concentration of dissolved oxygen.
In fact, reactive oxygen species (ROS) produced during fermentation have an effect on lovastatin biosynthesis The addition of N-Acetyl-L-cysteine (NAC), which reduces reactive oxygen species, can reduce lovastatin production. On the contrary, the addition of H2O2, which promotes reactive oxygen species (ROS) production, leads to lovastatin biosynthesis(Miranda, Gómez-Quiroz et al. 2014).
Redox potential of fermenters can also affect lovastatin synthesis(Pawlak and Bizukojc 2013). In the process with the highest redox potential levels maximum lovastatin concentration was equal to 83.8 mg/L, while at the lowest redox level it did not reach 67 mg/L.
2.1.3 Other effects