Polyketides in Aspergillus terreus : biosynthesis …
Hypolipidemic agent lovastatin produced by Aspergillus terreus ..
During growth on complex medium (glucose, peptonized milk, and yeast extract), glucose was rapidly metabolized under high oxygen consumption and biomass was formed (Fig. ). Ethanol was also formed, probably as result of a glycolytic overflow. Lactose and ethanol were consumed only after glucose exhaustion. The onset of lovastatin biosynthesis after glucose consumption can be attributed either to relief from carbon catabolite repression or to carbon source limitation. Carbon catabolite repression in Aspergillus is mediated by the negative-acting creA gene product (, ). The binding of protein CreAp to specific promoter sites of structural or regulatory genes involved in the utilization of alternative carbon sources, prevents their expression in the presence of glucose or another repressing carbon source (e.g., for alc genes see reference and for endoglucanase encoded by egl1 see reference ). The utilization of ethanol in A. nidulans is repressed by double lock control by CreAp of activator alcR and structural gene alcA, encoding alcohol dehydrogenase I (). The lovastatin biosynthetic gene cluster consists of 18 putative open reading frames (ORFs) (), among which 2 were annotated to encode regulatory proteins, lovE and ORF 13. Analysis of the lovastatin biosynthetic gene cluster revealed that closely spaced SYGGRG consensus sequences, the motif of functional CreAp binding sites in vivo (), are present in the 5′-proximal region of ORF 13 [SYGGRG(N)15SYGGRG] and in the putative promoter of the divergently transcribed ORF 8 and lovE [SYGGRG(N)7CYCCRW]. The presence of putative functional CreAp binding sites in two putative regulatory genes suggests that repression of lovastatin biosynthesis by glucose could be mediated by CreAp. Other carbon catabolite repression mechanisms might also be involved. Glucose represses penicillin synthesis in P. chrysogenum () by repressing pcbAB, pcbC, and penD, whereas in A. nidulans only pcbC is strongly repressed by glucose. In both species glucose repression of penicillin biosynthesis is not exclusively mediated by creA () but is mediated by another putative DNA-binding protein ().
Chisti, “Production of lovastatin by Aspergillus terreus: ..
Since growth requirements of A. terreus are limited, a chemically defined medium could be developed. The buffer capacity of this medium allowed us to keep the pH between 6.2 and 7.0. In the defined medium, all nitrogen sources tested (Table ) were consumed, which was confirmed by biomass formation. However, lovastatin biosynthesis proved dependent on the nitrogen source, as no lovastatin was detected during cultivation in presence of ammonium, nitrate, or urea (Table ). Only glutamate and histidine, and to a lesser extent glycine, supported lovastatin biosynthesis. Study of NAD- and NADP-glutamate dehydrogenase showed that glutamate and histidine play a key role in generation of idiophase conditions by the formation of α-ketoglutarate, which stimulates aflatoxin formation by inhibition of the tricarboxylic acid cycle (). The influence of nitrogen sources on secondary metabolism has been illustrated for fumonisin B1 biosynthesis in Gibberella fujikuroi (), for sterigmatocystin () and aflatoxin (, ) biosynthesis in Aspergillus nidulans and Aspergillus parasiticus, and for penicillin synthesis in Penicillium chrysogenum ().