Overexpression of acetyl-CoA carboxylase in Aspergillus terreus to increase lovastatin production

• Published in: New biotechnology 2018-09, Vol.44, p.64-71
• Main Authors: Hasan, Hanan, Abd Rahim, Muhammad Hafiz, Campbell, Leona, Carter, Dee, Abbas, Ali, Montoya, Alejandro
• Format: Article
• Language: English
• Subjects: Acetyl-CoA carboxylase; Aspergillus terreus; Biosynthesis; Chemical compounds; Fungi; Geodin; Glycerol; Homologous recombination; Homology; Lactose; Lovastatin; Metabolism; Metabolites; Overexpression; Precursors; Secondary metabolites
• ISSN: 1871-6784; 1876-4347
• DOI: 10.1016/j.nbt.2018.04.008

Aspergillus terreus has the ability to produce cholesterol-lowering drug, lovastatin but the yield is not fully maximize. A new engineered A. terreus strain was developed to overexpress acetyl-CoA carboxylase by inserting strong promoter PadhA (isolated from Aspergillus nidulans). When the engineered strain grew in a mixture of glycerol (low value feedstock) and lactose, the malonyl-CoA and acetyl-CoA (lovastatin precursors) levels were amplified and positively affect lovastatin production while suppressing unwanted lovastatin co-product, (+)-geodin. [Display omitted] •The overexpression of acetyl-CoA carboxylase (ACCase) in Aspergillus terreus.•Increasing level of malonyl-CoA and acetyl-CoA due to the overexpression of ACCase.•Change in precursors level affects lovastatin and (+)-geodin production.•Varying substrates on mutant strain can promote lovastatin and suppress (+)-geodin. The present work describes the application of homologous recombination techniques in a wild-type Aspergillus terreus (ATCC 20542) strain to increase the flow of precursors towards the lovastatin biosynthesis pathway. A new strain was generated to overexpress acetyl-CoA carboxylase (ACCase) by replacing the native ACCase promoter with a strong constitutive PadhA promoter from Aspergillus nidulans. Glycerol and a mixture of lactose and glycerol were used independently as the carbon feedstock to determine the degree of response by the A. terreus strains towards the production of acetyl-CoA, and malonyl-CoA. The new strain increased the levels of malonyl-CoA and acetyl-CoA by 240% and 14%, respectively, compared to the wild-type strain. As a result, lovastatin production was increased by 40% and (+)-geodin was decreased by 31% using the new strain. This study shows for the first time that the metabolism of Aspergillus terreus can be manipulated to attain higher levels of precursors and valuable secondary metabolites.