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Increasing Lovastatin Production by Re-routing the Precursors Flow of Aspergillus terreus via Metabolic Engineering

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Abstract

Lovastatin is an anti-cholesterol medicine that is commonly prescribed to manage cholesterol levels, and minimise the risk of suffering from heart-related diseases. Aspergillus terreus (ATCC 20542) supplied with carbohydrates or sugar alcohols can produce lovastatin. The present work explored the application of metabolic engineering in A. terreus to re-route the precursor flow towards the lovastatin biosynthetic pathway by simultaneously overexpressing the gene for acetyl-CoA carboxylase (acc) to increase the precursor flux, and eliminate ( +)-geodin biosynthesis (a competing secondary metabolite) by removing the gene for emodin anthrone polyketide synthase (gedC). Alterations to metabolic flux in the double mutant (gedCΔ*accox) strain and the effects of using two different substrate formulations were examined. The gedCΔ*accox strain, when cultivated with a mixture of glycerol and lactose, significantly (p < 0.05) increased the levels of metabolic precursors malonyl-CoA (48%) and acetyl-CoA (420%), completely inhibited the (+)-geodin biosynthesis, and increased the level of lovastatin [152 mg/L; 143% higher than the wild-type (WT) strain]. The present work demonstrated how the manipulation of A. terreus metabolic pathways could increase the efficiency of carbon flux towards lovastatin, thus elevating its overall production and enabling the use of glycerol as a substrate source. As such, the present work also provides a framework model for other medically or industrially important fungi to synthesise valuable compounds using sustainable carbon sources.

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Data Availability

The datasets generated and/or analysed in the present work are available from the corresponding author upon reasonable request.

Abbreviations

PKS:

Polyketide synthase

LNKS:

Lovastatin nonaketide synthase

KS:

Ketoacyl synthase

AT:

Acyl transferase

PDA:

Potato dextrose agar

G:

Glycerol

GL:

Glycerol–lactose

HPLC:

High-performance liquid chromatography

WT:

Wild-type

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Authors and Affiliations

  1. School of Chemical and Biomolecular Engineering, The University of Sydney, Sydney, Australia

    Hanan Hasan, Muhamad Hafiz Abd Rahim, Ali Abbas & Alejandro Montoya

  2. School of Life and Environmental Sciences, The University of Sydney, Sydney, Australia

    Leona Campbell & Dee Carter

  3. Department of Food Science, Faculty of Food Science and Technology, Universiti Putra Malaysia, 43400, Serdang, Selangor, Malaysia

    Hanan Hasan & Muhamad Hafiz Abd Rahim

  4. Laboratory of Halal Science Research, Halal Products Research Institute, Universiti Putra Malaysia, 43400, Serdang, Selangor, Malaysia

    Hanan Hasan

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  1. Hanan Hasan
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Hasan, H., Abd Rahim, M.H., Campbell, L. et al. Increasing Lovastatin Production by Re-routing the Precursors Flow of Aspergillus terreus via Metabolic Engineering. Mol Biotechnol 64, 90–99 (2022). https://doi.org/10.1007/s12033-021-00393-w

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