Engineering Yarrowia lipolytica as a chassis for de novo synthesis of aromatic-derived natural products and chemicals

BioRxiv : the Preprint Server for Biology
Y. GuPeng Xu

Abstract

Yarrowia lipolytica is an attractive host to upgrade renewable low-cost carbon feedstocks to high-value commodity chemicals and natural products. In this work, we systematically characterized and removed the rate-limiting steps of the shikimate pathway and achieved de novo synthesis of five aromatic chemicals in Y. lipolytica. We determined that engineering feedback-insensitive DAHP synthases and eliminating amino acids formation are critical steps to mitigate the feedback regulation of shikimate pathway. Further overexpression of heterologous phosphoketolase and deletion of pyruvate kinase provided a sustained metabolic driving force that channels E4P (erythrose 4-phosphate) and PEP (phosphoenolpyruvate) precursors through the shikimate pathway. Precursor competing pathways and byproduct formation pathways were also blocked by inactivating chromosomal genes. To demonstrate the utility of our engineered chassis strain, three natural products, 2-PE, p-coumaric acid and violacein, which were derived from phenylalanine, tyrosine and tryptophan, respectively, were chosen to test the chassis performance. We obtained 2426.22 mg/L of 2-phenylethanol (2-PE), 593.53 mg/L of p-coumaric acid, 366.30 mg/L of violacein and 55.12 mg/L of deo...Continue Reading

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