Journal
CHEMICAL ENGINEERING SCIENCE
Volume 196, Issue -, Pages 82-90Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.ces.2018.10.052
Keywords
Betulinic acid; Glycerol; Heterologous biosynthesis; Terpenoids; Yarrowia lipolytica
Categories
Funding
- National Natural Science Foundation of China [21878220]
- Major Research Plan of Tianjin [16YFXTSF00460]
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Glycerol is the main byproduct of the biodiesel production process and can be converted into valuable products by Yarrowia lipolytica. Betulinic acid is a pentacyclic triterpene with a variety of pharmacological properties. Herein we report heterologous biosynthesis of betulinic acid in Y. lipolytica by co-expressing lupeol synthase opAtLUP1, NADPH-cytochrome P450 monooxygenase opCYP716A12, and NADPH-cytochrome P450 reductase opAtCPR1. Initially, the engineered Y. lipolytica produced 0.32 mg/L betulinic acid. This titer was increased to 9.41 mg/L following P450 enzyme fusion and overexpression of key genes from the upstream mevalonate (MVA) pathway. Substitution of glycerol for glucose further enhanced betulinic acid production to 16.98 mg/L, 1.8-fold higher than the titer obtained with glucose. 26.53 mg/L betulinic acid was obtained with 40 g/L glycerol as the sole carbon source, which was comparable to the titer obtained from Saccharomyces cerevisiae with 50 g/L glucose in shake flask cultivation. Glycerol improved betulinic acid titer by increasing the expression of key genes in the MVA pathway, and by increasing the supply of acetyl-CoA. Our study highlights the possible applications of glycerol as carbon source in the production of valuable terpenoids by engineered Y. lipolytica. (C) 2018 Elsevier Ltd. All rights reserved.
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