Abstract
Campesterol is an important precursor for many sterol drugs, e.g. progesterone and hydrocortisone. In order to produce campesterol in Yarrowia lipolytica, C-22 desaturase encoding gene ERG5 was disrupted and the heterologous 7-dehydrocholesterol reductase (DHCR7) encoding gene was constitutively expressed. The codon-optimized DHCR7 from Rallus norvegicus, Oryza saliva and Xenapus laevis were explored and the strain with the gene DHCR7 from X. laevis achieved the highest titer of campesterol due to D409 in substrate binding sites. In presence of glucose as the carbon source, higher biomass conversion yield and product yield were achieved in shake flask compared to that using glycerol and sunflower seed oil. Nevertheless, better cell growth rate was observed in medium with sunflower seed oil as the sole carbon source. Through high cell density fed-batch fermentation under carbon source restriction strategy, a titer of 453±24.7 mg/L campesterol was achieved with sunflower seed oil as the carbon source, which is the highest reported microbial titer known. Our study has greatly enhanced campesterol accumulation in Y. lipolytica, providing new insight into producing complex and desired molecules in microbes.
Highlights
Campesterol is an important precursor for steroid drugs, which used as balance hormone drug in the pharmaceutical industry [1, 2]
Yeast is a conventional host for sterol production such as pregnenolone and hydrocortisone [3, 4], but campesterol tends to adhere to the membrane and forms membranes structure, which would be a burden to cells [5,6,7]
Campesterol synthesis pathway was constructed in Y. lipolytica via blocking ergosterol biosynthesis and introducing heterogeneous DHCR7
Summary
Campesterol is an important precursor for steroid drugs, which used as balance hormone drug in the pharmaceutical industry [1, 2]. Yeast is a conventional host for sterol production such as pregnenolone and hydrocortisone [3, 4], but campesterol tends to adhere to the membrane and forms membranes structure, which would be a burden to cells [5,6,7]. Yarrowia lipolytica lipid bodies accumulation is favorable for less polar compounds storage, Y. lipolytica is a promising host cell for hydrophobic metabolites production [8, 9]. Y. lipolytica was been used for the production of β-carotene [11], omega-3 fatty acids eicosapentaenoic acid (EPA) [12], citric acid [13,14,15] and microbial lipids for cocoa-butter.
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