The oleaginous yeast Yarrowia lipolytica was metabolically engineered to produce the chamomile sesquiterpene (−)-α-bisabolol in a green and sustainable way.
Sesquiterpenes
are natural compounds composed of three isoprene
units. They represent the largest class of terpene compounds found
in plants, and many have remarkable biological activities. Furthermore,
sesquiterpenes have broad applications in the flavor, pharmaceutical
and biofuel industries due to their complex structures. With the development
of metabolic engineering and synthetic biology, the production of
different sesquiterpenes has been realized in various chassis microbes.
The microbial production of sesquiterpenes provides a promising alternative
to plant extraction and chemical synthesis, enabling us to meet the
increasing market demand. In this review, we summarized the heterologous
production of different plant sesquiterpenes using the eukaryotic
yeasts Saccharomyces cerevisiae and Yarrowia
lipolytica, followed by a discussion of common metabolic
engineering strategies used in this field.
The oleaginous non-conventional yeast
Yarrowia lipolytica
has enormous potential as a microbial platform for the synthesis of various bioproducts. However, while the model yeast
Saccharomyces cerevisiae
has very high homologous recombination (HR) efficiency, non-homologous end-joining is dominant in
Y. lipolytica
, and foreign genes are randomly inserted into the genome. Consequently, the low HR efficiency greatly restricts the genetic engineering of this yeast. In this study, RAD52, the key component of the HR machinery in
S. cerevisiae
, was grafted into
Y. lipolytica
to improve HR efficiency. The gene
ade2
, whose deletion can result in a brown colony phenotype, was used as the reporter gene for evaluating the HR efficiency. The HR efficiency of
Y. lipolytica
strains before and after integrating the
ScRad52
gene was compared using insets with homology arms of different length. The results showed that the strategy could achieve gene targeting efficiencies of up to 95% with a homology arm length of 1000 bp, which was 6.5 times of the wildtype strain and 1.6 times of the traditionally used
ku70
disruption strategy. This study will
facilitate
the further genetic engineering of
Y. lipolytica
to make it a more efficient cell factory for the production of value-added compounds.
Terpenes are a large class of secondary metabolites with diverse structures and functions that are commonly used as valuable raw materials in food, cosmetics, and medicine. With the development of metabolic engineering and emerging synthetic biology tools, these important terpene compounds can be sustainably produced using different microbial chassis. Currently, yeasts such as Saccharomyces cerevisiae and Yarrowia lipolytica have received extensive attention as potential hosts for the production of terpenes due to their clear genetic background and endogenous mevalonate pathway. In this review, we summarize the natural terpene biosynthesis pathways and various engineering strategies, including enzyme engineering, pathway engineering, and cellular engineering, to further improve the terpene productivity and strain stability in these two widely used yeasts. In addition, the future prospects of yeast-based terpene production are discussed in light of the current progress, challenges, and trends in this field. Finally, guidelines for future studies are also emphasized.
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