Production of α-cuprenene in Xanthophyllomyces dendrorhous: a step closer to a potent terpene biofactory

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Abstract
Background: The red yeast Xanthophyllomyces dendrorhous is a natural producer of the carotenoid astaxanthin. Because of its high flux, the native terpene pathway leading to the production of the tetraterpene is of particular interest as it can be redirected toward the production of other terpene compounds. The genetic tools for the transformation of the yeast with the concurrent knock-out of genes involved in the astaxanthin biosynthesis are made available and here we show that the production of the sesquiterpene α-cuprenene is possible in mutant strains of X. dendrorhous transformed with the Cop6 gene originating from the fungus Coprinus cinereus. For the evaluation of the production levels, we chose to express the same gene and analyze the accumulation of α-cuprenene in Escherichia coli and Saccharomyces cerevisiae, as well. Here we propose that X. dendrorhous is a candidate in the search for the potential platform organism for the production of terpenes. Results: All three X. dendrorhous mutants functionally express the Cop6 gene and accumulate α-cuprenene. The production of α-cuprenene in the red yeast reached 80 mg/L, which represents a far higher concentration compared to the levels obtained in the E. coli and S. cerevisiae mutants. At this expression levels the pool of terpene precursors has not become a limiting factor in the X. dendrorhous mutants since the expression of the Cop6 gene in the genomic rDNA of the yeast allows production of both α-cuprenene and astaxanthin without affecting the growth or the accumulation levels of both compounds. Conclusions: We have shown that X. dendrorhous can produce α-cuprenene, and the results here presented, next to the capability of accumulating at least two more non-native sesquiterpenes, demonstrates the high potential of this yeast to become an interesting terpene-based drugs producer.

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