Bioengineering triacetic acid lactone production in <i>Yarrowia lipolytica</i> for pogostone synthesis

Yu, James; Landberg, Jenny Marie; Shavarebi, Farbod; Bilanchone, Virginia; Okerlund, Adam; Wanninayake, Umayangani K.; Zhao, Le; Kraus, George A.; Sandmeyer, Suzanne

doi:10.1002/bit.26733

Cited by 46 publications

(34 citation statements)

References 28 publications

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“…Liu et al demonstrated that the acetate uptake pathway in Y. lipolytica could function as an acetyl-CoA shortcut to achieve metabolic optimality in producing polyketides; the acetate-to-TAL conversion ratio (0.149 g/g) reached 31.9% of the theoretical maximum yield [10]. Yu et al increased TAL titer by using nitrogen-limited growth conditions and multiple copies of the 2-pyrone synthase gene and converted TAL at 96% yield to pogostone, a valuable antibiotic [11]. Asides from polyketide, terpenoids are also synthesized using acetyl-CoA as a precursor.…”

Section: Introductionmentioning

confidence: 99%

Engineering the oleaginous yeast Yarrowia lipolytica for production of α-farnesene

Liu

Xin

Cui

et al. 2019

Biotechnol Biofuels

106

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BackgroundYarrowia lipolytica, a non-traditional oil yeast, has been widely used as a platform for lipid production. However, the production of other chemicals such as terpenoids in engineered Y. lipolytica is still low. α-Farnesene, a sesquiterpene, can be used in medicine, bioenergy and other fields, and has very high economic value. Here, we used α-farnesene as an example to explore the potential of Y. lipolytica for terpenoid production.ResultsWe constructed libraries of strains overexpressing mevalonate pathway and α-farnesene synthase genes by non-homologous end-joining (NHEJ) mediated integration into the Y. lipolytica chromosome. First, a mevalonate overproduction strain was selected by overexpressing relevant genes and changing the cofactor specificity. Based on this strain, the downstream α-farnesene synthesis pathway was overexpressed by iterative integration. Culture conditions were also optimized. A strain that produced 25.55 g/L α-farnesene was obtained. This is the highest terpenoid titer reported in Y. lipolytica.ConclusionsYarrowia lipolytica is a potentially valuable species for terpenoid production, and NHEJ-mediated modular integration is effective for expression library construction and screening of high-producer strains.

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Section: Introductionmentioning

confidence: 99%

Engineering the oleaginous yeast Yarrowia lipolytica for production of α-farnesene

Liu

Xin

Cui

et al. 2019

Biotechnol Biofuels

106

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“…Extensive strain pathway, and synthase engineering have been performed to increase TAL synthesis in S. cerevisiae (Cardenas & Da Silva, , ; Saunders, Bowman, Mertens, Da Silva, & Hector, ). More recently, high TAL titers have been achieved via engineering of the oleaginous yeast Yarrowia lipolitica (Markham et al, ; Yu et al, ), taking advantage of the native high flux through acetyl‐CoA. In both yeast species, TAL was synthesized from glucose‐based media.…”

Section: Introductionmentioning

confidence: 99%

Synthesis of polyketides from low cost substrates by the thermotolerant yeast Kluyveromyces marxianus

McTaggart

Bever

Bassett

et al. 2019

Biotech & Bioengineering

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Kluyveromyces marxianus is a promising nonconventional yeast for biobased chemical production due to its rapid growth rate, high TCA cycle flux, and tolerance to low pH and high temperature. Unlike Saccharomyces cerevisiae, K. marxianus grows on low-cost substrates to cell densities that equal or surpass densities in glucose, which can be beneficial for utilization of lignocellulosic biomass (xylose), biofuel production waste (glycerol), and whey (lactose). We have evaluated K. marxianus for the synthesis of polyketides, using triacetic acid lactone (TAL) as the product. The 2-pyrone synthase (2-PS) was expressed on a CEN/ARS plasmid in three different strains, and the effects of temperature, carbon source, and cultivation strategy on TAL levels were determined.The highest titer was obtained in defined 1% xylose medium at 37°C, with substantial titers at 41 and 43°C. The introduction of a high-stability 2-PS mutant and a promoter substitution increased titer four-fold. 2-PS expression from a multi-copy pKD1-based plasmid improved TAL titers a further five-fold. Combining the best plasmid, promoter, and strain resulted in a TAL titer of 1.24 g/L and a yield of 0.0295 mol TAL/mol carbon for this otherwise unengineered strain in 3 ml tube culture. This is an excellent titer and yield (on xylose) before metabolic engineering or fed-batch culture relative to other hosts (on glucose), and demonstrates the promise of this rapidly growing and thermotolerant yeast species for polyketide production.

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“…Further, β‐oxidation related gene overexpression (PEX10) has supported the high TAL production with over 43% of the theoretical conversion yield under nitrogen (N) starvation condition. Three separate pathways in this host contributed to high TAL production via incorporation of acetyl CoA and malonyl‐CoA [82, 83]. Strain Y. lipolytica modifications have been implemented using a DNA cut and paste transposon to mobilize and integrate multiple copies of the 2‐PS gene for expression (from Gerbera hybrida ) to enhance TAL titers (2.6 g⋅L −1 ) in batch fermentation under nitrogen‐limited conditions.…”

Section: Primary Metabolitesmentioning

confidence: 99%

Primary metabolites from overproducing microbial system using sustainable substrates

Srivastava

Akhtar

Verma

et al. 2020

Biotech and App Biochem

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Primary (or secondary) metabolites are produced by animals, plants, or microbial cell systems either intracellularly or extracellularly. Production capabilities of microbial cell systems for many types of primary metabolites have been exploited at a commercial scale. But the high production cost of metabolites is a big challenge for most of the bioprocess industries and commercial production needs to be achieved. This issue can be solved to some extent by screening and developing the engineered microbial systems via reconstruction of the genome‐scale metabolic model. The predicted genetic modification is applied for an increased flux in biosynthesis pathways toward the desired product. Wherein the resulting microbial strain is capable of converting a large amount of carbon substrate to the expected product with minimum by‐product formation in the optimal operating conditions. Metabolic engineering efforts have also resulted in significant improvement of metabolite yields, depending on the nature of the products, microbial cell factory modification, and the types of substrate used. The objective of this review is to comprehend the state of art for the production of various primary metabolites by microbial strains system, focusing on the selection of efficient strain and genetic or pathway modifications, applied during strain engineering.

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Bioengineering triacetic acid lactone production in Yarrowia lipolytica for pogostone synthesis

Cited by 46 publications

References 28 publications

Engineering the oleaginous yeast Yarrowia lipolytica for production of α-farnesene

Engineering the oleaginous yeast Yarrowia lipolytica for production of α-farnesene

Synthesis of polyketides from low cost substrates by the thermotolerant yeast Kluyveromyces marxianus

Primary metabolites from overproducing microbial system using sustainable substrates

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