Surveying the lipogenesis landscape in Yarrowia lipolytica through understanding the function of a Mga2p regulatory protein mutant

Liu, Leqian; Markham, Kelly A.; Blazeck, John; Zhou, Nijia; Leon, Dacia; Otoupal, Peter B.; Alper, Hal S.

doi:10.1016/j.ymben.2015.07.004

Cited by 65 publications

(44 citation statements)

References 63 publications

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“…This approach has been successful as almost all carbons are diverted from citrate excretion into TAG biosynthesis. However, while efforts have been made to increase lipid production in Y. lipolytica, 4 currently our knowledge of how lipid accumulation is regulated in Y. lipolytica is limited, whereas regulators as SNF1, 5 MIG1 6 and MGA2 7 have been shown to affect lipid accumulation. Systems level analysis is an excellent tool for probing regulatory mechanisms, as demonstrated extensively for Sacchromyces cerevisiae.…”

Section: Introductionmentioning

confidence: 99%

Regulation of amino-acid metabolism controls flux to lipid accumulation in Yarrowia lipolytica

et al. 2016

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Yarrowia lipolytica is a promising microbial cell factory for the production of lipids to be used as fuels and chemicals, but there are few studies on regulation of its metabolism. Here we performed the first integrated data analysis of Y. lipolytica grown in carbon and nitrogen limited chemostat cultures. We first reconstructed a genome-scale metabolic model and used this for integrative analysis of multilevel omics data. Metabolite profiling and lipidomics was used to quantify the cellular physiology, while regulatory changes were measured using RNAseq. Analysis of the data showed that lipid accumulation in Y. lipolytica does not involve transcriptional regulation of lipid metabolism but is associated with regulation of amino-acid biosynthesis, resulting in redirection of carbon flux during nitrogen limitation from amino acids to lipids. Lipid accumulation in Y. lipolytica at nitrogen limitation is similar to the overflow metabolism observed in many other microorganisms, e.g. ethanol production by Sacchromyces cerevisiae at nitrogen limitation.

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Section: Introductionmentioning

confidence: 99%

Regulation of amino-acid metabolism controls flux to lipid accumulation in Yarrowia lipolytica

et al. 2016

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“…Although Y. lipolytica present two main drawbacks since it accumulates limited amounts of lipids (Beopoulos et al, 2009a) and it cannot consume some preferred substrates such as lignocellulosic biomass or starch, it has been metabolically engineered to overcome these issues. On the one hand, among many engineering approaches (Dulermo and Nicaud, 2011;Liu et al, 2015b;Liu et al, 2015c;Tai and Stephanopoulos, 2013), Blazeck et al (Blazeck et al, 2014) rewired lipogenesis generating a strain able to accumulate up to 90% of its DCW as lipids and Qiao et al (Qiao et al, 2015) engineered Yarrowia and reached 85% of the theoretical maximal yield. On the other hand, several groups have tuned its lipid metabolism to make it able to produce lipids from raw starch (Ledesma-Amaro et al, 2015), cellulose (Wei et al, 2014), cellobiose (Guo et al, 2015), fructose (Lazar et al, 2014) and lignocellulosic material (Tsigie et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

Combining metabolic engineering and process optimization to improve production and secretion of fatty acids

Ledesma-Amaro

Dulermo

Niehus

2016

Metabolic Engineering

145

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Microbial oils are sustainable alternatives to petroleum for the production of chemicals and fuels. Oleaginous yeasts are promising source of oils and Yarrowia lipolytica is the most studied and engineered one. Nonetheless the commercial production of biolipids is so far limited to high value products due to the elevated production and extraction costs. In order to contribute to overcoming these limitations we exploited the possibility of secreting lipids to the culture broth, uncoupling production and biomass formation and facilitating the extraction. We therefore considered two synthetic approaches, Strategy I where fatty acids are produced by enhancing the flux through neutral lipid formation, as typically occurs in eukaryotic systems and Strategy II where the bacterial system to produce free fatty acids is mimicked. The engineered strains, in a coupled fermentation and extraction process using alkanes, secreted the highest titer of lipids described so far, with a content of 120% of DCW.

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“…Understanding the regulation of lipid metabolism in Y. lipolytica is critical for the further development of this yeast into a versatile and robust microbial cell factory. Moreover, knowledge concerning the regulation of its lipid metabolism will allow further harnessing of Y. lipolytica ’s potential by surveying the full lipogenesis landscape (5). There have been a few studies on the regulation of Y. lipolytica lipid metabolism during nitrogen limitation (N- lim ) (6) that monitored transcriptional changes during a shift from biomass production to lipid accumulation (7) and that have identified roles for single regulators such as Mga2 (5), Snf1 (8), Mig1 (9), and TORC1 (4).…”

Section: Introductionmentioning

confidence: 99%

“…Similarly, it has been shown that lipid accumulation can be influenced by various factors, referred to as the lipogenesis landscape of Y. lipolytica (5). We focused on two categories of factors, environmental and genetic, by comparing the results of Y. lipolytica cultivation performed under conditions of either nitrogen or carbon limitation using two different strains: a diacylglycerol acyltransferase (DGA)-overexpressing strain with high lipid production and a control strain.…”

Section: Introductionmentioning

confidence: 99%

Leucine Biosynthesis Is Involved in Regulating High Lipid Accumulation in Yarrowia lipolytica

Kerkhoven

Kim

Wei

et al. 2017

mBio

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The yeast Yarrowia lipolytica is a potent accumulator of lipids, and lipogenesis in this organism can be influenced by a variety of factors, such as genetics and environmental conditions. Using a multifactorial study, we elucidated the effects of both genetic and environmental factors on regulation of lipogenesis in Y. lipolytica and identified how two opposite regulatory states both result in lipid accumulation. This study involved comparison of a strain overexpressing diacylglycerol acyltransferase (DGA1) with a control strain grown under either nitrogen or carbon limitation conditions. A strong correlation was observed between the responses on the transcript and protein levels. Combination of DGA1 overexpression with nitrogen limitation resulted in a high level of lipid accumulation accompanied by downregulation of several amino acid biosynthetic pathways, including that of leucine in particular, and these changes were further correlated with a decrease in metabolic fluxes. This downregulation was supported by the measured decrease in the level of 2-isopropylmalate, an intermediate of leucine biosynthesis. Combining the multi-omics data with putative transcription factor binding motifs uncovered a contradictory role for TORC1 in controlling lipid accumulation, likely mediated through 2-isopropylmalate and a Leu3-like transcription factor.

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Surveying the lipogenesis landscape in Yarrowia lipolytica through understanding the function of a Mga2p regulatory protein mutant

Cited by 65 publications

References 63 publications

Regulation of amino-acid metabolism controls flux to lipid accumulation in Yarrowia lipolytica

Regulation of amino-acid metabolism controls flux to lipid accumulation in Yarrowia lipolytica

Combining metabolic engineering and process optimization to improve production and secretion of fatty acids

Leucine Biosynthesis Is Involved in Regulating High Lipid Accumulation in Yarrowia lipolytica

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