Effects of terpenes on fluidity and lipid extraction in phospholipid membranes

Mendanha, Sebastião Antônio; Alonso, Antônio

doi:10.1016/j.bpc.2015.02.001

Cited by 46 publications

(29 citation statements)

References 31 publications

(53 reference statements)

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“…Because of their small volume, the solubilization of the short‐chain myrcene derivatives in diluted systems should cause minimal perturbation to the head‐group/chain tilt alignment that reflected relatively small depression of T d . However, upon saturation of the interfacial region with increasing drug concentration, solubilization of lipid molecules could take place because of partitioning of lipids into drug micelles …”

Section: Resultsmentioning

confidence: 99%

Novel type of isoprenoid membrane anchors: an investigation of binding properties with dipalmitoylphosphatidylcholine vesicles

Faizullin

Dzyurkevich

Valiullina

et al. 2016

J of Physical Organic Chem

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In this work, we present a new type of amphiphilic membrane‐anchoring agents that can be easily obtained by the Diels‐Alder reaction between terpene myrcene and N‐substituted maleimides. The interaction between the compounds and small unilamellar dipalmitoylphosphatidylcholine vesicles was investigated using infrared spectroscopy, microgravimetry, and turbidimetry. The ability of the compounds to embed in the phospholipid membrane was shown to be strongly dependent on the charge of their polar group. The insertion of the compounds studied into the lipid bilayer did not lead to disruption of the dipalmitoylphosphatidylcholine vesicles up to the highest tested drug to lipid molar ratio of 0.5 to 0.6. Low lipid solubilization ability of the compounds as well as their rigid nonplanar structure makes them an interesting alternative to the common membrane‐anchoring structural motifs.

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Section: Resultsmentioning

confidence: 99%

Novel type of isoprenoid membrane anchors: an investigation of binding properties with dipalmitoylphosphatidylcholine vesicles

Faizullin

Dzyurkevich

Valiullina

et al. 2016

J of Physical Organic Chem

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“…In contrast to previous studies, we creatively accelerated the e ux of relatively small-molecular terpenes by altering lipid metabolism via OLE1 overexpression and PAH1-DGK1 knockout. The resulting increase in the UFA/SFA ratio contributed to enhancing the membrane permeability of toxic substances [52] and potentially increasing the extra/intracellular partition coe cient of terpenoids with a highly nonpolar nature in the IPM phase [15].…”

Section: Discussionmentioning

confidence: 99%

“…For instance, lupeol, a typical triterpenoid, caused severe damage to cell viability even at a relatively low concentration of 60 mg/L [3,8]. To decrease the intractable cytotoxicity, extensive efforts aimed at creating oleaginous subcellular organelles by altering lipid-droplet composition and size potentially improved the terpene partition coe cient in oil droplets and the storage space so that lipophilic terpenes can accumulate in these compartments [9][10][11][12][13][14][15]. For instance, researchers successfully increased lycopene accumulation by creating supersized lipid droplets through manipulation of triacylglycerol (TAG) metabolism in Saccharomyces cerevisiae, which resulted in the highest yield (73.3 mg/g cdw and 2.37 g/L lycopene) reported in S. cerevisiae to date [10].…”

Section: Introductionmentioning

confidence: 99%

“…However, the relatively low permeability of the cell membrane is still a barrier to the e ux of triterpenoids [19]. Manipulation of the lipid composition in membranes, such as the unsaturated fatty acid/saturated fatty acid (UFA/SFA) ratio or the membrane phospholipid content, is an e cient approach to tune membrane permeability and potentially alter the extra/intracellular partition coe cient of terpenes [15,[19][20][21][22][23][24][25][26]. For example, upregulation of SFA content in E. coli resulted in membrane tightening with enhanced tolerance to toxic n-hexane in culture [25].…”

Section: Introductionmentioning

confidence: 99%

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High production of triterpenoids in Yarrowia lipolytica through manipulation of lipid components

Zhang

Bai

Peng

et al. 2020

Preprint

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Background Lupeol exhibits novel physiological and pharmacological activities, such as anticancer and immunity-enhancing activities. However, cytotoxicity remains a challenge for triterpenoid overproduction in microbial cell factories. As lipophilic and relatively small-molecular compounds, triterpenes are generally secreted into the extracellular space. The effect of increasing triterpene efflux on the synthesis capacity remains unknown.Results In this study, we developed a strategy to enhance triterpene efflux through manipulation of lipid components in Y. lipolytica by overexpressing the enzyme Δ9-fatty acid desaturase (OLE1) and disturbing phosphatidic acid phosphatase (PAH1) and diacylglycerol kinase (DGK1). By this strategy combined with two-phase fermentation, the highest lupeol production reported to date was achieved, where the titer in the organic phase reached 381.67 mg/L and the total production was 411.72 mg/L in shake flasks, exhibiting a 33.20-fold improvement over the initial strain. Lipid manipulation led to a two-fold increase in the unsaturated fatty acid (UFA) content, up to 61%~73%, and an exceptionally elongated cell morphology, which might have been caused by enhanced membrane phospholipid biosynthesis flux. Both phenotypes accelerated the export of toxic products to the extracellular space and ultimately stimulated the capacity for triterpenoid synthesis, which was proven by the 5.11-fold higher ratio of extra/intracellular lupeol concentrations, 2.79-fold higher biomass accumulation and 2.56-fold higher lupeol productivity per unit OD in the modified strains. This strategy was also highly efficient for the biosynthesis of other triterpenes and sesquiterpenes, including α-amyrin, β-amyrin, longifolene, longipinene and longicyclene.Conclusions In conclusion, we successfully created a high-yield lupeol-producing strain via lipid manipulation. We demonstrated that the enhancement of lupeol efflux and synthesis capacity was induced by the increased UFA content and elongated cell morphology. Our study provides a novel strategy to promote the biosynthesis of valuable but toxic products in microbial cell factories.

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“…For instance, lupeol, a typical triterpenoid, caused severe damage to cell viability even at a relatively low concentration of 60 mg/L [3,8]. To decrease the intractable cytotoxicity, extensive efforts aimed at creating oleaginous subcellular organelles by altering lipid-droplet composition and size potentially improved the terpene partition coefficient in oil droplets and the storage space so that lipophilic terpenes can accumulate in these compartments [9][10][11][12][13][14][15]. For instance, researchers successfully increased lycopene accumulation by creating supersized lipid droplets through manipulation of triacylglycerol (TAG) metabolism in Saccharomyces cerevisiae, which resulted in the highest yield (73.3 mg/g cdw and 2.37 g/L lycopene) reported in S. cerevisiae to date [10].…”

mentioning

confidence: 99%

High production of triterpenoids in Yarrowia lipolytica through manipulation of lipid components

Zhang

Bai

Peng

et al. 2020

Biotechnol Biofuels

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Background: Lupeol exhibits novel physiological and pharmacological activities, such as anticancer and immunityenhancing activities. However, cytotoxicity remains a challenge for triterpenoid overproduction in microbial cell factories. As lipophilic and relatively small molecular compounds, triterpenes are generally secreted into the extracellular space. The effect of increasing triterpene efflux on the synthesis capacity remains unknown. Results: In this study, we developed a strategy to enhance triterpene efflux through manipulation of lipid components in Y. lipolytica by overexpressing the enzyme Δ9-fatty acid desaturase (OLE1) and disturbing phosphatidic acid phosphatase (PAH1) and diacylglycerol kinase (DGK1). By this strategy combined with two-phase fermentation, the highest lupeol production reported to date was achieved, where the titer in the organic phase reached 381.67 mg/L and the total production was 411.72 mg/L in shake flasks, exhibiting a 33.20-fold improvement over the initial strain. Lipid manipulation led to a twofold increase in the unsaturated fatty acid (UFA) content, up to 61-73%, and an exceptionally elongated cell morphology, which might have been caused by enhanced membrane phospholipid biosynthesis flux. Both phenotypes accelerated the export of toxic products to the extracellular space and ultimately stimulated the capacity for triterpenoid synthesis, which was proven by the 5.11-fold higher ratio of extra/intracellular lupeol concentrations, 2.79-fold higher biomass accumulation and 2.56-fold higher lupeol productivity per unit OD in the modified strains. This strategy was also highly efficient for the biosynthesis of other triterpenes and sesquiterpenes, including α-amyrin, β-amyrin, longifolene, longipinene and longicyclene. Conclusions: In conclusion, we successfully created a high-yield lupeol-producing strain via lipid manipulation. We demonstrated that the enhancement of lupeol efflux and synthesis capacity was induced by the increased UFA content and elongated cell morphology. Our study provides a novel strategy to promote the biosynthesis of valuable but toxic products in microbial cell factories.

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Effects of terpenes on fluidity and lipid extraction in phospholipid membranes

Cited by 46 publications

References 31 publications

Novel type of isoprenoid membrane anchors: an investigation of binding properties with dipalmitoylphosphatidylcholine vesicles

Novel type of isoprenoid membrane anchors: an investigation of binding properties with dipalmitoylphosphatidylcholine vesicles

High production of triterpenoids in Yarrowia lipolytica through manipulation of lipid components

High production of triterpenoids in Yarrowia lipolytica through manipulation of lipid components

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