Engineering Strategies in Microorganisms for the Enhanced Production of Squalene: Advances, Challenges and Opportunities

Gohil, Nisarg; Bhattacharjee, Gargi; Khambhati, Khushal; Braddick, Darren; Singh, Vijai

doi:10.3389/fbioe.2019.00050

Cited by 121Plant biochemistry and biosynthesisMicrobial Metabolic Engineering and BioproductionMicrobial Natural Products and Biosynthesis

Engineering Strategies in Microorganisms for the Enhanced Production of Squalene: Advances, Challenges and Opportunities

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Gohil, Nisarg, Bhattacharjee, Gargi, Khambhati, Khushal, Braddick, Darren, Singh, Vijai·2019·Frontiers in Bioengineering and Biotechnology

DOI 10.3389/fbioe.2019.00050PMC PMC6439483

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Abstract

The triterpene squalene is a natural compound that has demonstrated an extraordinary diversity of uses in pharmaceutical, nutraceutical, and personal care industries. Emboldened by this range of uses, novel applications that can gain profit from the benefits of squalene as an additive or supplement are expanding, resulting in its increasing demand. Ever since its discovery, the primary source has been the deep-sea shark liver, although recent declines in their populations and justified animal conservation and protection regulations have encouraged researchers to identify a novel route for squalene biosynthesis. This renewed scientific interest has profited from immense developments in synthetic biology, which now allows fine-tuning of a wider range of plants, fungi, and microorganisms for improved squalene production. There are numerous naturally squalene producing species and strains; although they generally do not make commercially viable yields as primary shark liver sources can deliver. The recent advances made toward improving squalene output from natural and engineered species have inspired this review. Accordingly, it will cover in-depth knowledge offered by the studies of the natural sources, and various engineering-based strategies that have been used to drive the improvements in the pathways toward large-scale production. The wide uses of squalene are also discussed, including the notable developments in anti-cancer applications and in augmenting influenza vaccines for greater efficacy.

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Improving squalene production through up-regulation of genes for its synthesis or down-regulation of genes for its degradation is possible.
“Alternatively, improving squalene production through up-regulation of genes that lead to its synthesis or down-regulation of genes for its degradation is possible [60].”
From Key Targets for Improving Algal Biofuel Production (2021) · cites this paper as [60]

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Background
Overproduction of Geranylgeraniol by Metabolically Engineered Saccharomyces cerevisiae
Tokuhiro, K., Muramatsu, M., Ohto, C., Kawaguchi, T., Obata, S., Muramoto, N., Hirai, M., Takahashi, H., Kondo, A., Sakuradani, E., et al. (2009) · Applied and Environmental Microbiology · doi:10.1128/aem.00277-09 · Cited by 123 · see citing works
Mechanisms of xenobiotic receptor activation: Direct vs. indirect
Mackowiak, B., & Wang, H. (2016) · Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms · doi:10.1016/j.bbagrm.2016.02.006 · Cited by 121 · cited 1× · see citing works
“These compounds interfere with the normal physiological functioning by either acting as potential pro-carcinogens or by mimicking the receptor structure of sex hormones (Omiecinski et al., 2011; Mackowiak and Wang, 2016).”
The gene encoding squalene epoxidase from Saccharomyces cerevisiae: cloning and characterization
Jandrositz, A., Turnowsky, F., & Högenauer, G. (1991) · Gene · doi:10.1016/0378-1119(91)90310-8 · Cited by 119 · cited 1× · see citing works
“Blocking or disrupting the pathway following squalene synthesis, owing to the accumulation of squalene leads to the death of the fungus (Jandrositz et al., 1991).”
Background
A HIGHLY UNSATURATED HYDROCARBON IN SHARK LIVER OIL
Tsujimoto, M. (1916) · Journal of Industrial & Engineering Chemistry · doi:10.1021/i500010a005 · Cited by 117 · cited 2× · see citing works
“) liver by a Japanese chemist Mitsumaru Tsujimoto, hence the name “squalene” (Tsujimoto, 1916).”
Background
Oil components modulate physical characteristics and function of the natural oil emulsions as drug or gene delivery system
Chung, H., Kim, T. W., Kwon, M., Kwon, I. C., & Jeong, S. Y. (2001) · Journal of Controlled Release · doi:10.1016/s0168-3659(00)00363-1 · Cited by 115 · cited 1× · see citing works
“Additionally, squalene in comparison to other lipids can form fairly stable emulsions that facilitate the delivery of a lipophilic drug when loaded into the discontinuous oil phase (Chung et al., 2001).”
Background
Enhanced squalene biosynthesis in Yarrowia lipolytica based on metabolically engineered acetyl-CoA metabolism
Huang, Y., Jian, X., Lv, Y.-B., Nian, K.-Q., Gao, Q., Chen, J., Wei, L., & Hua, Q. (2018) · Journal of Biotechnology · doi:10.1016/j.jbiotec.2018.07.001 · Cited by 112 · cited 3× · see citing works
“The level of squalene was enhanced up to 7 and 10mg/g following supplementation of 20mM sodium acetate and 10mM citrate, respectively (Huang et al., 2018).”
BackgroundMethodInfluential
Extraction of tocotrienols from palm fatty acid distillates using molecular distillation
Posada, L. R., Shi, J., Kakuda, Y., & Xue, S. J. (2007) · Separation and Purification Technology · doi:10.1016/j.seppur.2007.04.016 · Cited by 111 · see citing works
Recent Advances, Challenges, and Opportunities in Bioremediation of Hazardous Materials
Ramirez-Garcia, R., Gohil, N., & Singh, V. (2018) · Elsevier eBooks · doi:10.1016/b978-0-12-813912-7.00021-1 · Cited by 110 · cited 1× · see citing works
“Nowadays, oceans are heavily polluted with tons of trash, oil spills, fertilizers, pesticides, chemicals, plastics, heavy metals, organic and other persistent organic pollutants (POPs), which results from manmade ecocide (Seltenrich, 2015; Ramírez-García et al., 2018).”
Emollient treatment of atopic dermatitis: latest evidence and clinical considerations
Hon, K. E., Kung, J. S. C., Ng, W. G. G., & Leung, T. F. (2018) · Drugs in Context · doi:10.7573/dic.212530 · Cited by 109 · cited 1× · see citing works
“Besides being an excellent hydrating agent, topical applications of squalene-based products are used to treat skin disorders including acne, psoriasis, xerosisrelated skin lesions, seborrheic dermatitis, and atopic dermatitis (Wołosik et al., 2013; Hon et al., 2018).”
Background
Production of Squalene in Synechocystis sp. PCC 6803
Englund, E., Pattanaik, B., Ubhayasekera, S. J. K. A., Stensjö, K., Bergquist, J., & Lindberg, P. (2014) · PLoS ONE · doi:10.1371/journal.pone.0090270 · Cited by 103 · cited 6× · see citing works
“…Furubayashi et al., 2014a; Katabami et al., 2015; Pan et al., 2015) in E. coli; overexpression of DXS and IDI, and the introduction of FPS into Synechococcus elongatus (Choi et al., 2016); deletion of SHC in Synechocystis (Englund et al., 2014) and Rhodopseudomonas palustris (Xu et al., 2016).”
Influential
Squalene: A natural antioxidant?
Amarowicz, R. (2009) · European Journal of Lipid Science and Technology · doi:10.1002/ejlt.200900102 · Cited by 103 · cited 2× · see citing works
“…an impressive range of human applications to date, ranging from a protective anti-cancer (Kim and Karadeniz, 2012; Günes, 2013) and anti-oxidant (Amarowicz, 2009; Günes, 2013) compound to one that assists cosmetics, pharmaceutical drugs, and vaccines and drug delivery (Del Giudice et al., 2006;…”
Background
Optimization of nitrogen source for enhanced production of squalene from thraustochytrid Aurantiochytrium sp.
Chen, G., Fan, K.-W., Lu, F., Li, Q., Aki, T., Chen, F., & Jiang, Y. (2010) · New Biotechnology · doi:10.1016/j.nbt.2010.04.005 · Cited by 103 · cited 24× · see citing works
“A number of microorganisms such as Euglena (Anding et al., 1971), Candida famata (Tsujiwaki et al., 1995), Rhodopseudomonas palustris (Xu et al., 2016) and archaeaHalobacterium cutirubrum (1mg/g DCW) (Goldberg and Shechter, 1978) were also reported to store squalene.”
BackgroundInfluential
Enhanced isoprenoid production f rom xylose by engineered Saccharomyces cerevisiae
Kwak, S., Kim, S. R., Xu, H., Zhang, G., Lane, S., Kim, H., & Jin, Y. (2017) · Biotechnology and Bioengineering · doi:10.1002/bit.26369 · Cited by 102 · see citing works
Regeneration of NADPH Coupled with HMG-CoA Reductase Activity Increases Squalene Synthesis in Saccharomyces cerevisiae
Paramasivan, K., & Mutturi, S. (2017) · Journal of Agricultural and Food Chemistry · doi:10.1021/acs.jafc.7b02945 · Cited by 99 · cited 2× · see citing works
“Hmg1p is another important NADPH dependent membrane-bound isomer of HMGR that contributes for more than 83% of enzyme activity in the wild-type strain (Basson et al., 1986; Paramasivan and Mutturi, 2017).”
Background
Squalene epoxidase as a promising metabolic target in cancer treatment
Cirmena, G., Franceschelli, P., Isnaldi, E., Ferrando, L., Mariano, M. D., Ballestrero, A., & Zoppoli, G. (2018) · Cancer Letters · doi:10.1016/j.canlet.2018.03.034 · Cited by 98 · cited 1× · see citing works
“A wide range of studies have shown that the regular consumption of squalene may inhibit the proliferation of tumor cells, especially those of the breast, pancreas, colon, and melanoma, the activation of which depends on the prenylation of proteins (Newmark, 1997; Cirmena et al., 2018).”
Background
Improved squalene production through increasing lipid contents in Saccharomyces cerevisiae
Wei, L., Kwak, S., Liu, J., Lane, S., Hua, Q., Kweon, D., & Jin, Y. (2018) · Biotechnology and Bioengineering · doi:10.1002/bit.26595 · Cited by 97 · cited 1× · see citing works
“Lately, a number of microorganisms have been engineered by inserting a squalene biosynthetic pathway or by the modification of existing biosynthetic pathway for over-production of squalene (Ghimire et al., 2009; Katabami et al., 2015; Han et al., 2018; Wei et al., 2018).”
Background
Biosynthesis of Squalene from Farnesyl Diphosphate in Bacteria: Three Steps Catalyzed by Three Enzymes
Pan, J.-J., Solbiati, J., Ramamoorthy, G., Hillerich, B., Seidel, R. D., III, Cronan, J. E., Almo, S. C., & Poulter, C. D. (2015) · ACS Central Science · doi:10.1021/acscentsci.5b00115 · Cited by 96 · see citing works
Antibodies to Squalene in Gulf War Syndrome
Asa, P. B., Cao, Y., & Garry, R. F. (2000) · Experimental and Molecular Pathology · doi:10.1006/exmp.1999.2295 · Cited by 96 · cited 1× · see citing works
“Several controversies have revolved around the use of squalene as an adjuvant for the anthrax vaccine (Asa et al., 2000).”
Background
Simultaneous determination of tocols, γ-oryzanols, phytosterols, squalene, cholecalciferol and phylloquinone in rice bran and vegetable oil samples
Pokkanta, P., Sookwong, P., Tanang, M., Setchaiyan, S., Boontakham, P., & Mahatheeranont, S. (2018) · Food Chemistry · doi:10.1016/j.foodchem.2018.07.225 · Cited by 96 · cited 2× · see citing works
“, 2002), soybean (3–22 mg/100 g) (Gutfinger and Letan, 1974; Frega et al., 1992; Maguire et al., 2004; Naziri et al., 2011b; Pokkanta et al., 2019), sunflower seed (0–19mg/100 g) (Tuberoso et al.”
Optimization of culture conditions of the thraustochytrid Aurantiochytrium sp. strain 18W-13a for squalene production
Nakazawa, A., Matsuura, H., Kose, R., Kato, S., Honda, D., Inouye, I., Kaya, K., & Watanabe, M. M. (2011) · Bioresource Technology · doi:10.1016/j.biortech.2011.09.127 · Cited by 95 · cited 2× · see citing works
“The level of squalene can be enhanced and improved in wide range of microorganisms by; (1) using fermentation with additionally optimized conditions (Chen et al., 2010; Fan et al., 2010; Nakazawa et al., 2012), (2) genetic manipulation or introduction of squalene producing gene(s) in native squalene biosynthesis pathw…”
BackgroundMethod
Solid phase extraction in the analysis of squalene and tocopherols in olive oil
Grigoriadou, D., Androulaki, A., Psomiadou, E., & Tsimidou, M. Z. (2007) · Food Chemistry · doi:10.1016/j.foodchem.2006.12.065 · Cited by 93 · see citing works
Squalene in virgin olive oil: Screening of variability in olive cultivars
Beltrán, G., Bucheli, M. E., Aguilera, M. P., Belaj, A., & Jiménez, A. (2015) · European Journal of Lipid Science and Technology · doi:10.1002/ejlt.201500295 · Cited by 93 · see citing works
Photosynthetic conversion of CO2 to farnesyl diphosphate-derived phytochemicals (amorpha-4,11-diene and squalene) by engineered cyanobacteria
Choi, S. Y., Lee, H. J., Choi, J., Kim, J., Sim, S. J., Um, Y., Kim, Y., Lee, T. S., Keasling, J. D., & Woo, H. M. (2016) · Biotechnology for Biofuels · doi:10.1186/s13068-016-0617-8 · Cited by 93 · see citing works
Separation and purification of squalene from soybean oil deodorizer distillate
Gunawan, S., Kasim, N. S., & Ju, Y. (2007) · Separation and Purification Technology · doi:10.1016/j.seppur.2007.08.001 · Cited by 92 · see citing works
Recent Advances in CRISPR‐Cas9 Genome Editing Technology for Biological and Biomedical Investigations
Singh, V., Gohil, N., Ramirez-Garcia, R., Braddick, D., & Fofié, C. K. (2017) · Journal of Cellular Biochemistry · doi:10.1002/jcb.26165 · Cited by 92 · see citing works
Squalene Selectively Protects Mouse Bone Marrow Progenitors Against Cisplatin and Carboplatin-Induced Cytotoxicity In Vivo Without Protecting Tumor Growth
Das, B., Antoon, R., Tsuchida, R., Lotfi, S., Morozova, O., Farhat, W. A., Malkin, D. M., Koren, G., Yeger, H., & Baruchel, S. (2008) · Neoplasia · doi:10.1593/neo.08466 · Cited by 90 · cited 1× · see citing works
“In the subsequent study, Das et al. (2008) presented the experimental evidence of squalene’s role in protecting healthy bone marrow cells while having no obvious effect on the neuroblastoma cells.”
Oxidization of squalene, a human skin lipid: a new and reliable marker of environmental pollution studies
Pham, D. ‐., Boussouira, B., Moyal, D., & Nguyen, Q. L. (2015) · International Journal of Cosmetic Science · doi:10.1111/ics.12208 · Cited by 89 · cited 1× · see citing works
“It has the capacity to entrap thermodynamically active singlet oxygen atoms that are generated from autohydrolytic reactions and resultant oxidative products (Pham et al., 2015).”
Background
Oxygen Addition and Sterol Synthesis in Saccharomyces cerevisiae during Enological Fermentation
Fornairon-Bonnefond, C., Demaretz, V., Rosenfeld, E., & Salmon, J. (2002) · Journal of Bioscience and Bioengineering · doi:10.1016/s1389-1723(02)80011-1 · Cited by 89 · cited 1× · see citing works
“Therefore, it is not a suitable candidate for squalene production unless the fermentation conditions are optimized (Bhattacharjee et al., 2001; Fornairon-Bonnefond et al., 2002).”
Background
Chemical Characterization of Major and Minor Compounds of Nut Oils: Almond, Hazelnut, and Pecan Nut
Fernandes, G. D., Gómez-Coca, R. B., del Camino, M., Moreda, W., & Arellano, D. B. (2017) · Journal of Chemistry · doi:10.1155/2017/2609549 · Cited by 88 · see citing works
Functional lipid characteristics, oxidative stability, and antioxidant activity of macadamia nut (Macadamia integrifolia) cultivars
Wall, M. M. (2010) · Food Chemistry · doi:10.1016/j.foodchem.2010.01.057 · Cited by 86 · see citing works
Studies of unsaponifiables in several vegetable oils
Gutfinger, T., & Letan, A. (1974) · Lipids · doi:10.1007/bf02532171 · Cited by 85 · cited 2× · see citing works
“Apart from this, avocado (34–37 mg/100 g squalene) (Gutfinger and Letan, 1974) has also been reported to contain a meager amount of squalene.”
Background
Attenuation of cyclophosphamide induced toxicity by squalene in experimental rats
Senthilkumar, S., Yogeeta, S. K., Subashini, R., & Devaki, T. (2006) · Chemico-Biological Interactions · doi:10.1016/j.cbi.2006.02.004 · Cited by 84 · see citing works
Improvement of cefpodoxime proxetil oral absorption in rats by an oil-in-water submicron emulsion
Nicolaos, G. (2003) · International Journal of Pharmaceutics · doi:10.1016/s0378-5173(03)00365-x · Cited by 84 · cited 1× · see citing works
“Moreover, reports suggest that the ease with which a lipid carrier interacts with endogenous body fluid and tissues readily decreases the possibility of adverse effects (Nicolaos et al., 2003; Huang et al., 2009).”
Background
Advances in Biochemistry and Microbial Production of Squalene and Its Derivatives
Ghimire, G. P., Thuấn, N. H., Koirala, N., & Sohng, J. K. (2016) · Journal of Microbiology and Biotechnology · doi:10.4014/jmb.1510.10039 · Cited by 84 · cited 1× · see citing works
“The pathway then continues onward to synthesize sterols (Ghimire et al., 2016; Mao et al., 2017).”
Background
Enhanced production of squalene in the thraustochytrid Aurantiochytrium mangrovei by medium optimization and treatment with terbinafine
Fan, K. W., Aki, T., Chen, F., & Jiang, Y. (2010) · World Journal of Microbiology and Biotechnology · doi:10.1007/s11274-009-0301-2 · Cited by 83 · cited 27× · see citing works
“A number of microorganisms such as Euglena (Anding et al., 1971), Candida famata (Tsujiwaki et al., 1995), Rhodopseudomonas palustris (Xu et al., 2016) and archaeaHalobacterium cutirubrum (1mg/g DCW) (Goldberg and Shechter, 1978) were also reported to store squalene.”
Influential
Extraction and refining of oil from amaranth seed
Lyon, C. K., & Becker, R. R. (1987) · Journal of the American Oil Chemists Society · doi:10.1007/bf02542008 · Cited by 80 · cited 1× · see citing works
“Apart from sources of microbial origin, a number of reports have described the production of squalene from some plants, predominantly amaranth (Lyon and Becker, 1987; Czaplicki et al., 2011; Naziri et al., 2011b; Rosales-García et al., 2017b) and olive (Gutfinger and Letan, 1974; Frega et al.”
Background
TLC screening of thraustochytrid strains for squalene production
Nakazawa, A., Kokubun, Y., Matsuura, H., Yonezawa, N., Kose, R., Yoshida, M., Tanabe, Y., Kusuda, E., Duong, V. T., Ueda, M., et al. (2013) · Journal of Applied Phycology · doi:10.1007/s10811-013-0080-x · Cited by 80 · cited 1× · see citing works
“could accumulate a considerable amount of squalene (Jiang et al., 2004; Chen et al., 2010; Fan et al., 2010; Kaya et al., 2011; Hoang et al., 2014, 2018; Nakazawa et al., 2014).”
Background
In vitro cytoprotective activity of squalene on a bone marrow versus neuroblastoma model of cisplatin-induced toxicity
Das, B., Yeger, H., Baruchel, H., Freedman, M. H., Koren, G., & Baruchel, S. (2003) · European Journal of Cancer · doi:10.1016/j.ejca.2003.07.002 · Cited by 79 · see citing works
Squalene epoxidase as a target for manipulation of squalene levels in the yeastSaccharomyces cerevisiae
Garaiová, M., Zambojová, V., Šimová, Z., Griač, P., & Hapala, I. (2013) · FEMS Yeast Research · doi:10.1111/1567-1364.12107 · Cited by 79 · cited 2× · see citing works
“Even point mutations in the ERG1 gene enable to achieve a higher amount of squalene yield (up to 1 mg/109 cells) without any growth retardation (Garaiová et al., 2014).”
Background
Vegetable Oil Deodorizer Distillate: A Rich Source of the Natural Bioactive Components
Sherazi, S. T. H., Mahesar, S. A., & Uddin, S. (2016) · Journal of Oleo Science · doi:10.5650/jos.ess16125 · Cited by 79 · cited 1× · see citing works
“At the end of this step, many bioactive compounds such as squalene, tocopherols, phytosterols, and fatty acids accumulate as byproducts, commonly called as “deodorizer distillate” (Popa et al., 2015; Sherazi and Mahesar, 2016).”
Background
Supercritical Carbon Dioxide Extraction of Oil and Squalene from Amaranthus Grain
He, H.-P., Corke, H., & Cai, J. (2003) · Journal of Agricultural and Food Chemistry · doi:10.1021/jf030488y · Cited by 78 · see citing works
Vaccines with the MF59 Adjuvant Do Not Stimulate Antibody Responses against Squalene
Giudice, G. D., Fragapane, E., Bugarini, R., Hora, M., Henriksson, T., Palla, E., O’Hagan, D. T., Donnelly, J., Rappuoli, R., & Podda, A. (2006) · Clinical and Vaccine Immunology · doi:10.1128/cvi.00191-06 · Cited by 78 · see citing works
Synthetic Metabolism: Engineering Biology at the Protein and Pathway Scales
Martin, C. H., Nielsen, D. R., Solomon, K., & Prather, K. L. J. (2009) · Chemistry & Biology · doi:10.1016/j.chembiol.2009.01.010 · Cited by 76 · cited 1× · see citing works
“Rapid and remarkable advances in genetic engineering, metabolic engineering and synthetic biology approaches over the last few decades have facilitated the insertion of heterologous genes and editing of the genome of an organism, enabling successful attempts to produce innumerable molecules of industrial importance (M…”
Background
Recent advancements in synthetic biology: Current status and challenges
Singh, V. (2013) · Gene · doi:10.1016/j.gene.2013.11.025 · Cited by 76 · cited 2× · see citing works
“…over the last few decades have facilitated the insertion of heterologous genes and editing of the genome of an organism, enabling successful attempts to produce innumerable molecules of industrial importance (Martin et al., 2009; Stephanopoulos, 2012; Singh, 2014; Jullesson et al., 2015).”
Background
Bioactive compounds in unsaponifiable fraction of oils from unconventional sources
Czaplicki, S., Ogrodowska, D., Derewiaka, D., Tańska, M., & Zadernowski, R. (2011) · European Journal of Lipid Science and Technology · doi:10.1002/ejlt.201000410 · Cited by 75 · cited 3× · see citing works
“Apart from sources of microbial origin, a number of reports have described the production of squalene from some plants, predominantly amaranth (Lyon and Becker, 1987; Czaplicki et al., 2011; Naziri et al., 2011b; Rosales-García et al., 2017b) and olive (Gutfinger and Letan, 1974; Frega et al.”
Background
Dietary Squalene Increases High Density Lipoprotein-Cholesterol and Paraoxonase 1 and Decreases Oxidative Stress in Mice
Gabás‐Rivera, C., Barranquero, C., Martínez‐Beamonte, R., Navarro, M. Á., Surra, J. C., & Osada, J. (2014) · PLoS ONE · doi:10.1371/journal.pone.0104224 · Cited by 74 · cited 2× · see citing works
“According to the clinical research data, about 60–85% of the total orally administrated squalene is absorbed and distributed efficiently to different tissues (Gabás-Rivera et al., 2014), namely the skin where it plays a salient role as an antioxidant to protect against the free radicals and environmental oxidative str…”
Production of squalene by squalene synthases and their truncated mutants in Escherichia coli
Katabami, A., Li, L., Iwasaki, M., Furubayashi, M., Saito, K., & Umeno, D. (2014) · Journal of Bioscience and Bioengineering · doi:10.1016/j.jbiosc.2014.07.013 · Cited by 73 · cited 11× · see citing works
“MVA, mevalonate; MEP, 2-C-methyl-d-erythritol 4-phosphate; AACT, acetoacetyl-CoA thiolase; HMGS, 3-hydroxy-3-methylglutaryl-CoA synthase; HMGR, HMG-CoA reductase; DMAPP, dimethylallyl diphosphate; IDI, isopentenyl diphosphate isomerase; IPP, isopentenyl pyrophosphate; FPS, farnesyl pyrophosphate synthase; GPP, geranyl…”
BackgroundMethodInfluential
Inhibition by squalene of the tumor‐promoting activity of 12‐O‐Tetradecanoylphorbol‐13‐acetate in mouse‐skin carcinogenesis
Murakoshi, M., Nishino, H., Tokuda, H., Iwashima, A., Okuzumi, J., Kitano, H., & Iwasaki, R. (1992) · International Journal of Cancer · doi:10.1002/ijc.2910520620 · Cited by 72 · cited 6× · see citing works
“5 g/day of squalene is proven to reduce the facial wrinkling, enhance the type I procollagen expression, and decrease the facial erythema along with substantially reducing the risk of UV-induced damage to the DNA (Murakoshi et al., 1992; Cho et al., 2009).”
Influential
Building terpene production platforms in yeast
Zhuang, X., & Chappell, J. (2015) · Biotechnology and Bioengineering · doi:10.1002/bit.25588 · Cited by 71 · cited 5× · see citing works
“Additionally, this has been further improved to 270 mg/L by expressing the truncated HMGR (tHMGR) gene (Zhuang and Chappell, 2015).”
Influential
Medical use of squalene as a natural antioxidant
GNES, F. (2013) · Clinical and Experimental Health Sciences · doi:10.5455/musbed.20131213100404 · Cited by 71 · cited 8× · see citing works
“Squalene has been known to play diverse biological roles as an anti-oxidant (Amarowicz, 2009; Günes, 2013), anti-cancer agent (Kim and Karadeniz, 2012; Günes, 2013), age defyer (Huang et al., 2009; Popa et al., 2015), chemopreventive agent (Aioi et al., 1995; Budiyanto et al., 2000; Smith, 2000),…”
BackgroundInfluential
Commercial Cold Pressed Flaxseed Oils Quality and Oxidative Stability at the Beginning and the End of Their Shelf Life
Tańska, M., Roszkowska, B., Skrajda, M., & Dąbrowski, G. (2016) · Journal of Oleo Science · doi:10.5650/jos.ess15243 · Cited by 71 · cited 1× · see citing works
“2mg/100 g) (Tanska et al., 2016), rapeseed (17 mg/100 g) (Tuberoso et al.”
Accumulation of Squalene in a Microalga Chlamydomonas reinhardtii by Genetic Modification of Squalene Synthase and Squalene Epoxidase Genes
Kajikawa, M., Kinohira, S., Ando, A., Shimoyama, M., Kato, M., & Fukuzawa, H. (2015) · PLoS ONE · doi:10.1371/journal.pone.0120446 · Cited by 70 · cited 1× · see citing works
“, 2018) in yeast; downregulation of SQE in algae (Kajikawa et al., 2015).”
Background
Studies on fermentative production of squalene
Bhattacharjee, P., Shukla, V. B., Singhal, R., & Kulkarni, P. R. (2001) · World Journal of Microbiology and Biotechnology · doi:10.1023/a:1013573912952 · Cited by 69 · cited 26× · see citing works
“A number of microorganisms such as Euglena (Anding et al., 1971), Candida famata (Tsujiwaki et al., 1995), Rhodopseudomonas palustris (Xu et al., 2016) and archaeaHalobacterium cutirubrum (1mg/g DCW) (Goldberg and Shechter, 1978) were also reported to store squalene.”
BackgroundInfluential
Simultaneous quantification of free fatty acids, free sterols, squalene, and acylglycerol molecular species in palm oil by high‐temperature gas chromatography‐flame ionization detection
Lau, H. L. N., Puah, C. W., Choo, Y. M., Ma, A. N., & Chuah, C. H. (2005) · Lipids · doi:10.1007/s11745-005-1413-1 · Cited by 69 · cited 1× · see citing works
“Palm oil has just 20–50 mg/100 g of squalene (Goh et al., 1985; Lau et al., 2005) but because of its large-scale production, it can be considered as an acceptable source of the squalene overall.”
Background
High-level recombinant production of squalene using selectedSaccharomyces cerevisiaestrains
Han, J. Y., Seo, S. H., Song, J. M., Lee, H., & Choi, E. (2018) · Journal of Industrial Microbiology & Biotechnology · doi:10.1007/s10295-018-2018-4 · Cited by 69 · cited 1× · see citing works
“Lately, a number of microorganisms have been engineered by inserting a squalene biosynthetic pathway or by the modification of existing biosynthetic pathway for over-production of squalene (Ghimire et al., 2009; Katabami et al., 2015; Han et al., 2018; Wei et al., 2018).”
Background
Screening and Characterization of Squalene-Producing Thraustochytrids from Hong Kong Mangroves
Li, Q., Chen, G., Fan, K.-W., Lu, F., Aki, T., & Jiang, Y. (2009) · Journal of Agricultural and Food Chemistry · doi:10.1021/jf9003972 · Cited by 68 · cited 23× · see citing works
“A number of microorganisms such as Euglena (Anding et al., 1971), Candida famata (Tsujiwaki et al., 1995), Rhodopseudomonas palustris (Xu et al., 2016) and archaeaHalobacterium cutirubrum (1mg/g DCW) (Goldberg and Shechter, 1978) were also reported to store squalene.”
BackgroundInfluential
Determination of squalene in olive oil using fractional crystallization for sample preparation
Nenadis, N., & Tsimidou, M. Z. (2002) · Journal of the American Oil Chemists Society · doi:10.1007/s11746-002-0470-1 · Cited by 66 · see citing works
Observations on squalene accumulation in Saccharomyces cerevisiae due to the manipulation of HMG2 and ERG6
Mantzouridou, F. T., & Tsimidou, M. Z. (2010) · FEMS Yeast Research · doi:10.1111/j.1567-1364.2010.00645.x · Cited by 66 · cited 1× · see citing works
“A wide range of microorganisms including yeast such as Saccharomyces cerevisiae (Mantzouridou and Tsimidou, 2010) and Torulaspora delbrueckii (Bhattacharjee et al.”
Background
Rubritalea spongiae sp. nov. and Rubritalea tangerina sp. nov., two carotenoid- and squalene-producing marine bacteria of the family Verrucomicrobiaceae within the phylum ‘Verrucomicrobia’, isolated from marine animals
Yoon, J., Matsuo, Y., Matsuda, S., Adachi, K., Kasai, H., & Yokota, A. (2007) · INTERNATIONAL JOURNAL OF SYSTEMATIC AND EVOLUTIONARY MICROBIOLOGY · doi:10.1099/ijs.0.65243-0 · Cited by 66 · cited 1× · see citing works
“Marine bacteria such as Rubritalea squalenifaciens sp.nov. (15mg/g DCW) (Kasai et al., 2007), R. spongiae sp.nov. (Yoon et al., 2007), R. tangerina sp.nov. (Yoon et al., 2007), and R. sabuli sp. nov. (Yoon et al., 2008) belong to the family Verrucomicrobiaceae are also known to accumulate squalene.”
Characterisation of seed oils from different grape cultivars grown in China
Wen, X., Zhu, M., Rui, H., Zhao, J., Chen, Z., Li, J., & Ni, Y. (2016) · Journal of Food Science and Technology · doi:10.1007/s13197-016-2286-9 · Cited by 66 · see citing works
Improvement of Squalene Production from CO2 in Synechococcus elongatus PCC 7942 by Metabolic Engineering and Scalable Production in a Photobioreactor
Choi, S. Y., Wang, J.-Y., Kwak, H. S., Lee, S., Um, Y., Kim, Y., Sim, S. J., Choi, J., & Woo, H. M. (2017) · ACS Synthetic Biology · doi:10.1021/acssynbio.7b00083 · Cited by 66 · cited 2× · see citing works
“2mg/g DCW) by using a 6 L CO2-fed bag-type photo-bioreactor with optimized conditions of 5% CO2 under 100 μmol photons/m2/s (Choi et al., 2017).”
Method
Squalene: a multi-task link in the crossroads of cancer and aging
Ronco, Á. L., & Stéfani, E. D. (2013) · Functional Foods in Health and Disease · doi:10.31989/ffhd.v3i12.30 · Cited by 65 · see citing works
Improved Squalene Production via Modulation of the Methylerythritol 4-Phosphate Pathway and Heterologous Expression of Genes from Streptomyces peucetius ATCC 27952 in Escherichia coli
Ghimire, G. P., Lee, H. C., & Sohng, J. K. (2009) · Applied and Environmental Microbiology · doi:10.1128/aem.01402-09 · Cited by 65 · cited 11× · see citing works
“MVA, mevalonate; MEP, 2-C-methyl-d-erythritol 4-phosphate; AACT, acetoacetyl-CoA thiolase; HMGS, 3-hydroxy-3-methylglutaryl-CoA synthase; HMGR, HMG-CoA reductase; DMAPP, dimethylallyl diphosphate; IDI, isopentenyl diphosphate isomerase; IPP, isopentenyl pyrophosphate; FPS, farnesyl pyrophosphate synthase; GPP, geranyl…”
Influential
Vaccination, squalene and anti-squalene antibodies: Facts or fiction?
Lippi, G., Targher, G., & Franchini, M. (2009) · European Journal of Internal Medicine · doi:10.1016/j.ejim.2009.12.001 · Cited by 63 · cited 4× · see citing works
“…was debated following its relation to treatments of Gulf War Syndrome (GWS) that included a pool of symptoms such as fatigue, headache, diarrhea, rashes and allergies, memory loss and neurological abnormalities, arthralgias, myalgias, and lymphadenopathy (Gronseth, 2005; Lippi et al., 2010).”
Influential
Direct gas chromatographic analysis of the unsaponifiable fraction of different oils with a polar capillary column
Frega, N. G., Bocci, F., & Lercker, G. (1992) · Journal of the American Oil Chemists Society · doi:10.1007/bf02540946 · Cited by 61 · cited 1× · see citing works
“, 2002), soybean (3–22 mg/100 g) (Gutfinger and Letan, 1974; Frega et al., 1992; Maguire et al., 2004; Naziri et al., 2011b; Pokkanta et al., 2019), sunflower seed (0–19mg/100 g) (Tuberoso et al.”
Extraction of squalene as value-added product from the residual biomass of Schizochytrium mangrovei PQ6 during biodiesel producing process
Hoang, M. H., Ha, N. C., Thom, L. T., Tam, L. T., Anh, H. T. L., Thu, N. T. H., & Hồng, Đ. D. (2014) · Journal of Bioscience and Bioengineering · doi:10.1016/j.jbiosc.2014.05.015 · Cited by 59 · cited 1× · see citing works
“Likewise, Schizochytriummangroveiwas also studied for squalene production using 30 and 150 L bioreactors (Hoang et al., 2014).”
Method
The importance and perspective of plant-based squalene in cosmetology.
Wołosik, K., Knaś, M., Zalewska, A., Niczyporuk, M., & Przystupa, A. W. (2013) · PubMed · Cited by 58 · see citing works
Squalene Stimulates a Key Innate Immune Cell to Foster Wound Healing and Tissue Repair
Sánchez‐Quesada, C., López-Biedma, A., Toledo, E., & Gaforio, J. J. (2018) · Evidence-based Complementary and Alternative Medicine · doi:10.1155/2018/9473094 · Cited by 58 · cited 1× · see citing works
“Although the exact biological mechanism is not yet clear, it is predicted that MF59 elicits an immune response by recruiting the phagocytic cells to the site of delivery, promoting maturation of monocytes into dendritic cells, and facilitating their transport to nearby lymph nodes to trigger the adaptive immune respon…”
Background
Squalene versus Ergosterol Formation Using Saccharomyces cerevisiae: Combined Effect of Oxygen Supply, Inoculum Size, and Fermentation Time on Yield and Selectivity of the Bioprocess
Mantzouridou, F. T., Naziri, E., & Tsimidou, M. Z. (2009) · Journal of Agricultural and Food Chemistry · doi:10.1021/jf900673n · Cited by 57 · cited 1× · see citing works
“cerevisiae BY4741 and EGY48, respectively (Mantzouridou et al., 2009).”
Enhanced Squalene Production by Wild-Type Saccharomyces cerevisiae Strains Using Safe Chemical Means
Naziri, E., Mantzouridou, F. T., & Tsimidou, M. Z. (2011) · Journal of Agricultural and Food Chemistry · doi:10.1021/jf201328a · Cited by 57 · see citing works
Squalene resources and uses point to the potential of biotechnology
Naziri, E., Mantzouridou, F. T., & Tsimidou, M. Z. (2011) · Lipid Technology · doi:10.1002/lite.201100157 · Cited by 55 · cited 7× · see citing works
“45 g/kg squalene (Giacometti and Milin, 2001), whereas the deodorizing distillates of olive oil contain 100–300 g/kg squalene (Naziri et al., 2011b).”
BackgroundInfluential
Recent advances and challenges of the use of cyanobacteria towards the production of biofuels
Singh, V., Chaudhary, D. K., Mani, I., & Dhar, P. K. (2016) · Renewable and Sustainable Energy Reviews · doi:10.1016/j.rser.2016.01.099 · Cited by 55 · see citing works
In vivo studies of sterol and squalene secretion by human skin
Nikkari, T., Schreibman, P. H., & AHRENS, E. H. (1974) · Journal of Lipid Research · doi:10.1016/s0022-2275(20)36757-2 · Cited by 52 · cited 1× · see citing works
“The amount of secreted squalene ranges from 125 to 475 mg/day, depending upon the individuals and their diet (Nikkari et al., 1974).”
Background
Surface Properties of Squalene/Meibum Films and NMR Confirmation of Squalene in Tears
Ivanova, S., Tonchev, V., Yokoi, N., Yappert, M. C., Borchman, D., & Georgiev, G. A. (2015) · International Journal of Molecular Sciences · doi:10.3390/ijms160921813 · Cited by 51 · cited 1× · see citing works
“, 2015), and detoxifier (Kim and Karadeniz, 2012; Ivanova et al., 2015) among others.”
The isolation and characterization of Pseudozyma sp. JCC 207, a novel producer of squalene
Chang, M.-H., Kim, H., Jahng, K., & Hong, S. (2008) · Applied Microbiology and Biotechnology · doi:10.1007/s00253-008-1395-4 · Cited by 51 · see citing works
Antibodies to Squalene in Recipients of Anthrax Vaccine
Asa, P. B., Wilson, R. B., & Garry, R. F. (2002) · Experimental and Molecular Pathology · doi:10.1006/exmp.2002.2429 · Cited by 51 · cited 1× · see citing works
“The unexpected finding of the anti-squalene antibodies in patients with GWS spiked speculation about its safety and its adverse effects (Asa et al., 2002).”
Background
Gulf War Syndrome: A Toxic Exposure? A Systematic Review
Gronseth, G. (2005) · Neurologic Clinics · doi:10.1016/j.ncl.2004.12.011 · Cited by 51 · cited 2× · see citing works
“…was debated following its relation to treatments of Gulf War Syndrome (GWS) that included a pool of symptoms such as fatigue, headache, diarrhea, rashes and allergies, memory loss and neurological abnormalities, arthralgias, myalgias, and lymphadenopathy (Gronseth, 2005; Lippi et al., 2010).”
BackgroundMethod
Enhanced Elimination of Theophylline, Phenobarbital and Strychnine from the Bodies of Rats and Mice by Squalane Treatment.
Kamimura, H., Koga, N., Oguri, K., & Yoshimura, H. (1992) · Journal of Pharmacobio-Dynamics · doi:10.1248/bpb1978.15.215 · Cited by 50 · cited 1× · see citing works
“Animal studies reveal that squalene also enhances the removal of xenobiotics such as theophylline, strychnine, and phenobarbital (Kamimura et al., 1992; Kelly, 1999).”
Background
Potentiation by squalene of the cytotoxicity of anticancer agents against cultured mammalian cells and murine tumor.
Nakagawa, M., Yamaguchi, T., Fukawa, H., Ogata, J., Komiyama, S., Akiyama, S., & Kuwano, M. (1985) · PubMed · Cited by 47 · see citing works
The effects of serum on the stability and the transfection activity of the cationic lipid emulsion with various oils
Kim, Y. J. (2003) · International Journal of Pharmaceutics · doi:10.1016/s0378-5173(02)00676-2 · Cited by 47 · cited 1× · see citing works
“Squalene emulsions possess a high degree of transfection activity and are known to delineate very low systemic toxicity following intravenous administration in vivo (Kim et al., 2003).”
Background
Sterols and squalene in apricot (Prunus armeniaca L.) kernel oils: the variety as a key factor
Rudzińska, M., Górnaś, P., Raczyk, M., & Soliven, A. (2016) · Natural Product Research · doi:10.1080/14786419.2015.1135146 · Cited by 47 · cited 1× · see citing works
“Furthermore, presence of squalene in some unconventional oil sources such as apricot kernels (12–43 mg/100 g) (Rudzinska et al., 2017) and borage (22 mg/100 g) (Czaplicki et al.”
Background
Sterol Biosynthesis in Euglena gracilis Z.
Anding, C., Brandt, R. D., & Ourisson, G. (1971) · European Journal of Biochemistry · doi:10.1111/j.1432-1033.1971.tb19679.x · Cited by 46 · cited 4× · see citing works
“…2010) and Torulaspora delbrueckii (Bhattacharjee et al., 2001), fungus Aurantiochytrium sp. (Jiang et al., 2004; Nakazawa et al., 2014; Pora et al., 2014), Euglena (Anding et al., 1971), archaea Halobacterium cutirubrum, and several other species have the natural ability to produce squalene.”
BackgroundInfluential
Rubritalea squalenifaciens sp. nov., a squalene-producing marine bacterium belonging to subdivision 1 of the phylum ‘Verrucomicrobia’
Kasai, H., Katsuta, A., Sekiguchi, H., Matsuda, S., Adachi, K., Shindo, K., Yoon, J., Yokota, A., & Shizuri, Y. (2007) · INTERNATIONAL JOURNAL OF SYSTEMATIC AND EVOLUTIONARY MICROBIOLOGY · doi:10.1099/ijs.0.65010-0 · Cited by 46 · see citing works
Alga-Produced Malaria Transmission-Blocking Vaccine Candidate Pfs25 Formulated with a Human Use-Compatible Potent Adjuvant Induces High-Affinity Antibodies That Block Plasmodium falciparum Infection of Mosquitoes
Patra, K. P., Li, F., Carter, D., Gregory, J. A., Baga, S., Reed, S. G., Mayfield, S. P., & Vinetz, J. M. (2015) · Infection and Immunity · doi:10.1128/iai.02980-14 · Cited by 45 · cited 2× · see citing works
“The emulsion has worked well for several vaccines including malaria (Patra et al., 2015), herpes virus (Hensel et al.”
The Manipulation of Micro-organisms for the Production of Secondary Metabolites
Bunch, A. W., & Harris, R. E. (1986) · Biotechnology and Genetic Engineering Reviews · doi:10.1080/02648725.1986.10647825 · Cited by 43 · cited 1× · see citing works
“, 2012), (2) genetic manipulation or introduction of squalene producing gene(s) in native squalene biosynthesis pathways (Bunch and Harris, 1986; Singh et al., 2017, 2018; Valachovič and Hapala, 2017), and (3) addition of an inhibitor (e.”
Background
Metabolic engineering for the microbial production of marine bioactive compounds
Mao, X., Liu, Z., Sun, J., & Lee, S. Y. (2017) · Biotechnology Advances · doi:10.1016/j.biotechadv.2017.03.001 · Cited by 43 · cited 1× · see citing works
“The pathway then continues onward to synthesize sterols (Ghimire et al., 2016; Mao et al., 2017).”
Background
Detergent-induced epidermal barrier dysfunction and its prevention
Okuda, M., Yoshiike, T., & Ogawa, H. (2002) · Journal of Dermatological Science · doi:10.1016/s0923-1811(02)00106-8 · Cited by 42 · cited 1× · see citing works
“Squalene has been found to reverse the elevated transepidermal water loss (TEWL) along with riboflavin penetration in sodium lauryl sulfate (SLS)-treated rats and human skin (Okuda et al., 2002).”
Background
Lipid Composition of Brewer's Yeast
Blagović, B., Rupčić, J., Mesarić, M., Georgiú, K., & Marić, V. (2001) · Food Technology and Biotechnology · Cited by 42 · see citing works
Catalytic Hydrogenation of Squalene to Squalane
Ciriminna, R., Pandarus, V., Béland, F., & Pagliaro, M. (2014) · Organic Process Research & Development · doi:10.1021/op5002337 · Cited by 41 · cited 4× · see citing works
“, 2016), with most of it fulfilling the global demand of squalene for cosmetic industries (Ciriminna et al., 2014).”
BackgroundInfluential
Squalene Extraction: Biological Sources and Extraction Methods
Rosales-García, T., Jiménez‐Martínez, C., & Dávila-Ortíz, G. (2017) · International Journal of Environment Agriculture and Biotechnology · doi:10.22161/ijeab/2.4.26 · Cited by 41 · cited 2× · see citing works
“Squalene From Shark Liver Oil Over the years, deep-sea shark liver oil has been themajor natural source of squalene (Ronco and De Stéfani, 2013; Popa et al., 2015; Rosales-Garcia et al., 2017a).”
Background
Interaction of a new anticancer prodrug, gemcitabine–squalene, with a model membrane
Pili, B., Bourgaux, C., Amenitsch, H. W., Keller, G., Lepêtre‐Mouelhi, S., Desmaële, D., Couvreur, P., & Ollivon, M. (2010) · Biochimica et Biophysica Acta (BBA) - Biomembranes · doi:10.1016/j.bbamem.2010.04.011 · Cited by 40 · cited 1× · see citing works
“An example of this is the enhanced membrane permeability and interaction of the gemcitabin-squalene complex as compared to free gemcitabin (Castelli et al., 2007; Pili et al., 2010; Peramo et al., 2018).”
Background
Detection of antibodies to squalene
Matyas, G. R., Rao, M., Pittman, P. R., Burge, R., Robbins, I. E., Wassef, N. M., Thivierge, B., & Alving, C. R. (2003) · Journal of Immunological Methods · doi:10.1016/j.jim.2003.11.002 · Cited by 40 · cited 3× · see citing works
“The unexpected finding of the anti-squalene antibodies in patients with GWS spiked speculation about its safety and its adverse effects (Asa et al., 2002).”
Background
Rubritalea sabuli sp. nov., a carotenoid- and squalene-producing member of the family Verrucomicrobiaceae, isolated from marine sediment
Yoon, J., Matsuo, Y., Matsuda, S., Adachi, K., Kasai, H., & Yokota, A. (2008) · INTERNATIONAL JOURNAL OF SYSTEMATIC AND EVOLUTIONARY MICROBIOLOGY · doi:10.1099/ijs.0.65540-0 · Cited by 39 · see citing works
Occurrence of squalene and cholesterol in various species of Czech freshwater fish
Kopicová, Z., & Vavreinová, S. (2007) · Czech Journal of Food Sciences · doi:10.17221/733-cjfs · Cited by 39 · cited 1× · see citing works
“, 2000; Smith, 2000), antibacterial agent (Kopicová and Vavreinová, 2007; Popa et al., 2015), adjuvant for vaccines and drug carrier (Del Giudice et al.”
Background
Enhancement of gemcitabine affinity for biomembranes by conjugation with squalene: Differential scanning calorimetry and Langmuir–Blodgett studies using biomembrane models
Castelli, F., Sarpietro, M. G., Micieli, D., Stella, B., Rocco, F., & Cattel, L. (2007) · Journal of Colloid and Interface Science · doi:10.1016/j.jcis.2007.07.064 · Cited by 38 · cited 1× · see citing works
“An example of this is the enhanced membrane permeability and interaction of the gemcitabin-squalene complex as compared to free gemcitabin (Castelli et al., 2007; Pili et al., 2010; Peramo et al., 2018).”
Background
Construction of carotenoid biosynthetic pathways using squalene synthase
Furubayashi, M., Li, L., Katabami, A., Saito, K., & Umeno, D. (2013) · FEBS Letters · doi:10.1016/j.febslet.2013.12.003 · Cited by 38 · cited 4× · see citing works
“Insertion of a single squalene synthase gene (encoding SQS) can also catalyze the conversion of two molecules of FPP (the end-product of the MEP pathway) into squalene (Figure 3C) (Furubayashi et al., 2014a; Katabami et al., 2015).”
BackgroundInfluential
Separation of squalene and oil from Amaranthus seeds by supercritical carbon dioxide
Wejnerowska, G., Heinrich, P., & Gaca, J. (2013) · Separation and Purification Technology · doi:10.1016/j.seppur.2013.02.032 · Cited by 38 · cited 1× · see citing works
“, 2018), despite the fact that amaranth has the highest squalene content (600 g/kg) of all the reported plant sources (Wejnerowska et al., 2013).”
Background
Effect of squalene on superoxide anion generation induced by a skin irritant, lauroylsarcosine
Aioi, A., Shimizu, T., & Kuriyama, K. (1995) · International Journal of Pharmaceutics · doi:10.1016/0378-5173(94)00190-g · Cited by 37 · see citing works
Lanolin-derived lipid mixtures mimic closely the lipid composition and organization of vernix caseosa lipids
Rißmann, R., Oudshoorn, M. H. M., Kocks, E., Hennink, W. E., Ponec, M., & Bouwstra, J. A. (2008) · Biochimica et Biophysica Acta (BBA) - Biomembranes · doi:10.1016/j.bbamem.2008.06.017 · Cited by 36 · see citing works
Shark Conservation: An Educational Approach Based on Children’s Knowledge and Perceptions toward Sharks
Tsoi, K. H., Chan, S. Y., Lee, Y. C., Ip, B. H. Y., & Cheang, C. C. (2016) · PLoS ONE · doi:10.1371/journal.pone.0163406 · Cited by 36 · cited 2× · see citing works
“While living up to its Japanese name as a biologically precious gift, the biggest immediate hurdle in expanding the growth of squalene supplies and markets are its primary sources, and specifically their link with the decimation of shark populations (Ciriminna et al., 2014; Tsoi et al., 2016).”
Background
High-dose squalene ingestion increases type I procollagen and decreases ultraviolet-induced DNA damage in human skin<i>in vivo</i>but is associated with transient adverse effects
Cho, S., Choi, C.-W., Lee, D. H., Won, C.-H., Kim, S. M., Lee, S., Lee, M.-J., & Chung, J. H. (2009) · Clinical and Experimental Dermatology · doi:10.1111/j.1365-2230.2008.03133.x · Cited by 35 · cited 5× · see citing works
“5 g/day of squalene is proven to reduce the facial wrinkling, enhance the type I procollagen expression, and decrease the facial erythema along with substantially reducing the risk of UV-induced damage to the DNA (Murakoshi et al., 1992; Cho et al., 2009).”
BackgroundInfluential
Characteristics of Biologically-Active Substances of Amaranth Oil Obtained by Various Techniques.
Czaplicki, S., Ogrodowska, D., Zadernowski, R., & Derewiaka, D. (2012) · Polish Journal of Food and Nutrition Sciences · doi:10.2478/v10222-012-0054-8 · Cited by 35 · cited 1× · see citing works
“Squalene From Plants Besides shark liver oil, most plant oils contain a minute amount of squalene (Czaplicki et al., 2012).”
Background
Chemical Characterization of Canola and Sunflower Oil Deodorizer Distillates
Naz, S., Sherazi, S. T. H., Talpur, F. N., Kara, H., Uddin, S., & Khaskheli, A. R. (2014) · Polish Journal of Food and Nutrition Sciences · doi:10.2478/pjfns-2013-0008 · Cited by 34 · cited 1× · see citing works
“Similarly, soybean, sunflower, canola, and palm fatty acid distillates encompass about 18–55, 43–45, 30–35, and 2–13 g/kg of squalene, respectively (Dumont and Narine, 2007; Naziri et al., 2011b; Naz et al., 2014).”
Background
Occurrence of an unsaturated hydrocarbon in olive oil
Thorbjarnarson, T., & Drummond, J. C. (1935) · The Analyst · doi:10.1039/an9356000023 · Cited by 33 · cited 1× · see citing works
“Phytosqualene was first found and extracted from olive oil (Thorbjarnarson and Drummond, 1935), and since then, the quest for alternatives is still in progress.”
Background
The delivery and antinociceptive effects of morphine and its ester prodrugs from lipid emulsions
WANG, J., SUNG, K., Yeh, C.-L., & FANG, J. (2007) · International Journal of Pharmaceutics · doi:10.1016/j.ijpharm.2007.11.013 · Cited by 33 · cited 1× · see citing works
“The antinociceptive activity analyzed through the cold ethanol tail-flick test revealed that as compared to the aqueous formulations, the lipid-based emulsions exhibit an extended analgesic response (Wang et al., 2008).”
Background
Metabolic engineering ofRhodopseudomonas palustris for squalene production
Xu, W., Changbin, C., Shao, L., Yao, J., & Wang, Y. (2016) · Journal of Industrial Microbiology & Biotechnology · doi:10.1007/s10295-016-1745-7 · Cited by 33 · see citing works
Recovery of Squalene from Wine Lees Using Ultrasound Assisted Extraction—A Feasibility Study
Naziri, E., Mantzouridou, F. T., & Tsimidou, M. Z. (2012) · Journal of Agricultural and Food Chemistry · doi:10.1021/jf301059y · Cited by 33 · cited 1× · see citing works
“08 g/kg of squalene can be obtained using dry lees (Naziri et al., 2012).”
Background
Characterization of oils of hazelnuts from Asturias, Spain
Bada, J. C., León‐Camacho, M., Prieto, M., & Alonso, L. (2004) · European Journal of Lipid Science and Technology · doi:10.1002/ejlt.200300922 · Cited by 32 · cited 3× · see citing works
“…2019 Palm 20–50 Goh et al., 1985 43.3 Lau et al., 2005 Coriander seed 45.1 Pokkanta et al., 2019 Apricot kernel 12.6–43.9 Rudzinska et al., 2017 Hazelnut 9.3–39.2 Bada et al., 2004 27.9 Frega et al., 1992 25.7 Derewiaka et al., 2014 Macadamia nut 38.3 Derewiaka et al., 2014 18.5 Maguire et al.,…”
Influential
Overproduction of squalene synergistically downregulates ethanol production in Saccharomyces cerevisiae
Rasool, A., Ahmed, M. S., & Li, C. (2016) · Chemical Engineering Science · doi:10.1016/j.ces.2016.06.014 · Cited by 32 · cited 2× · see citing works
“It was noted during the investigation that overexpression of the squalene biosynthetic pathway downregulates both ethanol production as well as post-squalene biosynthetic pathways (Rasool et al., 2016a).”
Background
Prophylactic Herpes Simplex Virus 2 (HSV-2) Vaccines Adjuvanted with Stable Emulsion and Toll-Like Receptor 9 Agonist Induce a Robust HSV-2-Specific Cell-Mediated Immune Response, Protect against Symptomatic Disease, and Reduce the Latent Viral Reservoir
Hensel, M. T., Marshall, J. D., Dorwart, M. R., Heeke, D., Rao, E., Tummala, P., Li, Y., Cohen, G. H., Eisenberg, R. J., & Sloan, D. D. (2017) · Journal of Virology · doi:10.1128/jvi.02257-16 · Cited by 32 · cited 1× · see citing works
“, 2015), herpes virus (Hensel et al., 2017), hepatitis B and C viruses (Del Giudice et al.”
Background
Towards a Sustainable Route for the Production of Squalene Using Cyanobacteria
Fagundes, M. B., Vendruscolo, R. G., Maroneze, M. M., Barin, J. S., de Menezes, C. R., Zepka, L. Q., Lopes, E. J., & Wagner, R. C. (2018) · Waste and Biomass Valorization · doi:10.1007/s12649-017-0191-8 · Cited by 32 · cited 1× · see citing works
“autumnale, which could use literal waste and rubbish as a source to generate low amounts of squalene (Fagundes et al., 2018).”
Background
High Production of Squalene Using a Newly Isolated Yeast-like Strain Pseudozyma sp. SD301
Song, X., Wang, X., Tan, Y., Feng, Y., Li, W., & Cui, Q. (2015) · Journal of Agricultural and Food Chemistry · doi:10.1021/acs.jafc.5b03539 · Cited by 31 · cited 2× · see citing works
“Highest titre of 2.44 g/L squalene was achieved using fed-batch fermentation by providing glucose and yeast extracts to a ratio of 3, maintaining the system at pH 6 and 25◦C, with supplementation of 15 g/L of sea salt (Song et al., 2015).”
Influential
Tumor regression after intralesional injection of mycobacterial components emulsified in 2,6,10,15,19,23-hexamethyl-2,6,10,14,18,22-tetracosahexaene (squalene), 2,6,10,15,19,23-hexamethyltetracosane (squalane), peanut oil, or mineral oil.
Yarkoni, E., & Rapp, H. J. (1979) · PubMed · Cited by 30 · see citing works
Co-production of ethanol and squalene using a Saccharomyces cerevisiae ERG1 (squalene epoxidase) mutant and agro-industrial feedstock
Hull, C. M., Loveridge, E. J., Rolley, N. J., Donnison, I. S., Kelly, S. L., & Kelly, D. E. (2014) · Biotechnology for Biofuels · doi:10.1186/s13068-014-0133-7 · Cited by 30 · cited 1× · see citing works
“This ERG1 gene is a potent target of genetic manipulation toward increasing squalene production in yeast (Garaiová et al., 2014; Hull et al., 2014).”
Background
Fast UPLC/PDA determination of squalene in Sicilian P.D.O. pistachio from Bronte: Optimization of oil extraction method and analytical characterization
Salvo, A., Torre, G. L. L., Stefano, V. A. D., Capocchiano, V. G., Mangano, V., Saija, E., Pellizzeri, V., Casale, K. E., & Dugo, G. (2016) · Food Chemistry · doi:10.1016/j.foodchem.2016.10.126 · Cited by 29 · cited 2× · see citing works
“…33.8 Tuberoso et al., 2007 30.6 Frega et al., 1992 10–17 Naziri et al., 2011b Pecan 29.8 Fernandes et al., 2017 20.8 Derewiaka et al., 2014 Pistachio 5.5–22.6 Salvo et al., 2017 8.2 Derewiaka et al., 2014 Borage 22 Czaplicki et al., 2011 Soybean 22 Maguire et al., 2004 3–20 Naziri et al.,…”
Influential
PHYSICOCHEMICAL PROPERTIES AND COMPOSITION OF LIPID FRACTION OF SELECTED EDIBLE NUTS
Derewiaka, D., & Szwed, E. (2014) · Cited by 28 · see citing works
Fatty acid, tocopherol and squalene contents of Rosaceae seed oils
Matthäus, B., & Özcan, M. M. (2014) · Botanical studies · doi:10.1186/s40529-014-0048-4 · Cited by 27 · cited 1× · see citing works
“2 mg/100 g) (Matthaus and Özcan, 2014) have also been reported to contain squalene.”
Background
Squalene containing solid lipid nanoparticles, a promising adjuvant system for yeast vaccines
Stelzner, J. J., Behrens, M., Behrens, S., & Mäder, K. (2018) · Vaccine · doi:10.1016/j.vaccine.2018.03.019 · Cited by 27 · cited 1× · see citing works
“The designed complex could successfully produce immune stimulating effects that were comparable to Freund’s adjuvant and the commercially available squalene nanoemulsion AddaVaxTM (Stelzner et al., 2018).”
Different fermentation strategies by Schizochytrium mangrovei strain pq6 to produce feedstock for exploitation of squalene and omega‐3 fatty acids
Hoang, L. A. T., Nguyen, H. C., Le, T. T., Hoang, T. H. Q., Pham, V. N., Hoang, M. H., Ngo, H. T. T., & Hồng, Đ. D. (2018) · Journal of Phycology · doi:10.1111/jpy.12757 · Cited by 27 · cited 1× · see citing works
“07mg/g of lipid) was attained after 48 h of incubation in a 15 L medium containing 22% glucose (Hoang et al., 2018).”
Method
Composition and qualitative characteristics of virgin olive oils produced in northern Adriatic region, Republic of Croatia
Giacometti, J., & Milin, Č. (2001) · Grasas y Aceites · doi:10.3989/gya.2001.v52.i6.350 · Cited by 26 · cited 2× · see citing works
“45 g/kg squalene (Giacometti and Milin, 2001), whereas the deodorizing distillates of olive oil contain 100–300 g/kg squalene (Naziri et al.”
BackgroundInfluential
Effects of dietary paraffin, squalane and sucrose polyester on residue disposition and elimination of hexachlorobenzene in rats
Richter, E., Fichtl, B., & Schäfer, S. G. (1982) · Chemico-Biological Interactions · doi:10.1016/0009-2797(82)90156-9 · Cited by 26 · cited 1× · see citing works
“A diet supplemented with 8% of squalene has been found to improve the faecal elimination of organochlorine xenobiotics including hexachlorobiphenyl (6-CB) and hexachlorobenzene (HCB) (Richter and Schäfer, 1982; Richter et al., 1982).”
Method
Production of squalene by lactose-fermenting yeast Kluyveromyces lactis with reduced squalene epoxidase activity
Drozdíková, E., Garaiová, M., Csáky, Z., Obernauerova, M., & Hapala, I. (2015) · Letters in Applied Microbiology · doi:10.1111/lam.12425 · Cited by 26 · cited 1× · see citing works
“3mg/g DCW) (Goldberg and Shechter, 1978), Kluyveromyces lactis (Drozdíková et al., 2015), and industrial yeast Saccharomyces uvarum (14.”
Background
Squalene production in the cell suspension cultures of Indian sandalwood (Santalum album L.) in shake flasks and air lift bioreactor
Rani, A., Meghana, R., & Kush, A. K. (2018) · Plant Cell Tissue and Organ Culture (PCTOC) · doi:10.1007/s11240-018-1452-3 · Cited by 26 · cited 2× · see citing works
“Squalene (C30H50), an intermediate of cholesterol biosynthesis, is a naturally occurring highly unsaturated triterpenic hydrocarbon compound that forms solely via the mevalonic acid (MVA) or 2-C-methyl-D-erythritol 4-phosphate (MEP) pathways (Spanova and Daum, 2011; Popa et al., 2015; Rani et al., 2018).”
Background
Effect of squalane on hexachlorobenzene (HCB) concentrations in tissues of mice
Richter, E., & Schäfer, S. G. (1982) · Journal of Environmental Science and Health Part B · doi:10.1080/03601238209372313 · Cited by 24 · cited 1× · see citing works
“A diet supplemented with 8% of squalene has been found to improve the faecal elimination of organochlorine xenobiotics including hexachlorobiphenyl (6-CB) and hexachlorobenzene (HCB) (Richter and Schäfer, 1982; Richter et al., 1982).”
Method
Book Review: Recent Advances in Yeast Metabolic Engineering
Gohil, N., Panchasara, H., Patel, S. K., Ramirez-Garcia, R., & Singh, V. (2017) · Frontiers in Bioengineering and Biotechnology · doi:10.3389/fbioe.2017.00071 · Cited by 24 · cited 1× · see citing works
“In addition, quantum leap in molecular biology, synthetic biology, metabolic engineering and genome engineering have opened up new avenues for the production of numerous valuable chemicals, biofuels, and important metabolites from renewable sources (Rabinovitch-Deere et al., 2013; Singh et al., 2014, 2016; Chubukov et…”
Background
Metabolic Engineering of Biosynthetic Pathway for Production of Renewable Biofuels
Singh, V., Mani, I., Chaudhary, D. K., & Dhar, P. K. (2013) · Applied Biochemistry and Biotechnology · doi:10.1007/s12010-013-0606-3 · Cited by 23 · cited 1× · see citing works
“…biology, metabolic engineering and genome engineering have opened up new avenues for the production of numerous valuable chemicals, biofuels, and important metabolites from renewable sources (Rabinovitch-Deere et al., 2013; Singh et al., 2014, 2016; Chubukov et al., 2016; Gohil et al., 2017).”
Occurrence of squalene in methanol-grown bacteria
Goldberg, I., & Shechter, I. (1978) · Journal of Bacteriology · doi:10.1128/jb.135.2.717-720.1978 · Cited by 22 · cited 3× · see citing works
“(Goldberg and Shechter, 1978; Uragami and Koga, 1986), Methylomonas methanolica (Goldberg and Shechter, 1978) and Methylococcus capsulatus (Goldberg and Shechter, 1978) were found to produce squalene up to 0.”
Background
Isolation and Characterization of Two Squalene Epoxidase Genes from Botryococcus braunii, Race B
Uchida, H., Sumimoto, K., Ferriols, V. M. E. N., Imou, K., Saga, K., Furuhashi, K., Matsunaga, S., & Okada, S. (2015) · PLoS ONE · doi:10.1371/journal.pone.0122649 · Cited by 21 · see citing works
Characterization of Flax and Soybean Soapstocks, and Soybean Deodorizer Distillate by GC‐FID
Dumont, M., & Narine, S. S. (2007) · Journal of the American Oil Chemists Society · doi:10.1007/s11746-007-1154-1 · Cited by 19 · cited 1× · see citing works
“Similarly, soybean, sunflower, canola, and palm fatty acid distillates encompass about 18–55, 43–45, 30–35, and 2–13 g/kg of squalene, respectively (Dumont and Narine, 2007; Naziri et al., 2011b; Naz et al., 2014).”
Background
Biosynthetic Approaches to Squalene Production: The Case of Yeast
Valachovič, M., & Hapala, I. (2016) · Methods in molecular biology · doi:10.1007/978-1-4939-6445-1_7 · Cited by 19 · cited 1× · see citing works
“…or introduction of squalene producing gene(s) in native squalene biosynthesis pathways (Bunch and Harris, 1986; Singh et al., 2017, 2018; Valachovič and Hapala, 2017), and (3) addition of an inhibitor (e.g., terbinafine) that blocks the competitive pathway thus allowing squalene…”
Engineering of the terpenoid pathway in Saccharomyces cerevisiae co-overproduces squalene and the non-terpenoid compound oleic acid
Rasool, A., Zhang, G., Li, Z., & Li, C. (2016) · Chemical Engineering Science · doi:10.1016/j.ces.2016.06.004 · Cited by 18 · see citing works
Construction of squalene-accumulating Saccharomyces cerevisiae mutants by gene disruption through homologous recombination
Kamimura, N., Hidaka, M., Masaki, H., & Uozumi, T. (1994) · Applied Microbiology and Biotechnology · doi:10.1007/bf00902741 · Cited by 15 · cited 1× · see citing works
“Accordingly, by feeding ergosterol into the system, squalene production could be increased up to 5mg/g DCW under aerobic condition (Kamimura et al., 1994).”
Background
Squalene versus cholesterol: Which is the best nanocarrier for the delivery to cells of the anticancer drug gemcitabine?
Peramo, A., Mura, S., Yesylevskyy, S. O., Cardey, B., Sobot, D., Denis, S., Ramseyer, C., Desmaële, D., & Couvreur, P. (2018) · Comptes Rendus Chimie · doi:10.1016/j.crci.2018.02.008 · Cited by 15 · cited 1× · see citing works
“An example of this is the enhanced membrane permeability and interaction of the gemcitabin-squalene complex as compared to free gemcitabin (Castelli et al., 2007; Pili et al., 2010; Peramo et al., 2018).”
Squalene Extraction by Supercritical Fluids from Traditionally Puffed Amaranthus hypochondriacus Seeds
Rosales-García, T., Jiménez‐Martínez, C., Cardador‐Martínez, A., del Campo, S. T. M., Galicia-Luna, L. A., Téllez‐Medina, D. I., & Dávila-Ortíz, G. (2017) · Journal of Food Quality · doi:10.1155/2017/6879712 · Cited by 14 · see citing works
Directed evolution of squalene synthase for dehydrosqualene biosynthesis
Furubayashi, M., Li, L., Katabami, A., Saito, K., & Umeno, D. (2014) · FEBS Letters · doi:10.1016/j.febslet.2014.07.028 · Cited by 13 · cited 21× · see citing works
“MVA, mevalonate; MEP, 2-C-methyl-d-erythritol 4-phosphate; AACT, acetoacetyl-CoA thiolase; HMGS, 3-hydroxy-3-methylglutaryl-CoA synthase; HMGR, HMG-CoA reductase; DMAPP, dimethylallyl diphosphate; IDI, isopentenyl diphosphate isomerase; IPP, isopentenyl pyrophosphate; FPS, farnesyl pyrophosphate synthase; GPP, geranyl…”
BackgroundInfluential
Commodity Chemicals Production by Fermentation: An Overview
Badal Chandra, S. A. H. A. (2003) · ACS symposium series · doi:10.1021/bk-2003-0862.ch001 · Cited by 11 · cited 1× · see citing works
“In order to elevate the industrial scale production of valuable products, fermentation technology uses the adaptability of the natural pathways to produce a desired molecule from the organisms by utilizing cheaper sources of substrates (Saha, 2003).”
How squalene GLAdly helps generate antigen‐specific T cells via antigen‐carrying neutrophils and IL‐18
Kedl, J. D., & Kedl, R. M. (2015) · European Journal of Immunology · doi:10.1002/eji.201445379 · Cited by 10 · cited 2× · see citing works
“…17 March 2019 | Volume 7 | Article 50 Squalene prepared into emulsion either as the lone ingredient or in combination with other components can readily improve the functioning of a drug and may also help to elicit a favorable immune response against the exogenous antigen (Kedl and Kedl, 2015).”
Construction of squalene-accumulating Saccharomyces cerevisiae mutants by gene disruption through homologous recombination
Kamimura, N., Hidaka, M., Masaki, H., et al. (1994) · Applied Microbiology and Biotechnology · doi:10.1007/s002530050262 · Cited by 3 · see citing works

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Bhattacharjee P. Singhal R. S. (2003). Extraction of squalene from yeast by supercritical carbon dioxide. World J. Microbiol. Biotechnol. 19, 605– 608. 10.1023/A:1025146132281 · DOI

Sorted by citations

Tailoring the Saccharomyces cerevisiae endoplasmic reticulum for functional assembly of terpene synthesis pathway
Kim, J.-E., Jang, I.-S., Son, S., Ko, Y., Cho, B., Kim, S. C., & Lee, J. Y. (2019) · Metabolic Engineering · doi:10.1016/j.ymben.2019.08.013 · Cited by 190 · see citing works
Archaea Biotechnology
Pfeifer, K., Ergal, İ., Koller, M., Basen, M., Schuster, B., & Rittmann, S. K. ‐. R. (2020) · Biotechnology Advances · doi:10.1016/j.biotechadv.2020.107668 · Cited by 154 · see citing works
Metabolic compartmentalization in yeast mitochondria: Burden and solution for squalene overproduction
Zhu, Z.-T., Du, M.-M., Gao, B., Tao, X., Zhao, M., Ren, Y., Wang, F., & Wei, D. (2021) · Metabolic Engineering · doi:10.1016/j.ymben.2021.10.011 · Cited by 148 · see citing works
From sequence to function through structure: Deep learning for protein design
(2022) · doi:10.1016/j.csbj.2022.11.014 · Cited by 124 · see citing works
“Proteins can serve as factories increasingly engineered to manufacture other products, such as the triterpene squalene [117].”
Background
Squalene monooxygenase: a journey to the heart of cholesterol synthesis
Chua, N. K., Coates, H. W., & Brown, A. J. (2020) · Progress in Lipid Research · doi:10.1016/j.plipres.2020.101033 · Cited by 110 · see citing works
Recent advances in squalene: Biological activities, sources, extraction, and delivery systems
Cheng, L., Ji, T., Zhang, M., & Fang, B. (2024) · Trends in Food Science & Technology · doi:10.1016/j.tifs.2024.104392 · Cited by 110 · see citing works
Co-production of DHA and squalene by thraustochytrid from forest biomass
Patel, A., Liefeldt, S., Rova, U., Christakopoulos, P., & Μάτσακας, Λ. (2020) · Scientific Reports · doi:10.1038/s41598-020-58728-7 · Cited by 98 · see citing works
Simultaneous production of DHA and squalene from Aurantiochytrium sp. grown on forest biomass hydrolysates
Patel, A., Rova, U., Christakopoulos, P., & Μάτσακας, Λ. (2019) · Biotechnology for Biofuels · doi:10.1186/s13068-019-1593-6 · Cited by 89 · see citing works
“Squalene acts as a precursor of thousands of bioactive compounds, including sterols and hopanoids [27].”
Background
Production, Biosynthesis, and Commercial Applications of Fatty Acids From Oleaginous Fungi
Zhang, X., Li, B. J., Huang, B.-C., Wang, F.-B., Zhang, Y., Zhao, S.-G., Li, M., Wang, H., Yu, X., Liu, X., et al. (2022) · Frontiers in Nutrition · doi:10.3389/fnut.2022.873657 · Cited by 85 · see citing works
From Sharks to Yeasts: Squalene in the Development of Vaccine Adjuvants
Mendes, A., Azevedo‐Silva, J., & Fernandes, J. C. (2022) · Pharmaceuticals · doi:10.3390/ph15030265 · Cited by 87 · see citing works
Efficient synthesis of squalene by cytoplasmic-peroxisomal engineering and regulating lipid metabolism in Yarrowia lipolytica
Yang, N., Liu, M., Ru, Z., Zeng, W., Liu, S., & Zhou, J. (2024) · Bioresource Technology · doi:10.1016/j.biortech.2024.130379 · Cited by 77 · see citing works
Engineering peroxisomal biosynthetic pathways for maximization of triterpene production in Yarrowia lipolytica
Ma, Y., Shang, Y., & Stephanopoulos, G. N. (2024) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2314798121 · Cited by 65 · see citing works
“Currently, it is commercially sourced mainly from shark liver oil and plant seeds (16).”
Mining of squalene as a value-added byproduct from DHA producing marine thraustochytrid cultivated on food waste hydrolysate
Patel, A., Rova, U., Christakopoulos, P., & Μάτσακας, Λ. (2020) · The Science of The Total Environment · doi:10.1016/j.scitotenv.2020.139691 · Cited by 65 · see citing works
Recent advances in the microbial production of squalene
Paramasivan, K., & Mutturi, S. (2022) · World Journal of Microbiology and Biotechnology · doi:10.1007/s11274-022-03273-w · Cited by 60 · see citing works
“Squalene synthesis in microbes, plants, and mammals and their applications has been recently reviewed (Gohil et al. 2019).”
Background
Extension of cell membrane boosting squalene production in the engineered Escherichia coli
Meng, Y., Shao, X., Wang, Y., Li, Y., Zheng, X., Wei, G., Kim, S.-W., & Wang, C. (2020) · Biotechnology and Bioengineering · doi:10.1002/bit.27511 · Cited by 56 · see citing works
Production of Squalene in Bacillus subtilis by Squalene Synthase Screening and Metabolic Engineering
Song, Y., Guan, Z., van Merkerk, R., Pramastya, H., Abdallah, I. I., Setroikromo, R., & Quax, W. J. (2020) · Journal of Agricultural and Food Chemistry · doi:10.1021/acs.jafc.0c00375 · Cited by 54 · see citing works
Microbial genetic engineering approach to replace shark livering for squalene
Patel, A., Bettiga, M., Rova, U., Christakopoulos, P., & Μάτσακας, Λ. (2022) · Trends in biotechnology · doi:10.1016/j.tibtech.2022.03.008 · Cited by 54 · see citing works
“Squalene serves as a precursor to numerous bioactive compounds including sterols and hopanoids [2].”
Background
Advancing the protection of marine life through genomics
van Oppen, M. J. H., & Coleman, M. A. (2022) · PLoS Biology · doi:10.1371/journal.pbio.3001801 · Cited by 49 · see citing works
Key Targets for Improving Algal Biofuel Production
Griffiths, G., Hossain, A. K., Sharma, V., & Duraisamy, G. (2021) · Clean Technologies · doi:10.3390/cleantechnol3040043 · Cited by 49 · see citing works
Fine-tuning the expression of pathway gene in yeast using a regulatory library formed by fusing a synthetic minimal promoter with different Kozak variants
Xu, L., Liu, P., Dai, Z., Fan, F., & Zhang, X. (2021) · Microbial Cell Factories · doi:10.1186/s12934-021-01641-z · Cited by 46 · see citing works
“111-02-4) is a linear polyunsaturated triterpene and is traditionally sourced from shark liver oil [39].”
Background
Regulation of Ethanol Assimilation for Efficient Accumulation of Squalene in Saccharomyces cerevisiae
Zhang, Y.-L., Wang, W., Wei, W., Lu, X., Gao, S., Zeng, W., Liu, S., & Zhou, J. (2023) · Journal of Agricultural and Food Chemistry · doi:10.1021/acs.jafc.3c00515 · Cited by 46 · see citing works
Sustainable protein production through genetic engineering of cyanobacteria and use of atmospheric N2 gas
Nawaz, T., Gu, L., Fahad, S., Saud, S., Harrison, M. T., & Zhou, R. (2024) · Food and Energy Security · doi:10.1002/fes3.536 · Cited by 45 · see citing works
Haloarchaea have a high genomic diversity for the biosynthesis of carotenoids of biotechnological interest
Serrano, S., Mendo, S., & Caetano, T. (2021) · Research in Microbiology · doi:10.1016/j.resmic.2021.103919 · Cited by 40 · see citing works
Metabolic Engineering for Squalene Production: Advances and Perspectives
Chai, L., Che, J., Qi, Q., & Hou, J. (2024) · Journal of Agricultural and Food Chemistry · doi:10.1021/acs.jafc.4c09608 · Cited by 38 · see citing works
A polycistronic system for multiplexed and precalibrated expression of multigene pathways in fungi
Yue, Q., Meng, J., Qiu, Y., Yin, M., Zhang, L., Zhou, W., An, Z., Liu, Z., Yuan, Q., Sun, W., et al. (2023) · Nature Communications · doi:10.1038/s41467-023-40027-0 · Cited by 37 · see citing works
Microbial Squalene: A Sustainable Alternative for the Cosmetics and Pharmaceutical Industry – A Review
Shalu, S., Karthikanath, P. K. R., Vaidyanathan, V. K., Blank, L. M., Germer, A., & Balakumaran, P. A. (2024) · Engineering in Life Sciences · doi:10.1002/elsc.202400003 · Cited by 29 · see citing works
“Squalene production in S. cerevisiae is strictly controlled and is negligible (0.041 mg/g of biomass) during its growth [13, 87].”
BackgroundInfluential
Overexpression of Key Sterol Pathway Enzymes in Two Model Marine Diatoms Alters Sterol Profiles in Phaeodactylum tricornutum
Jaramillo-Madrid, A. C., Abbriano, R. M., Ashworth, J., Fabris, M., Pernice, M., & Ralph, P. J. (2020) · Pharmaceuticals · doi:10.3390/ph13120481 · Cited by 28 · see citing works
Engineering of cis-Element in Saccharomyces cerevisiae for Efficient Accumulation of Value-Added Compound Squalene via Downregulation of the Downstream Metabolic Flux
Zhou, C., Li, M., Lu, S., Cheng, Y., Guo, X., He, X., Wang, Z., & He, X. (2021) · Journal of Agricultural and Food Chemistry · doi:10.1021/acs.jafc.1c04978 · Cited by 28 · see citing works
Overexpression of Two New Acyl-CoA:Diacylglycerol Acyltransferase 2-Like Acyl-CoA:Sterol Acyltransferases Enhanced Squalene Accumulation in Aurantiochytrium limacinum
Rau, E.-M., Bartošová, Z., Kristiansen, K. A., Aasen, I. M., Bruheim, P., & Ertesvåg, H. (2022) · Frontiers in Microbiology · doi:10.3389/fmicb.2022.822254 · Cited by 25 · see citing works
“Currently, the primary commercial source of squalene is shark liver oil, and the amount that can be harvested in a sustainable manner is limited and cannot meet an increasing demand (Gohil et al., 2019).”
Background
The ABC transporter Pdr18 is required for yeast thermotolerance due to its role in ergosterol transport and plasma membrane properties
Godinho, C. P., Costa, R., & Sá‐Correia, I. (2020) · Environmental Microbiology · doi:10.1111/1462-2920.15253 · Cited by 23 · see citing works
“Interestingly, squalene is a molecule of great medical and cosmetic interest, and cells accumulating high squalene levels might be of high biotechnological potential (Gohil et al., 2019).”
Background
Recycling deteriorated silage to remove hazardous mycotoxins and produce a value-added product
Zong, C., Wu, Q., Dong, Z., Wu, A., Wu, J., Shao, T., & Liu, Q. (2021) · Journal of Hazardous Materials · doi:10.1016/j.jhazmat.2021.127627 · Cited by 22 · see citing works
Media Supplementation with Mannitol and Biotin Enhances Squalene Production of Thraustochytrium ATCC 26185 through Increased Glucose Uptake and Antioxidative Mechanisms
Ali, M. K., Sen, B., He, Y., Bai, M., & Wang, G. (2022) · Molecules · doi:10.3390/molecules27082449 · Cited by 22 · see citing works
“Therefore, sustainable production of squalene from renewable sources has been the biggest challenge for the industrial applications of squalene [4].”
Background
Genomic analysis of heavy metal-resistant Halobacterium salinarum isolated from Sfax solar saltern sediments
Baati, H., Siala, M., Azri, C., Ammar, E., Dunlap, C. A., & Trigui, M. (2022) · Extremophiles · doi:10.1007/s00792-022-01273-0 · Cited by 22 · see citing works
“Squalene has been known to play diverse biological roles as an anti-oxidant, anti-cancer agent, antibacterial agent, skin care products, and adjuvant for vaccines and drug carrier (Gohil et al. 2019).”
Background
Genome analysis of a halophilic Virgibacillus halodenitrificans ASH15 revealed salt adaptation, plant growth promotion, and isoprenoid biosynthetic machinery
Sharma, A., Singh, R. N., Song, X., Singh, R. K., Guo, D.-J., Singh, P., VERMA, K. K., & Li, Y. (2023) · Frontiers in Microbiology · doi:10.3389/fmicb.2023.1229955 · Cited by 22 · see citing works
“Therefore, it has enormous potential in the food, cosmetics, and pharmaceutical industries (Huang et al., 2009; Gohil et al., 2019).”
Background
Squalene synthase in plants – Functional intricacy and evolutionary divergence while retaining a core catalytic structure
Hazra, A., Dutta, M., Dutta, R., Bhattacharya, E., Bose, R., & Biswas, S. M. (2023) · Plant Gene · doi:10.1016/j.plgene.2023.100403 · Cited by 21 · see citing works
Rhodosporidium sp. DR37: a novel strain for production of squalene in optimized cultivation conditions
Shakeri, S., Khoshbasirat, F., & Maleki, M. (2021) · Biotechnology for Biofuels · doi:10.1186/s13068-021-01947-5 · Cited by 21 · see citing works
“squalene has increased during the last decade, microbial production of squalene has been investigated as a promising alternative source for traditional extraction methods from shark liver or plant oils [11].”
Background
Sterols from microalgae
Fagundes, M. B., Vendruscolo, R. G., & Wagner, R. C. (2020) · Elsevier eBooks · doi:10.1016/b978-0-12-818536-0.00021-x · Cited by 20 · see citing works
From pollutants to products: Microbial cell factories driving sustainable biomanufacturing and environmental conservation
Gavrilescu, M. C. (2024) · Chemical Engineering Journal · doi:10.1016/j.cej.2024.157152 · Cited by 19 · see citing works
Thraustochytrids as a promising source of fatty acids, carotenoids, and sterols: bioactive compound biosynthesis, and modern biotechnology
Song, Y., Yang, X., Li, S., Luo, Y., Chang, J., & Hu, Z. (2023) · Critical Reviews in Biotechnology · doi:10.1080/07388551.2023.2196373 · Cited by 18 · see citing works
“It is attracting increasing attention because of its potential antioxidant activity, and ability to inhibit tumor development and is a naturally abundant precursor of other bioactive compounds [112,113].”
Background
In-depth genome and pan-genome analysis of a metal-resistant bacterium Pseudomonas parafulva OS-1
Kumari, K., Rawat, V. R. S., Shadan, A., Sharma, P. K., Deb, S., & Singh, R. P. (2023) · Frontiers in Microbiology · doi:10.3389/fmicb.2023.1140249 · Cited by 17 · see citing works
Metal cofactor regulation combined with rational genetic engineering of Schizochytrium sp. for high‐yield production of squalene
Xu, Y., Ma, W., Li, J., Huang, P., Sun, X., & Huang, H. (2022) · Biotechnology and Bioengineering · doi:10.1002/bit.28311 · Cited by 14 · see citing works
“Squalene can improve oxygen tolerance as an oxygen carrier, and can protect cells from harmful free radicals and reactive oxygen species by preventing lipid peroxidation as a strong natural antioxidant (Guirimand et al., 2021; Zhu et al., 2021).”
Background
Repurposing the cellulase workhorse Trichoderma reesei as a ROBUST chassis for efficient terpene production
Xiao, M., Wang, Y., Wang, Y., Yan, X., Zhu, Z., Tian, E., Yang, C., Ma, E., Zou, G., Zhou, Z., et al. (2023) · Green Chemistry · doi:10.1039/d3gc01770b · Cited by 14 · see citing works
Squalene in Nanoparticles Improves Antiproliferative Effect on Human Colon Carcinoma Cells Through Apoptosis by Disturbances in Redox Balance
Bidooki, S. H., Quero, J., Sánchez-Marco, J., Herrero‐Continente, T., Mármol, I., Lasheras, R., Sebastián, V., Arruebo, M., Osada, J., & Rodriguez‐Yoldi, M. J. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms252313048 · Cited by 15 · see citing works
“A number of studies have demonstrated that a variety of anticancer agents, including adriamycin, 5-fluorouracil, hydroxytyrosol, and bleomycin, exhibit enhanced antitumor activity when combined with squalene [39,43,44].”
By-Product of the Red Ginseng Manufacturing Process as Potential Material for Use as Cosmetics: Chemical Profiling and In Vitro Antioxidant and Whitening Activities
Zhang, H.-E., Chu, M.-Y., Tao, J., Xin-Hong, S. O. N. G., Hou, J.-F., Cheng, L.-Y., Feng, Y., Chen, C., & Wang, E. (2022) · Molecules · doi:10.3390/molecules27238202 · Cited by 14 · see citing works
High-Level Squalene Production from Methane Using a Metabolically Engineered Methylomonas sp. DH-1 Strain
Kang, C. K., Jeong, S.-W., Jo, J.-H., Park, J., Kim, M., Yang, J. E., & Choi, Y. J. (2021) · ACS Sustainable Chemistry & Engineering · doi:10.1021/acssuschemeng.1c06776 · Cited by 13 · see citing works
An introduction to microbial cell factories for production of biomolecules
Gohil, N., Bhattacharjee, G., & Singh, V. (2021) · Elsevier eBooks · doi:10.1016/b978-0-12-821477-0.00021-0 · Cited by 13 · see citing works
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Authors: Gohil, N., Bhattacharjee, G., Khambhati, K., Braddick, D., & Singh, V.
Affiliations: Indian Institute of Advanced Research (IN)
Genopole (France) (FR)
Corresponding author: Singh, Vijai
ORCID: Gohil, Nisarg
Bhattacharjee, Gargi
Singh, Vijai
Venue: Frontiers in Bioengineering and Biotechnology
Publisher: Frontiers Media SA
Published: 2019-03-22
Volume: 7
Pages: 114-114
ISSN: 2296-4185 (ISSN-L)
DOI: 10.3389/fbioe.2019.00050
PMC: PMC6439483
OpenAlex: W2924306915
Cited by: 121
References: 199
Citations by year: 2026: 15 · 2025: 15 · 2024: 20 · 2023: 21 · 2022: 19 · 2021: 15 · 2020: 14 · 2019: 2
FWCI: 1.10
Type: journal article
Language: en
Update notices: corrigendum (2019-05-28)
Open access: gold
doi.org
Licence: cc-by
creativecommons.org/licenses/by/4.0/ (vor)
Locations: Frontiers in Bioengineering and Biotechnology (publishedVersion, cc-by)
PubMed Central (publishedVersion, cc-by)
Europe PMC (PubMed Central) (publishedVersion, cc-by)
PubMed (publishedVersion)
DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Plant biochemistry and biosynthesis
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Microbial Metabolic Engineering and Bioproduction
Health Sciences › Medicine › Pharmacology › Microbial Natural Products and Biosynthesis
Keywords: squalene, triterpenoids, synthetic biology, influenza vaccine adjuvants, nutraceuticals, pharmaceutical applications, industrial biotechnology

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Engineering Strategies in Microorganisms for the Enhanced Production of Squalene: Advances, Challenges and Opportunities

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