CORRECTION article

Front. Bioeng. Biotechnol., 28 May 2019

Sec. Synthetic Biology

Volume 7 - 2019 | https://doi.org/10.3389/fbioe.2019.00114

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

  • 1. School of Biological Sciences and Biotechnology, Institute of Advanced Research, Koba Institutional Area, Gandhinagar, India

  • 2. Department of R&D, Cementic S. A. S., Genopole, Paris, France

This article is a correction to:

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

    1. Read original article

A Corrigendum on Engineering Strategies in Microorganisms for the Enhanced Production of Squalene: Advances, Challenges and Opportunities by Gohil, N., Bhattacharjee, G., Khambhati, K., Braddick, D., and Singh, V. (2019). Front. Bioeng. Biotechnol. 7:50. doi: 10.3389/fbioe.2019.00050

In the original article, there were mistakes in Tables 1, 3, and 4.

Table 1

Plant sourceConcentration
(mg/100 g DCW)		Reference
OILS
Amaranth60,000Wejnerowska et al., 2013
46,000Rosales-García et al., 2017b
2,000–8,000Naziri et al., 2011b
1,040–6,980He and Corke, 2003
6,960Lyon and Becker, 1987
5,220Czaplicki et al., 2011
Olive99–1,245Giacometti and Milin, 2001
80–1,200Lanzón et al., 1994
250–925Gutfinger and Letan, 1974
110–839Beltrán et al., 2016
375–652Nenadis and Tsimidou, 2002
564Frega et al., 1992
170–460Grigoriadou et al., 2007
342–450Manzi et al., 1998
Ginseng seed514–569Beveridge et al., 2002
Pumpkin seed523Czaplicki et al., 2011
352.9Tuberoso et al., 2007
260–350Naziri et al., 2011b
Rice bran320Rukmini and Raghuram, 1991
318.9Pokkanta et al., 2019
Brazil nut145.8Derewiaka et al., 2014
Peanuts132.9Pokkanta et al., 2019
127.6Tuberoso et al., 2007
27.4Frega et al., 1992
White sesame seed60.7Pokkanta et al., 2019
Black sesame seed57.2Pokkanta et al., 2019
Palm20–50Goh et al., 1985
43.3Lau et al., 2005
Coriander seed45.1Pokkanta et al., 2019
Apricot kernel12.6–43.9Rudzinska et al., 2017
Hazelnut9.3–39.2Bada et al., 2004
27.9Frega et al., 1992
25.7Derewiaka et al., 2014
Macadamia nut38.3Derewiaka et al., 2014
18.5Maguire et al., 2004
7.2–17.1Wall, 2010
Avocado34.1–37.0Gutfinger and Letan, 1974
Corn33.8Tuberoso et al., 2007
30.6Frega et al., 1992
10–17Naziri et al., 2011b
Pecan29.8Fernandes et al., 2017
20.8Derewiaka et al., 2014
Pistachio5.5–22.6Salvo et al., 2017
8.2Derewiaka et al., 2014
Borage22Czaplicki et al., 2011
Soybean22Maguire et al., 2004
3–20Naziri et al., 2011b
18.4Pokkanta et al., 2019
12.5–14.3Gutfinger and Letan, 1974
9.9Frega et al., 1992
Sunflower seed0-19Naziri et al., 2011b
17Tuberoso et al., 2007
Rape seed43.7Tuberoso et al., 2007
Grape seed10.2–16.2Wen et al., 2016
14.1Frega et al., 1992
Cashew11.6Derewiaka et al., 2014
Almond9.6Fernandes et al., 2017
1.3Liu et al., 1976
Cotton-seed9.10Gutfinger and Letan, 1974
2.78Liu et al., 1976
Flaxseed1.0–4.2Tanska et al., 2016
Coconut1.6Gutfinger and Letan, 1974
Walnut0.94Maguire et al., 2004
0.09Liu et al., 1976
Rosaceae seed0.02–0.29Matthaus and Özcan, 2014
DISTILLATES
Olive oil10,000–30,000Naziri et al., 2011b
28,000Bondioli et al., 1993
Soybean oil5,500Dumont and Narine, 2007
1,800–3,500Naziri et al., 2011b
1,830Gunawan et al., 2008
Sunflower oil4,300–4,500Naz et al., 2014
Canola oil3,000–3,500Naz et al., 2014
Palm fatty acid200–1,300Naziri et al., 2011b
1,030Posada et al., 2007
Wine lees6,000Naziri et al., 2012

Plant sources of squalene.

DCW, dry cell weight.

Table 3

MicroorganismConditionsFermentation
volume/mode		SqualeneReference
Yield
(mg/g DCW)		Titre
(g/L)
S. cerevisiaeNutrients (GPY medium), 30°C temp., pH 5.5.
Optimized: inoculum size (5%), incubation period (48 h), anaerobic conditions		100 mL shake flask1.38NDBhattacharjee et al., 2001
T. delbrueckiiNutrients (GPY medium), 30°C temp., pH 5.5.
Optimized: inoculum size (5%), incubation period (24 h), anaerobic conditions		100 mL shake flask1.89NDBhattacharjee et al., 2001
S. cerevisiae EGY48Nutrients (glucose, yeast extract, and soy peptone).
Optimized: terbinafine (0.44 mM) plus methyl jasmonate (0.04 mM) for squalene content, terbinafine (0.30 mM) for squalene yield		100 mL shake flask10.020.020Naziri et al., 2011a
S. cerevisiae BY4741Nutrients (glucose, soy peptone, yeast, and malt extracts), 30°C temp., pH 5.5, 200 rpm.
Optimized: oxygen supply (low), inoculum size (5%), incubation time (28.5 h)		100 mL shake flaskND2.96*10−3Mantzouridou et al., 2009
Nutrients (glucose, soy peptone, yeast, and malt extracts), 30°C temp., pH 5.5, 200 rpm.
Optimized: oxygen supply (low), inoculum size (8%), incubation time (45 h)		100 mL shake flaskND3.12*10−3
T. delbrueckiiNutrients (glucose, yeast extract, peptone), pH 5.5, anaerobic, 30°C temp.
Optimized: temp.60°C, pressure 250–255 bar and 0.2 L/min CO2flowSFE technique		2.5 L shake flask0.01NDBhattacharjee and Singhal, 2003
Nutrients (glucose, yeast extract, peptone), pH 5.5, anaerobic, 30°C temp.
Optimized: lyophilization prior to SFE under the above mentioned conditions		2.5 L shake flask0.43ND
K. lactisNutrients (YPL medium).
Optimized: terbinafine (7.5 mg/L)		ND0.6 mg/109 cellsNDDrozdíková et al., 2015
A. mangrovei FB3Nutrients (GPY medium), 25°C temp., inoculum size 5%.
Optimized: glucose (30 g/L)		100 mL shake flask0.372.21*10−3Fan et al., 2010
Aurantiochytrium sp. strain 18W-13aNutrients (GPY medium), 25°C temp., 100 rpm.
Optimized: Incubation time (96 h)		ND1981.29Kaya et al., 2011
Aurantiochytrium sp. strain 18W-13aNutrients (GPY medium), 130 rpm.
Optimized: temp. 25°C, seawater (25–50%), glucose (2–6%)		200 mL shake flask1710.9Nakazawa et al., 2012
Aurantiochytrium sp. BR-MP4-A1Nutrients (glucose, yeast extract,salts), temp. 25°C, pH 6, inoculum size 5%, 200 rpm, dark.
Optimized: N-source (monosodium glutamate (6.61–6.94 g/L), yeast extract (6.13–6.22 g/L), tryptone (4.40–4.50 g/L))		50 mL shake flask0.725.90*10−3Chen et al., 2010
Schizochytrium mangroveiPQ6Nutrients: (M12 medium: glucose, yeast, artificial sea water), inoculum size 2–3%, temp. 28°C, pH 6.5–7.515 L33.00 ± 0.020.99Hoang et al., 2014
Nutrients: (M12 medium: glucose, yeast, artificial sea water), inoculum size 2–3%, temp. 28°C, pH 6.5–7.5100 L33.04 ± 0.031.01
S. mangroveiPQ6Nutrients (glucose, yeast extract, urea, salts).
Optimized: fermentation mode (fed-batch), incubation time (48 h)		15 L fed-batch fermentation98.07 mg/g of lipidNDHoang et al., 2018
Pseudozyma SD301Nutrients (GPY medium).
Optimized: temp. 25°C, pH 6, carbon (glucose), nitrogen (yeast extract), C/N ratio (3), sea salt (15 g/L)		50 mL shake flask for optimization, 3.5L for fed-batch fermentationND2.44Song et al., 2015
Phormidium autumnaleIndustrial slaughterhouse wastewater, C/N ratio 30, temperature 26°C, pH 7.6, keptdarkBubble column bioreactor0.18NDFagundes et al., 2018

Fermentation optimization for squalene production.

DCW, dry cell weight; ND, no data; temp, temperature; GPY, glucose peptone yeast; C/N, carbon/nitrogen; rpm, revolutions per minute; YPL, yeast peptone lactose; SFE, supercritical fluid extraction.

Table 4

MicroorganismsStrategySqualeneReference
Content (mg/g DCW)Yield (mg/L)
S. cerevisiae SHY3Disruption of a gene involved in the conversion of squalene to ergosterol by homologous recombination5NDKamimura et al., 1994
S. cerevisiae BY4741Point mutations in ERG1, the gene responsible for conversion of squalene to squalene epoxide, thereby promoting hypersensitivity to terbinafine1 mg/109 cellsNDGaraiová et al., 2014
S. cerevisiae YUG37Regulation of ERG1 expression by promoter tet07-CYC17.85 ± 0.02NDHull et al., 2014
S. cerevisiae YPH499Overexpression of HMG1 (encodes HMGR)ND191.9Tokuhiro et al., 2009
S. cerevisiae EGY48Overexpression of HMG2 with a K6R stabilizing mutation in Hmg2p, an HMGR isoenzyme18.3NDMantzouridou and Tsimidou, 2010
S. cerevisiae BY4741Overexpression of tHMG1 and POS5 with mitochondrial presequence58.6 ± 1.4328.4 ± 1.08Paramasivan and Mutturi, 2017
Overexpression of tHMG1 and POS5 without mitochondrial presequence33.0 ± 2.9646.0 ± 4.08
S. cerevisiae BY4741Overexpression of ERG9 and POS5 without mitochondrial presequenceND85Zhuang and Chappell, 2015
Overexpression of ERG9and tHMGR, insertion mutation in ERG1ND270
S. cerevisiae AH22Overexpression of tHMG1 under constitutive promoterNDNDPolakowski et al., 1998
S. cerevisiae BY4742-TRPOverexpression of tHMG1, LYS2ND150.9Dai et al., 2014
Overexpression of tHMG1, LYS2, ERG9, ERG1, expression of bAS (b-amyrin synthase) from Glycyrrhiza glabraND183.4
S. cerevisiae SR7Co-expression oftHMG1 and ERG10 gene in xylose-rich mediumND532Kwak et al., 2017
S. cerevisiae Y2805Overexpression of tHMG1, expression of ispAND400 ± 45Han et al., 2018
Overexpression of tHMG1, expression of ispA, fed-batch fermentationND1026 ± 37
Overexpression of tHMG1, expression of ispA, fed-batch fermentation with supplementation of terbinafineND2011 ± 75
S. cerevisiae BY4742Overexpression of tHMGR and upc2.1 (a mutated regulatory factor that induces sterol biosynthetic gene)ND78Dai et al., 2012
S. cerevisiae INVSc1Overexpression of tHMG1, IDI1 (isopentenyl diphosphate-isomerase), ERG20 (farnesyl diphosphate synthase), and ERG9ND34Rasool et al., 2016a
Overexpression of tHMG1, IDI1, ERG20, and ERG9, supplementation of terbinafineND119.08
Overexpression of tHMG1, IDI1, ERG20, ERG9, ERG10 (encoding acetyl-CoA C-acetyltransferase), ERG13 (HMG-CoA synthase), ERG12 (mevalonate kinase), ERG8 (phosphomevalonate kinase), and MVD1 (diphosphomevalonate decarboxylase)ND304.49
S. cerevisiae INVSc1Overexpression of squalene biosynthetic pathway using a library of 13 new constitutive promotersND100Rasool et al., 2016b
Overexpression of squalene biosynthetic pathway using a library of 13 new constitutive promoters, supplementation of terbinafineND304.16
S. cerevisiae D452-2Overexpression of tHMG1 and DGA1, fed-batch fermentation in nitrogen restricted minimal mediaND445.6Wei et al., 2018
E. coli BL21(DE3)Expression of hopA and hopB (squalene/phytoene synthases) together with hopD (farnesyl diphosphate synthase) from Streptomyces peucetiusND4.1Ghimire et al., 2009
Overexpression of dxs and idi (rate limiting enzymes), expression of hopA and hopB together with hopD from Streptomyces peucetiusND11.8
E. coliExpression of hpnC, hpnD, and hpnE from Zymomonas mobilisNDNDPan et al., 2015
Expression of hpnC, hpnD, and hpnE from Rhodopseudomonas palustrisNDND
E. coli XL1-BlueExpression of human SQS (hSQS)ND4.2Katabami et al., 2015
Co-expression of hSQS, chimeric mevalonate pathway containing tHMGR, ERG13 (hydroxymethylglutaryl-CoA synthase), ERG12 (mevalonate kinase), ERG8 (phosphomevalonate kinase) and MVD1 (mevalonate diphosphate decarboxylase) from S. cerevisiae, overexpression of atoB (acetyl-CoA acetyltransferase), idi (isoprenyl diphosphate isomerise) and ispA (farnesyl diphosphate synthase)54230
Co-expression of Thermosynechococcus elongatus SQS (tSQS), chimeric mevalonate pathway containing tHMGR, ERG13, ERG12, ERG8, and MVD1 from S. cerevisiae, overexpression of atoB, idi, and ispA55150
E. coli XL1-BlueExpression of hSQSND2.7 mg/LFurubayashi et al., 2014a
Synechocystis sp. PCC 6803Disabling shc (squalene hopene cyclase)ND0.67 /OD750Englund et al., 2014
Synechococcuselongatus PCC 7942Overexpression of dxs and idi, expression of ispA from E. coliND4.98 ± 0.90 /OD730Choi et al., 2016
S. elongatus PCC 7942Expression of CpcB1-SQS proteinND7.16 ± 0.05/OD730Choi et al., 2017
Increased gene dosage of CpcB1-SQS by strong endogenous cpcB1 promoterND11.98 ± 0.49 /OD730
Rhodopseudomonas palustris TIE-1Disabling shc3.8NDXu et al., 2016
Disabling shc gene, co-expression of crtE and hpnD12.6ND
Disabling shc gene, co-expression of crtE and hpnD, overexpression of dxs15.8ND
Yarrowia lipolyticaOverexpression of acs (from Salmonella enterica), ylACL1 (encodes acetyl-CoA synthase), and ylHMG13.3NDHuang et al., 2018
Overexpression of acs (from Salmonella enterica), ylACL1 (encodes acetyl-CoA synthase), and ylHMG1, addition of 20mM sodium acetate7ND
Overexpression of acs (from Salmonella enterica), ylACL1 (encodes acetyl-CoA synthase), and ylHMG1, addition of 10mM citrate10ND
Chlamydomonas reinhardtii C-9Overexpression of CrSQS, knocked down CrSQE.0.9-1.1NDKajikawa et al., 2015

Squalene production in engineered microorganisms.

HMGR, HMG-CoA reductase; tHMG1, truncated HMG1; tHMGR, truncated Hydroxymethylglutaryl-CoA reductase.

From Table 1, all squalene values associated with Ryan et al. (2006) work (brazil nut, pecan, pistachio, cashew, and pine nut) have been deleted as the authors consider the values in their original article to be impractical. Also, the concentration of squalene in rape seed and wine lees were mentioned as 17 and 60 mg/100 g DCW, respectively, which has been corrected. For rape seed it is 43.7 mg/100 g and for wine lees it is 6,000 mg/100 g.

In Table 3, some titer values (Mantzouridou et al., 2009; Chen et al., 2010; Fan et al., 2010) were mistakenly stated incorrectly following errors while converting units. In the case of Mantzouridou et al. (2009), the titers were incorrectly provided as “2.96*103 and 3.12*103 g/L” while they should be “2.96*10−3 and 3.12*10−3” g/L, respectively. As for Fan et al. (2010), the corrected titer value is “2.21*10−3” instead of “21.2 g/L.” Additionally, the biomass weight was earlier stated as “No Data (ND)” but it was later found to be “0.37 mg/g” dry cell weight (DCW) when the glucose concentration was 30 g/L. Lastly, for Chen et al. (2010), the titer was incorrectly provided as “5.90 g/L” while it is “5.90*10−3 g/L.” The work of Kaya et al. (2011) has been cited again in Table 3 (cited priorly in Table 2) pertaining to its fermentation parameter optimization.

As for Table 4, the squalene biomass and yield values under Paramasivan and Mutturi's work 2017 have been corrected. Upon correction, the squalene biomass and yield in presence and absence of mitochondrial presequence have been labeled separately. The squalene biomass with the mitochondrial sequence happens to be 58.6 ± 1.43 mg/g DCW, while the yield is 28.4 ± 1.08 mg/L. Squalene biomass and yield without the mitochondrial presequence is 33.0 ± 2.96 mg/g DCW and 46.0 ± 4.08 mg/L, respectively.

The corrected Tables 1, 3, and 4 appear below.

Additionally, there were errors in the text. Following the deletion of Ryan et al.'s work from Table 1, paragraph 2 under “Squalene From Plants” has been reformed as follows:

“Rice bran, a co-product of the rice milling process also contains a good amount (318.9–320 mg/100 g) of squalene (Rukmini and Raghuram, 1991; Pokkanta et al., 2019). 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. 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. Some nuts also contain small amounts of squalene, including brazil nut (145.8 mg/100 g) (Derewiaka et al., 2014), peanut (27.4–132.9 mg/100 g) (Frega et al., 1992; Tuberoso et al., 2007; Pokkanta et al., 2019), hazelnut (9.3–39.2 mg/100 g) (Frega et al., 1992; Bada et al., 2004; Derewiaka et al., 2014), macadamia (7.2–38.3 mg/100 g) (Maguire et al., 2004; Wall, 2010; Derewiaka et al., 2014), pecan (20.8–29.8 mg/100 g) (Derewiaka et al., 2014; Fernandes et al., 2017), pistachio (5.5–22.6 mg/100 g) (Derewiaka et al., 2014; Salvo et al., 2017), cashew (11.6 mg/100 g) (Derewiaka et al., 2014), almond (1.3–9.6 mg/100 g) (Liu et al., 1976; Fernandes et al., 2017), and walnut (0.09–0.94 mg/100 g).”

Following the correction in the concentration of squalene in rape seed in Table 1, the value of the same in the manuscript (“Squalene From Plants”; paragraph 3) been corrected as 43.7 mg of squalene per 100 gm DCW.

Additionally, in paragraph 4, the following correction has been made: “Similarly, soybean, sunflower, canola, and palm fatty acid distillates encompass about 18–35, 43–45, 30–35, and 2–13 g/kg of squalene, respectively (Naziri et al., 2011b)” has been changed to “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).”

Two corrections have been made in “Fermentation Optimization for Squalene Production.” In paragraph 2, “The maximum squalene production was noted to be 2.97 ± 0.12 and 3.13 ± 0.11 mg/L, whilst productivity of 0.10±0.04 and 0.16±0.05 mg/L/h was gained for S. cerevisiae BY4741 and EGY48, respectively (Mantzouridou et al., 2009).” has been changed to “The maximum squalene production was noted to be 2.97 ± 0.12 and 3.13 ± 0.11 mg/L, whilst productivity of 0.10 and 0.16 mg/L/h was gained for S. cerevisiae BY4741 and EGY48, respectively (Mantzouridou et al., 2009).”.

In paragraph 3, It was stated “In an experiment, squalene content was lifted to 21.2 g/L with a glucose concentration of 60 g/L.” while it should be “In an experiment, squalene content was lifted to 2.21 mg/L with a glucose concentration of 30 g/L.”

In “EngineeringSaccharomyces cerevisiae for Squalene Production”, paragraph 2, “Additionally, this has been further improved to 250 mg/L by expressing the truncated HMGR (tHMGR) gene (Zhuang and Chappell, 2015).” has been changed to “Additionally, this has been further improved to 270 mg/L by expressing the truncated HMGR (tHMGR) gene (Zhuang and Chappell, 2015)”. Additionally, in paragraph 3, “Eventually, the complete biosynthetic pathway for squalene was overexpressed and that obtained a yield reaching as high as 304.09 mg/L (Rasool et al., 2016a).” has been changed to “Eventually, the complete biosynthetic pathway for squalene was overexpressed and that obtained a yield reaching as high as 304.49 mg/L (Rasool et al., 2016a).”

The authors apologize for these errors and state that this does not change the scientific conclusions of the article in any way. The original article has been updated.

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Summary

Keywords

squalene, metabolic engineering, fermentation, biosynthesis, production, synthetic biology, anti-oxidant, anti-aging

Citation

Gohil N, Bhattacharjee G, Khambhati K, Braddick D and Singh V (2019) Corrigendum: Engineering Strategies in Microorganisms for the Enhanced Production of Squalene: Advances, Challenges and Opportunities. Front. Bioeng. Biotechnol. 7:114. doi: 10.3389/fbioe.2019.00114

Received

08 April 2019

Accepted

07 May 2019

Published

28 May 2019

Volume

7 - 2019

Edited by

Pablo Carbonell, University of Manchester, United Kingdom

Reviewed by

Yan Xiao, Qingdao Institute of Bioenergy and Bioprocess Technology (CAS), China

Updates

Copyright

© 2019 Gohil, Bhattacharjee, Khambhati, Braddick and Singh.

This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

*Correspondence: Vijai Singh ;

This article was submitted to Synthetic Biology, a section of the journal Frontiers in Bioengineering and Biotechnology

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All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.

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