Research advances on arachidonic acid production by fermentation and genetic modification of Mortierella alpina.
Arachidonic acid
Biosynthesis
Environmental conditions
Metabolic engineering strategy
Mortierella alpine
Journal
World journal of microbiology & biotechnology
ISSN: 1573-0972
Titre abrégé: World J Microbiol Biotechnol
Pays: Germany
ID NLM: 9012472
Informations de publication
Date de publication:
04 Jan 2021
04 Jan 2021
Historique:
received:
14
08
2020
accepted:
20
12
2020
entrez:
4
1
2021
pubmed:
5
1
2021
medline:
10
7
2021
Statut:
epublish
Résumé
Arachidonic acid (ARA, 5, 8, 11, 14-cis-eicosatetraenoic acid) is a relevant ω-6 polyunsaturated fatty acid, which plays essential roles in human immune, cardiovascular, and nervous systems. It is widely used in medicine, cosmetics, nutrition, and other fields. Traditionally, ARA is obtained from animal tissues. However, due to the limitation and unsustainability of existing resources, microorganisms are a potential alternative resource for ARA production. In this regard, major efforts have been made on algae and filamentous fungi, among which Mortierella alpina is the most effective strain for industrial ARA production. In this review, we summarized the recent progress in enhancing M. alpina production by optimization of culture medium and fermentation process and genetic modification. In addition, we provided perspectives in synthetic biology methods and technologies to further increase ARA production.
Identifiants
pubmed: 33392832
doi: 10.1007/s11274-020-02984-2
pii: 10.1007/s11274-020-02984-2
doi:
Substances chimiques
Culture Media
0
Arachidonic Acid
27YG812J1I
Oxygen
S88TT14065
Types de publication
Journal Article
Review
Langues
eng
Sous-ensembles de citation
IM
Pagination
4Subventions
Organisme : National Key Research and Development Program
ID : 2016YFA0601400
Organisme : Natural Science Foundation of Shandong Province (CN)
ID : ZR2018ZB0208
Organisme : Key Technology Research and Development Program of Shandong
ID : 2019GHY112006
Organisme : Key Deployment Project of Centre for Ocean Mega-Research of Science
ID : COMS2019J07
Références
Ando A, Sakuradani E, Horinaka K, Ogawa J, Shimizu S (2009a) Transformation of an oleaginous zygomycete Mortierella alpina 1S–4 with the carboxin resistance gene conferred by mutation of the iron-sulfur subunit of succinate dehydrogenase. Curr Genet 55:349–356. https://doi.org/10.1007/s00294-009-0250-1
doi: 10.1007/s00294-009-0250-1
pubmed: 19466416
Ando A, Sumida Y, Negoro H, Suroto DA, Ogawa J, Sakuradani E, Shimizu S (2009b) Establishment of Agrobacterium tumefaciens-mediated transformation of an oleaginous fungus, Mortierella alpina 1S–4, and its application for eicosapentaenoic acid producer breeding. Appl Environ Microbiol 75:5529–5535. https://doi.org/10.1128/AEM.00648-09
doi: 10.1128/AEM.00648-09
pubmed: 19581481
pmcid: 2737901
Béligon V, Christophe G, Fontanille P, Larroche C (2016) Microbial lipids as potential source to food supplements. Curr Opin Food Sci 7:35–42. https://doi.org/10.1016/j.cofs.2015.10.002
doi: 10.1016/j.cofs.2015.10.002
Bellou S, Triantaphyllidou IE, Aggeli D, Elazzazy AM, Baeshen MN, Aggelis G (2016) Microbial oils as food additives: recent approaches for improving microbial oil production and its polyunsaturated fatty acid content. Curr Opin Biotechnol 37:24–35. https://doi.org/10.1016/j.copbio.2015.09.005
doi: 10.1016/j.copbio.2015.09.005
pubmed: 26431717
Brenna JT (2016) Arachidonic acid needed in infant formula when docosahexaenoic acid is present. Nutr Rev 74:329–336. https://doi.org/10.1093/nutrit/nuw007
doi: 10.1093/nutrit/nuw007
pubmed: 27013482
Burns JL, Nakamura MT, Ma DWL (2018) Differentiating the biological effects of linoleic acid from arachidonic acid in health and disease Prostaglandins. Leukot Essent Fatty Acids 135:1–4. https://doi.org/10.1016/j.plefa.2018.05.004
doi: 10.1016/j.plefa.2018.05.004
Carlson SE, Colombo J (2016) Docosahexaenoic acid and arachidonic acid nutrition in early development. Adv Pediatr 63:453–471. https://doi.org/10.1016/j.yapd.2016.04.011
doi: 10.1016/j.yapd.2016.04.011
pubmed: 27426911
pmcid: 5207030
Dedyukhina EG, Chistyakova TI, Mironov AA, Kamzolova SV, Minkevich IG, Vainshtein MB (2015) The effect of pH, aeration, and temperature on arachidonic acid synthesis by Mortierella alpina. Appl Biochem Micro 51:242–248. https://doi.org/10.1134/s0003683815020040
doi: 10.1134/s0003683815020040
Diao J, Song X, Guo T, Wang F, Chen L, Zhang W (2020) Cellular engineering strategies toward sustainable omega-3 long chain polyunsaturated fatty acids production: State of the art and perspectives. Biotechnol Adv 40:107497. https://doi.org/10.1016/j.biotechadv.2019.107497
doi: 10.1016/j.biotechadv.2019.107497
pubmed: 31830520
Eroshin VK, Satroutdinov AD, Dedyukhina EG, Chistyakova TI (2000) Arachidonic acid production by Mortierella alpina with growth-coupled lipid synthesis. Process Biochem 35:1171–1175. https://doi.org/10.1016/S0032-9592(00)00151-5
doi: 10.1016/S0032-9592(00)00151-5
Fu Y, Liu X, Zhou B, Jiang AC, Chai L (2016) An updated review of worldwide levels of docosahexaenoic and arachidonic acid in human breast milk by region. Public Health Nutr 19:2675–2687. https://doi.org/10.1017/S1368980016000707
doi: 10.1017/S1368980016000707
pubmed: 27056340
Hadley KB, Ryan AS, Forsyth S, Gautier S, Salem N Jr (2016) The essentiality of arachidonic acid in infant development. Nutrients 8:216. https://doi.org/10.3390/nu8040216
doi: 10.3390/nu8040216
pubmed: 27077882
pmcid: 4848685
Hao G et al (2014) Role of malic enzyme during fatty acid synthesis in the oleaginous fungus Mortierella alpina. Appl Environ Microbiol 80:2672–2678. https://doi.org/10.1128/AEM.00140-14
doi: 10.1128/AEM.00140-14
pubmed: 24532075
pmcid: 3993310
Hao G, Chen H, Gu Z, Zhang H, Chen W, Chen YQ, Cullen D (2016) Metabolic engineering of Mortierella alpina for enhanced arachidonic acid production through the NADPH-supplying strategy. Appl Environ Microb 82:3280–3288. https://doi.org/10.1128/aem.00572-16
doi: 10.1128/aem.00572-16
Harwood JL, Guschina IA (2009) The versatility of algae and their lipid metabolism. Biochimie 91:679–684. https://doi.org/10.1016/j.biochi.2008.11.004
doi: 10.1016/j.biochi.2008.11.004
pubmed: 19063932
Hayashi S, Naka M, Ikeuchi K, Ohtsuka M, Kobayashi K, Satoh Y et al (2019) Control mechanism for carbon-chain length in polyunsaturated fatty-acid synthases. Angew Chem Int Ed Engl 58:6605–6610
doi: 10.1002/anie.201900771
Ho S-Y, Chen F (2008) Lipid characterization of Mortierella alpina grown at different NaCl concentrations. J Agr Food Chem 56:7903–7909. https://doi.org/10.1021/jf801404y
doi: 10.1021/jf801404y
Hosoya S, Arunpairojana V, Suwannachart C, Kanjana-Opas A, Yokota A (2006) Aureispira marina gen. nov., sp. nov., a gliding, arachidonic acid-containing bacterium isolated from the southern coastline of Thailand. Int J Syst Evol Microbiol 56:2931–2935
doi: 10.1099/ijs.0.64504-0
Huang M et al (2020) Two-stage pH control combined with oxygen-enriched air strategies for the highly efficient production of EPA by Mortierella alpina CCFM698 with fed-batch fermentation. Bioprocess Biosyst Eng 43:1725–1733. https://doi.org/10.1007/s00449-020-02367-9
doi: 10.1007/s00449-020-02367-9
pubmed: 32377940
Hwang BH, Kim JW, Park CY, Park CS, Kim YS, Ryu YW (2005) High-level production of arachidonic acid by fed-batch culture of Mortierella alpina using NH
doi: 10.1007/s10529-005-5362-1
pubmed: 16049743
Ji XJ, Zhang AH, Nie ZK, Wu WJ, Ren LJ, Huang H (2014) Efficient arachidonic acid-rich oil production by Mortierella alpina through a repeated fed-batch fermentation strategy. Bioresour Technol 170:356–360. https://doi.org/10.1016/j.biortech.2014.07.098
doi: 10.1016/j.biortech.2014.07.098
pubmed: 25151081
Jin MJ, Huang H, Xiao AH, Gao Z, Liu X, Peng C (2009) Enhancing arachidonic acid production by Mortierella alpina ME-1 using improved mycelium aging technology. Bioprocess Biosyst Eng 32:117–122. https://doi.org/10.1007/s00449-008-0229-1
doi: 10.1007/s00449-008-0229-1
pubmed: 18481102
Kawashima H (2019) Intake of arachidonic acid-containing lipids in adult humans: dietary surveys and clinical trials. Lipids Health Dis 18:101. https://doi.org/10.1186/s12944-019-1039-y
doi: 10.1186/s12944-019-1039-y
pubmed: 30992005
pmcid: 6469145
Kenichi Higashiyama SF, Park EY, Shimizu S (2002) Production of arachidonic acid by Mortierella fungi. Biotechnol Bioprocess Eng 7:252–262
doi: 10.1007/BF02932833
Kikukawa H, Sakuradani E, Ando A, Okuda T, Ochiai M, Shimizu S, Ogawa J (2015) Disruption of lig4 improves gene targeting efficiency in the oleaginous fungus Mortierella alpina 1S–4. J Biotechnol 208:63–69. https://doi.org/10.1016/j.jbiotec.2015.05.020
doi: 10.1016/j.jbiotec.2015.05.020
pubmed: 26052021
Kikukawa H, Sakuradani E, Ando A, Shimizu S, Ogawa J (2018) Arachidonic acid production by the oleaginous fungus Mortierella alpina 1S–4: a review. J Adv Res 11:15–22. https://doi.org/10.1016/j.jare.2018.02.003
doi: 10.1016/j.jare.2018.02.003
pubmed: 30034872
pmcid: 6052653
Koike Y, Cai HJ, Higashiyama K, Fujikawa S, Park EY (2001) Effect of consumed carbon to nitrogen ratio of mycelial morphology and arachidonic acid production in cultures of Mortierella alpina. J Biosci Bioeng 91:382–389
doi: 10.1016/S1389-1723(01)80156-0
Koizumi K, Higashiyama K, Park EY (2006) Effects of amino acid on morphological development and nucleus formation of arachidonic acid-producing filamentous micro-organism, Mortierella alpina. J Appl Microbiol 100:885–892. https://doi.org/10.1111/j.1365-2672.2005.02820.x
doi: 10.1111/j.1365-2672.2005.02820.x
pubmed: 16553746
Levering J, Broddrick J, Zengler K (2015) Engineering of oleaginous organisms for lipid production. Curr Opin Biotechnol 36:32–39. https://doi.org/10.1016/j.copbio.2015.08.001
doi: 10.1016/j.copbio.2015.08.001
pubmed: 26319892
Li X, Lin Y, Chang M, Jin Q, Wang X (2015a) Efficient production of arachidonic acid by Mortierella alpina through integrating fed-batch culture with a two-stage pH control strategy. Bioresour Technol 181:275–282. https://doi.org/10.1016/j.biortech.2015.01.009
doi: 10.1016/j.biortech.2015.01.009
pubmed: 25661306
Li X, Liu R, Li J, Chang M, Liu Y, Jin Q, Wang X (2015b) Enhanced arachidonic acid production from Mortierella alpina combining atmospheric and room temperature plasma (ARTP) and diethyl sulfate treatments. Bioresour Technol 177:134–140. https://doi.org/10.1016/j.biortech.2014.11.051
doi: 10.1016/j.biortech.2014.11.051
pubmed: 25484124
Liang MH, Jiang JG (2013) Advancing oleaginous microorganisms to produce lipid via metabolic engineering technology. Prog Lipid Res 52:395–408. https://doi.org/10.1016/j.plipres.2013.05.002
doi: 10.1016/j.plipres.2013.05.002
pubmed: 23685199
Lu J, Peng C, Ji XJ, You J, Cong L, Ouyang P, Huang H (2011) Fermentation characteristics of Mortierella alpina in response to different nitrogen sources. Appl Biochem Biotechnol 164:979–990. https://doi.org/10.1007/s12010-011-9189-z
doi: 10.1007/s12010-011-9189-z
pubmed: 21336613
Mackenzie D, Wongwathanarat P, Carte A, Archer D (2000) Isolation and use of a homologous histone H4 promoter and a ribosomal DNA region in a transformation vector for the oil-producing fungus Mortierella alpina. Appl Environ Microbiol 66:4655–4661
doi: 10.1128/AEM.66.11.4655-4661.2000
Malaiwong N, Yongmanitchai W, Chonudomkul D (2016) Optimization of arachidonic acid production from Mortierella alpina PRAO7-10 by response surface methodology. Agric Nat Resour 50:162–172. https://doi.org/10.1016/j.anres.2016.06.003
doi: 10.1016/j.anres.2016.06.003
Mamani LDG, Magalhães AI, Ruan Z, Carvalho JCd, Soccol CR (2019) Industrial production, patent landscape, and market trends of arachidonic acid-rich oil of Mortierella alpina. Biotechnol Res Innov 3:103–119. https://doi.org/10.1016/j.biori.2019.02.002
doi: 10.1016/j.biori.2019.02.002
Martin SA, Brash AR, Murphy RC (2016) The discovery and early structural studies of arachidonic acid. J Lipid Res 57:1126–1132. https://doi.org/10.1194/jlr.R068072
doi: 10.1194/jlr.R068072
pubmed: 27142391
pmcid: 4918860
Meng H, Liu Y, Lai L (2015) Diverse ways of perturbing the human arachidonic acid metabolic network to control inflammation. Acc Chem Res 48:2242–2250. https://doi.org/10.1021/acs.accounts.5b00226
doi: 10.1021/acs.accounts.5b00226
pubmed: 26237215
Nakamura H, Murayama T (2014) The role of sphingolipids in arachidonic acid metabolism. J Pharmacol Sci 124:307–312. https://doi.org/10.1254/jphs.13R18CP
doi: 10.1254/jphs.13R18CP
pubmed: 24599139
Nie ZK, Ji XJ, Shang JS, Zhang AH, Ren LJ, Huang H (2014) Arachidonic acid-rich oil production by Mortierella alpina with different gas distributors. Bioprocess Biosyst Eng 37:1127–1132. https://doi.org/10.1007/s00449-013-1104-2
doi: 10.1007/s00449-013-1104-2
pubmed: 24374968
Nisha A, Venkateswaran G (2011) Effect of culture variables on mycelial arachidonic acid production by Mortierella alpina. Food Bioprocess Technol 4:232–240. https://doi.org/10.1007/s11947-008-0146-y
doi: 10.1007/s11947-008-0146-y
O’Conner DL, Hall R, Adamkin D, Austad N, Castillo M, Conner WE, Conner SJ (2001) Growth and development in preterm infants fed long-chain polyunsaturated fatty acids. A prospective randomized controlled trial. Pediatrics 108(2):359–371
doi: 10.1542/peds.108.2.359
Okuda T et al (2014) Selection and characterization of promoters based on genomic approach for the molecular breeding of oleaginous fungus Mortierella alpina 1S–4. Curr Genet 60:183–191. https://doi.org/10.1007/s00294-014-0423-4
doi: 10.1007/s00294-014-0423-4
pubmed: 24562865
Okuda T et al (2014) Characterization of galactose-dependent promoters from an oleaginous fungus Mortierella alpina 1S–4. Curr Genet 60:175–182. https://doi.org/10.1007/s00294-014-0422-5
doi: 10.1007/s00294-014-0422-5
pubmed: 24549368
Peng C et al (2010) A temperature-shift strategy for efficient arachidonic acid fermentation by Mortierella alpina in batch culture. Biochem Eng J 53:92–96. https://doi.org/10.1016/j.bej.2010.09.014
doi: 10.1016/j.bej.2010.09.014
Qiu X, Xie X, Meesapyodsuk D (2020) Molecular mechanisms for biosynthesis and assembly of nutritionally important very long chain polyunsaturated fatty acids in microorganisms. Prog Lipid Res 79:101047. https://doi.org/10.1016/j.plipres.2020.101047
doi: 10.1016/j.plipres.2020.101047
pubmed: 32540152
Ratledge C (2014) The role of malic enzyme as the provider of NADPH in oleaginous microorganisms: a reappraisal and unsolved problems. Biotechnol Lett 36(8):1557–1568. https://doi.org/10.1007/s10529-014-1532-3
doi: 10.1007/s10529-014-1532-3
pubmed: 24752812
Raychaudhuri S, Young BP, Espenshade PJ, Loewen C Jr (2012) Regulation of lipid metabolism: a tale of two yeasts. Curr Opin Cell Biol 24:502–508. https://doi.org/10.1016/j.ceb.2012.05.006
doi: 10.1016/j.ceb.2012.05.006
pubmed: 22694927
pmcid: 4339016
Richard C, Lewis ED, Field CJ (2016) Evidence for the essentiality of arachidonic and docosahexaenoic acid in the postnatal maternal and infant diet for the development of the infant’s immune system early in life. Appl Physiol Nutr Metab 41:461–475. https://doi.org/10.1139/apnm-2015-0660
doi: 10.1139/apnm-2015-0660
pubmed: 27138971
Šajbidor J, Koželouhov’a D, Ĉert’ik M (1992) Influence of some metal ions on the lipid content and arachidonic acid production by Mortierella sp. Folia Microbiol 37:404–406. https://doi.org/10.1007/BF02899897
doi: 10.1007/BF02899897
Sakuradani E (2010) Advances in the production of various polyunsaturated fatty acids through Oleaginous Fungus Mortierella alpina breeding. Biosci Biotechnol Biochem 74:908–917. https://doi.org/10.1271/bbb.100001
doi: 10.1271/bbb.100001
pubmed: 20460719
Sakuradani E, Shimizu S (2009) Single cell oil production by Mortierella alpina. J Biotechnol 144:31–36. https://doi.org/10.1016/j.jbiotec.2009.04.012
doi: 10.1016/j.jbiotec.2009.04.012
pubmed: 19409938
Shanab SMM, Hafez RM, Fouad AS (2018) A review on algae and plants as potential source of arachidonic acid. J Adv Res 11:3–13. https://doi.org/10.1016/j.jare.2018.03.004
doi: 10.1016/j.jare.2018.03.004
pubmed: 30034871
pmcid: 6052662
Sonnweber T, Pizzini A, Nairz M, Weiss G, Tancevski I (2018) Arachidonic acid metabolites in cardiovascular and metabolic diseases. Int J Mol Sci. https://doi.org/10.3390/ijms19113285
doi: 10.3390/ijms19113285
pubmed: 30360467
pmcid: 6274989
Takeno S, Sakuradani E, Murata S, Inohara-Ochiai M, Kawashima H, Ashikari T, Shimizu S (2004a) Cloning and sequencing of the ura3 and ura5 genes, and isolation and characterization of uracil auxotrophs of the fungus Mortierella alpina 1S–4. Biosci Biotechnol Biochem 68:277–285. https://doi.org/10.1271/bbb.68.277
doi: 10.1271/bbb.68.277
pubmed: 14981288
Takeno S, Sakuradani E, Murata S, Inohara-Ochiai M, Kawashima H, Ashikari T, Shimizu S (2004b) Establishment of an overall transformation system for an oil-producing filamentous fungus, Mortierella alpina 1S–4. Appl Microbiol Biotechnol 65:419–425. https://doi.org/10.1007/s00253-004-1622-6
doi: 10.1007/s00253-004-1622-6
pubmed: 15138730
Takeno S, Sakuradani E, Tomi A, Inohara-Ochiai M, Kawashima H, Shimizu S (2005) Transformation of oil-producing fungus, Mortierella alpina 1S–4, using zeocin, and application to arachidonic acid production. J Biosci Bioeng 100:617–622. https://doi.org/10.1263/jbb.100.617
doi: 10.1263/jbb.100.617
pubmed: 16473770
Wang H et al (2016) Role of dihydrofolate reductase in tetrahydrobiopterin biosynthesis and lipid metabolism in the oleaginous fungus Mortierella alpina. Microbiology (Reading) 162:1544–1553. https://doi.org/10.1099/mic.0.000345
doi: 10.1099/mic.0.000345
Wang Y, Tang X, Wang S, Zhang H, Chen YQ, Chen H, Chen W (2020) Application of the cbh1 promoter in Mortierella alpina and optimization of induction conditions. Lett Appl Microbiol 71:164–170. https://doi.org/10.1111/lam.13300
doi: 10.1111/lam.13300
pubmed: 32306412
Wu WJ et al (2015) Lipid characterization of an arachidonic acid-rich oil producing fungus Mortierella alpina. Chin J Chem Eng 23:1183–1187. https://doi.org/10.1016/j.cjche.2015.04.015
doi: 10.1016/j.cjche.2015.04.015
Wu WJ et al (2017) An efficient multi-stage fermentation strategy for the production of microbial oil rich in arachidonic acid in Mortierella alpina. Bioresour Bioprocess 4:8. https://doi.org/10.1186/s40643-017-0138-8
doi: 10.1186/s40643-017-0138-8
pubmed: 28163995
pmcid: 5243910
Yarla NS et al (2016) Targeting arachidonic acid pathway by natural products for cancer prevention and therapy. Semin Cancer Biol 40–41:48–81. https://doi.org/10.1016/j.semcancer.2016.02.001
doi: 10.1016/j.semcancer.2016.02.001
You JY et al (2011) Enzymatic hydrolysis and extraction of arachidonic acid rich lipids from Mortierella alpina. Bioresour Technol 102:6088–6094. https://doi.org/10.1016/j.biortech.2011.01.074
doi: 10.1016/j.biortech.2011.01.074
pubmed: 21377361
Yu AQ, Zhu JC, Zhang B, Xing LJ, Li M (2011) Effects of different carbon sources on the growth, fatty acids production, and expression of three desaturase genes of Mortierella alpina ATCC 16266. Curr Microbiol 62:1617–1622. https://doi.org/10.1007/s00284-011-9902-8
doi: 10.1007/s00284-011-9902-8
pubmed: 21365447
Yu Y, Li T, Wu N, Jiang L, Ji X, Huang H (2017) The role of lipid droplets in Mortierella alpina aging revealed by integrative subcellular and whole-cell proteome analysis. Sci Rep 7:43896. https://doi.org/10.1038/srep43896
doi: 10.1038/srep43896
pubmed: 28266581
pmcid: 5339828
Yu Y, Zhang L, Li T, Wu N, Jiang L, Ji X, Huang H (2018) How nitrogen sources influence Mortierella alpina aging: From the lipid droplet proteome to the whole-cell proteome and metabolome. J Proteomics 179:140–149. https://doi.org/10.1016/j.jprot.2018.03.014
doi: 10.1016/j.jprot.2018.03.014
pubmed: 29567293
Zhang H, Feng Y, Cui Q, Song X (2017) Expression of Vitreoscilla hemoglobin enhances production of arachidonic acid and lipids in Mortierella alpina. BMC Biotechnol 17:68. https://doi.org/10.1186/s12896-017-0388-8
doi: 10.1186/s12896-017-0388-8
pubmed: 28854910
pmcid: 5577678
Zhang H, Lu D, Li X, Feng Y, Cui Q, Song X (2018) Heavy ion mutagenesis combined with triclosan screening provides a new strategy for improving the arachidonic acid yield in Mortierella alpina. BMC Biotechnol 18:23. https://doi.org/10.1186/s12896-018-0437-y
doi: 10.1186/s12896-018-0437-y
pubmed: 29716562
pmcid: 5930740
Zhang H, Wang Z, Feng Y, Cui Q, Song X (2019) Phytohormones as stimulators to improve arachidonic acid biosynthesis in Mortierella alpina. Enzyme Microb Technol 131:109381. https://doi.org/10.1016/j.enzmictec.2019.109381
doi: 10.1016/j.enzmictec.2019.109381
pubmed: 31615662
Zorn K, Oroz-Guinea I, Brundiek H, Bornscheuer UT (2016) Engineering and application of enzymes for lipid modification, an update. Prog Lipid Res 63:153–164. https://doi.org/10.1016/j.plipres.2016.06.001
doi: 10.1016/j.plipres.2016.06.001
pubmed: 27301784