Abstract
Alpha ketoglutaric acid is a biological compound found naturally in the human body. It plays an important role in the cell metabolism and has a role in various metabolic pathways including Kreb’s cycle, protein metabolism and so on. Keto glutaric acid is chemically prepared from succinic acid and oxalic acid. It is a direct precursor of glutamic acid and triazines. It can be produced by oxidative decarboxylation of isocitrate by isocitrate dehydrogenase. The yeast Yarrowia lipolytica is used as a prospective producer of alpha ketoglutaric acid from ethanol. The capability to synthesize Keto glutaric acid has so far been investigated for many microorganisms such as Pseudomonas fluoroscens , Bacillus subtilis etc. P. fluoroscens have the ability to synthesize a huge amount of alpha ketoglutaric acid in a glycerol medium supplemented with manganese (Mn). The Mangnese has a significant impact on glycerol metabolism resulting in the buildup of alpha ketoglutaric acid. The metabolism of succinate may result in the production of alpha ketoglutarate. Despite its importance in TCA cycle, alpha ketoglutaric acid buildup as an intermediate product of bacterial glucose oxidation. Along with chemical synthesis and microbial fermentation, enzymatic transformation can also be used to produce alpha ketoglutaric acid. Biodiesel waste is considered as cheap and renewable carbon source for the development of alpha ketoglutaric acid. Alpha ketoglutarate is used for kidney disease, intestinal and stomach disorders and many other conditions. It also plays an important role in the food industry as food and nutrient enhancers. The review is covering all the aspects related with the Alpha ketoglutaric acid production, utilization and product recovery.
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Author contributions: All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.
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Research funding: None declared.
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Conflict of interest statement: The authors declare no conflicts of interest regarding this article.
References
1. Szczygiełda, M, Prochaska, K. Alpha-ketoglutaric acid production using electrodialysis with bipolar membrane. J Membr Sci 2017;536:37–43.10.1016/j.memsci.2017.04.059Search in Google Scholar
2. Bak, LK, Schousboe, A, Waagepetersen, HS. The glutamate/GABA-glutamine cycle: aspects of transport, neurotransmitter homeostasis and ammonia transfer. J Neurochem 2006;98:641–53. https://doi.org/10.1111/j.1471-4159.2006.03913.x.Search in Google Scholar PubMed
3. Burdyliuk, N, Bayliak, M. Effects of long-term cultivation on medium with alpha-ketoglutarate supplementation on metabolic processes of Saccharomyces cerevisiae. J Aging Res 2017;2017:8754879. https://doi.org/10.1155/2017/8754879.Search in Google Scholar PubMed PubMed Central
4. Velvizhi, S, Nagalashmi, T, Essa, MM, Dakshayani, KB, Subramanian, P. Effects of α-ketoglutarate on lipid peroxidation and antioxidant status during chronic ethanol administration in wistar rats. Pol J Pharmacol 2002;54:231–6.Search in Google Scholar
5. Wu, D, Fan, Z, Li, J, Zhang, Y, Wang, C, Xu, Q, et al.. Evaluation of alpha-ketoglutarate supplementation on the improvement of intestinal antioxidant capacity and immune response in songpu mirror carp (Cyprinus carpio) after infection with aeromonas hydrophila. Front Immunol 2021;12:1–14. https://doi.org/10.3389/fimmu.2021.690234.Search in Google Scholar PubMed PubMed Central
6. Luo, Z, Yu, S, Zeng, W, Zhou, J. Comparative analysis of the chemical and biochemical synthesis of keto acids. Biotechnol Adv 2021;47:107706. https://doi.org/10.1016/j.biotechadv.2021.107706.Search in Google Scholar PubMed
7. Morgunov, IG, Kamzolova, SV, Samoilenko, VA. Enhanced α-ketoglutaric acid production and recovery in Yarrowia lipolytica yeast by effective pH controlling. Appl Microbiol Biotechnol 2013;97:8711–8. https://doi.org/10.1007/s00253-013-5170-9.Search in Google Scholar PubMed
8. Semkiv, M, Sibirny, A. Yeasts for bioconversion of crude glycerol to high-value chemicals. In Sibirny A, editor. Non-conventional Yeasts: from basic research to application. Cham: Springer; 2019: pp. 389–451. https://doi.org/10.1007/978-3-030-21110-3_12.Search in Google Scholar
9. Zhang, D, Liang, N, Shi, Z, Liu, L, Chen, J, Du, G. Enhancement of α-ketoglutarate production in Torulopsis glabrata: redistribution of carbon flux from pyruvate to α-ketoglutarate. Biotechnol Bioproc Eng 2009;14:134–9. https://doi.org/10.1007/s12257-008-0169-2.Search in Google Scholar
10. Li, Y, Yang, S, Ma, D, Song, W, Gao, C, Liu, L, et al.. Microbial engineering for the production of C2-C6organic acids. Nat Prod Rep 2021;38:1518–46. https://doi.org/10.1039/d0np00062k.Search in Google Scholar PubMed
11. Otto, C, Yovkova, V, Barth, G. Overproduction and secretion of α-ketoglutaric acid by microorganisms. Appl Microbiol Biotechnol 2011;92:689–95. https://doi.org/10.1007/s00253-011-3597-4.Search in Google Scholar PubMed
12. Chernyavskaya, OG, Shishkanova, NV, Il’chenko, AP, Finogenova, TV. Synthesis of α-ketoglutaric acid by Yarrowia lipolytica yeast grown on ethanol. Appl Microbiol Biotechnol 2000;53:152–8. https://doi.org/10.1007/s002530050002.Search in Google Scholar PubMed
13. Zhou, J, Zhou, H, Du, G, Liu, L, Chen, J. Screening of a thiamine-auxotrophic yeast α-ketoglutaric acid overproduction. Lett Appl Microbiol 2010;51:264–71. https://doi.org/10.1111/j.1472-765x.2010.02889.x.Search in Google Scholar
14. Allison, MJ, Robinson, IM. Biosynthesis of alpha-ketoglutarate by the reductive carboxylation of succinate in Bacteroides ruminicola. J Bacteriol 1970;104:50–6. https://doi.org/10.1128/jb.104.1.50-56.1970.Search in Google Scholar PubMed PubMed Central
15. Kitadai, N, Kameya, M, Fujishima, K. Origin of the reductive tricarboxylic acid (RTCA) cycle-type CO2 fixation: a perspective. Life 2017;7:39. https://doi.org/10.3390/life7040039.Search in Google Scholar
16. Watanabe, S, Zimmermann, M, Goodwin, MB, Sauer, U, Barry, CE, Boshoff, HI. Fumarate reductase activity maintains an energized membrane in anaerobic Mycobacterium tuberculosis. PLoS Pathog 2011;7:e1002287. https://doi.org/10.1371/journal.ppat.1002287.Search in Google Scholar PubMed PubMed Central
17. Legendre, F, MacLean, A, Appanna, VP, Appanna, VD. Biochemical pathways to α-ketoglutarate, a multi-faceted metabolite. World J Microbiol Biotechnol 2020;36:1–11. https://doi.org/10.1007/s11274-020-02900-8.Search in Google Scholar PubMed
18. Hujber, Z, Horváth, G, Petovári, G, Krencz, I, Dankó, T, Mészáros, K, et al.. GABA, glutamine, glutamate oxidation and succinic semialdehyde dehydrogenase expression in human gliomas. J Exp Clin Cancer Res 2018;37:1–12. https://doi.org/10.1186/s13046-018-0946-5.Search in Google Scholar PubMed PubMed Central
19. Alhasawi, AA, Thomas, SC, Tharmalingam, S, Legendre, F, Appanna, VD. Isocitrate lyase and succinate semialdehyde dehydrogenase mediate the synthesis of α-ketoglutarate in pseudomonas fluorescens. Front Microbiol 2019;10:1029. https://doi.org/10.3389/fmicb.2019.01929.Search in Google Scholar PubMed PubMed Central
20. Pradima, J, Kulkarni, MR, Archna. Review on enzymatic synthesis of value added products of glycerol, a by-product derived from biodiesel production. Resour Technol 2017;3:394–405. https://doi.org/10.1016/j.reffit.2017.02.009.Search in Google Scholar
21. Alhasawi, AA, Appanna, VD. Manganese orchestrates a metabolic shift leading to the increased bioconversion of glycerol into α-ketoglutarate. AIMS Bioeng 2016;4:12–27. https://doi.org/10.3934/bioeng.2017.1.12.Search in Google Scholar
22. Hertz, L. The glutamate-glutamine (GABA) cycle: importance of late postnatal development and potential reciprocal interactions between biosynthesis and degradation. Front Endocrinol 2013;4:1–17. https://doi.org/10.3389/fendo.2013.00059.Search in Google Scholar PubMed PubMed Central
23. Asai, T, Aida, K, Sugisaki, Z, Yakeishi, N. On α-ketoglutaric acid fermentation. J Gen Appl Microbiol 1955;1:308–46. https://doi.org/10.2323/jgam.1.308.Search in Google Scholar
24. Stanier, RY. Acetic acid production from ethanol by fluorescent pseudomonads. J Bacteriol 1947;54:191–4. https://doi.org/10.1128/jb.54.2.191-194.1947.Search in Google Scholar PubMed PubMed Central
25. Liu, L, Chen, J. Systems and synthetic biotechnology for production of nutraceuticals. Singapore: Springer Nature; 2019:1–208 p.10.1007/978-981-15-0446-4Search in Google Scholar
26. Katagiri, H, Tochikura, T, Imai, K. Microbiological studies of coli-aerogenes bacteria: Part IV. Production of α-ketoglutaric acid. J Agric Chem Soc Jpn 1957;21:351–6. https://doi.org/10.1271/bbb1924.21.351.Search in Google Scholar
27. Park, SA, Bhatia, SK, Park, HA, Kim, SY, Sudheer, PDVN, Yang, YH, et al.. Bacillus subtilis as a robust host for biochemical production utilizing biomass. Crit Rev Biotechnol 2021;41:827–48. https://doi.org/10.1080/07388551.2021.1888069.Search in Google Scholar PubMed
28. Du, G, Liu, L, Chen, J. White biotechnology for organic acids. In: Pandey A, Höfer R, Taherzadeh M, Nampoothiri KM, Larroche C, editors. Industrial biorefineries and white biotechnology. Amsterdam: Netherlands: Elsevier; 2015: pp. 409–444.10.1016/B978-0-444-63453-5.00013-6Search in Google Scholar
29. Gonçalves, FAG, Colen, G, Takahashi, JA. Takahashi JA. Yarrowia lipolytica and its multiple applications in the biotechnological industry. Sci World J 2014;2014:476207.10.1155/2014/476207Search in Google Scholar PubMed PubMed Central
30. Satyanarayana, T, Kunze, G. Yeast biotechnology: diversity and applications. Dordrecht: Springer; 2009: 744 p.10.1007/978-1-4020-8292-4Search in Google Scholar
31. Rywińska, A, Juszczyk, P, Wojtatowicz, M, Robak, M, Lazar, Z, Tomaszewska, L, et al.. Glycerol as a promising substrate for Yarrowia lipolytica biotechnological applications. Biomass Bioenergy 2013;48:148–66.10.1016/j.biombioe.2012.11.021Search in Google Scholar
32. Groenewald, M, Boekhout, T, Neuvéglise, C, Gaillardin, C, Van Dijck, PWM, Wyss, M. Yarrowia lipolytica: safety assessment of an oleaginous yeast with a great industrial potential. Crit Rev Microbiol 2014;40:187–206. https://doi.org/10.3109/1040841x.2013.770386.Search in Google Scholar
33. Davidow, LS, Apostolakos, D, O’Donnell, MM, Proctor, AR, Ogrydziak, DM, Wing, RA, et al.. Integrative transformation of the yeast Yarrowia lipolytica. Curr Genet 1985;10:39–48. https://doi.org/10.1007/bf00418492.Search in Google Scholar
34. Yu, Z, Du, G, Zhou, J, Chen, J. Enhanced α-ketoglutaric acid production in Yarrowia lipolytica WSH-Z06 by an improved integrated fed-batch strategy. Bioresour Technol 2012;114:597–602. https://doi.org/10.1016/j.biortech.2012.03.021.Search in Google Scholar PubMed
35. Kamzolova, SV, Morgunov, IG. α-Ketoglutaric acid production from rapeseed oil by Yarrowia lipolytica yeast. Appl Microbiol Biotechnol 2013;97:5517–25. https://doi.org/10.1007/s00253-013-4772-6.Search in Google Scholar PubMed
36. Mauersberger, S. Cytochromes p450 of the alkane-utilising yeast Yarrowia lipolytica. In: Barth, G, editor. Yarrowia lipolytica. Berlin, Heidelberg: Springer; 2013:227–62 pp.10.1007/978-3-642-38583-4_8Search in Google Scholar
37. Liu, HH, Ji, XJ, Huang, H. Biotechnological applications of Yarrowia lipolytica: past, present and future. Biotechnol Adv 2015;33:1522–46. https://doi.org/10.1016/j.biotechadv.2015.07.010.Search in Google Scholar PubMed
38. Cybulski, K, Tomaszewska-Hetman, L, Rymowicz, W, Rakicka, M, Rywińska, A. Yarrowia lipolytica application as a prospective approach for biosynthesis of pyruvic acid from glycerol. Chem Pap 2018;72:3077–83. https://doi.org/10.1007/s11696-018-0513-8.Search in Google Scholar
39. Yovkova, V, Otto, C, Aurich, A, Mauersberger, S, Barth, G. Engineering the α-ketoglutarate overproduction from raw glycerol by overexpression of the genes encoding NADP+-dependent isocitrate dehydrogenase and pyruvate carboxylase in Yarrowia lipolytica. Appl Microbiol Biotechnol 2014;98:2003–13. https://doi.org/10.1007/s00253-013-5369-9.Search in Google Scholar PubMed
40. Madzak, C. Yarrowia lipolytica strains and their biotechnological applications: how natural biodiversity and metabolic engineering could contribute to cell factories improvement. J Fungi 2021;7:548. https://doi.org/10.3390/jof7070548.Search in Google Scholar PubMed PubMed Central
41. Wu, J, Fan, X, Liu, J, Luo, Q, Xu, J, Chen, X. Promoter engineering of cascade biocatalysis for α-ketoglutaric acid production by coexpressing l-glutamate oxidase and catalase. Appl Microbiol Biotechnol 2018;102:4755–64. https://doi.org/10.1007/s00253-018-8975-8.Search in Google Scholar PubMed
42. Taylor, PP, Pantaleone, DP, Senkpeil, RF, Fotheringham, IG. Novel biosynthetic approaches to the production of unnatural amino acids using transaminases. Trends Biotechnol 1998;16:412–8. https://doi.org/10.1016/s0167-7799(98)01240-2.Search in Google Scholar PubMed
43. John, RP, Nampoothiri, KM, Pandey, A. Fermentative production of lactic acid from biomass: an overview on process developments and future perspectives. Appl Microbiol Biotechnol 2007;74:524–34. https://doi.org/10.1007/s00253-006-0779-6.Search in Google Scholar PubMed
44. Baek, JO, Seo, JW, Kwon, O, Seong, SI, Kim, IH, Kim, CH. Expression and characterization of a second L-amino acid deaminase isolated from Proteus mirabilis in Escherichia coli. J Basic Microbiol 2011;51:129–35. https://doi.org/10.1002/jobm.201000086.Search in Google Scholar PubMed
45. Hou, Y, Hossain, GS, Li, J, Shindong, H, Liu, L, Du, G. Production of phenylpyruvic acid from l-phenylalanine using an l-amino acid deaminase from Proteus mirabilis: comparison of enzymatic and whole-cell biotransformation approaches. Appl Microbiol Biotechnol 2015;99:8391–402. https://doi.org/10.1007/s00253-015-6757-0.Search in Google Scholar PubMed
46. Liu, L, Hossain, GS, Shin, HD, Li, J, Du, G, Chen, J. One-step production of α-ketoglutaric acid from glutamic acid with an engineered l-amino acid deaminase from Proteus mirabilis. J Biotechnol 2013;164:97–104. https://doi.org/10.1016/j.jbiotec.2013.01.005.Search in Google Scholar PubMed
47. Hossain, GS, Li, J, Shindong, H, Chen, RR, Du, G, Liu, L, et al.. Bioconversion of l-glutamic acid to α-ketoglutaric acid by an immobilized whole-cell biocatalyst expressing l-amino acid deaminase from Proteus mirabilis. J Biotechnol 2014;169:112–20. https://doi.org/10.1016/j.jbiotec.2013.10.026.Search in Google Scholar PubMed
48. Kamzolova, SV, Morgunov, IG. Optimization of medium composition and fermentation conditions for α-ketoglutaric acid production from biodiesel waste by Yarrowia lipolytica. Appl Microbiol Biotechnol 2020;104:7979–89. https://doi.org/10.1007/s00253-020-10805-7.Search in Google Scholar PubMed
49. Cavallo, E, Charreau, H, Cerrutti, P, Foresti, ML. Yarrowia lipolytica: a model yeast for citric acid production. FEMS Yeast Res 2017;17:fox084. https://doi.org/10.1093/femsyr/fox084.Search in Google Scholar PubMed
50. Bergmann, JC, Tupinambá, DD, Costa, OYA, Almeida, JRM, Barreto, CC, Quirino, BF. Biodiesel production in Brazil and alternative biomass feedstocks. Renew Sustain Energy Rev 2013;21:411–20. https://doi.org/10.1016/j.rser.2012.12.058.Search in Google Scholar
51. Markham, KA, Alper, HS. Synthetic biology expands the industrial potential of Yarrowia lipolytica. Trends Biotechnol 2018;36:1085–95. https://doi.org/10.1016/j.tibtech.2018.05.004.Search in Google Scholar PubMed
52. Wenten, IG, Khoiruddin, K, Alkhadra, MA, Tian, H, Bazant, MZ. Novel ionic separation mechanisms in electrically driven membrane processes. Adv Colloid Interface Sci 2020;284:102269. https://doi.org/10.1016/j.cis.2020.102269.Search in Google Scholar PubMed
53. Pourcelly, G. Electrodialysis with bipolar membranes: principles, optimization, and applications. Russ J Electrochem 2002;38:919–26. https://doi.org/10.1023/a:1016882216287.10.1023/A:1016882216287Search in Google Scholar
54. Szczygiełda, M, Prochaska, K. Recovery of alpha-ketoglutaric acid from model fermentation broth using electrodialysis with bipolar membrane. Sep Sci Technol 2020;55:165–75. https://doi.org/10.1080/01496395.2018.1563160.Search in Google Scholar
55. Joshi, SJ, Geetha, SJ. Recent advances in biotechnology. USA: Nova Science Publishers Inc.; 2019:290 p. https://novapublishers.com/shop/recent-advances-in-biotechnology/.Search in Google Scholar
56. Blom, W, Huijmans, JG. Differential diagnosis of (inherited) amino acid metabolism or transport disorders. Amino acids 1992;2:25–67. https://doi.org/10.1007/BF00806075.Search in Google Scholar PubMed
57. Aparicio, M, Bellizzi, V, Chauveau, P, Cupisti, A, Ecder, T, Fouque, D, et al.. Keto acid therapy in predialysis chronic kidney disease patients: final consensus. J Ren Nutr 2012;22:S22–4. https://doi.org/10.1053/j.jrn.2011.09.006.Search in Google Scholar PubMed
58. Song, Y, Li, J, Shindong, H, Liu, L, Du, G, Chen, J. Biotechnological production of alpha-keto acids: current status and perspectives. Bioresour Technol 2016;219:716–24. https://doi.org/10.1016/j.biortech.2016.08.015.Search in Google Scholar PubMed
59. Cappelaere L, Le Cour Grandmaison J, Martin N, Lambert W. Amino acid supplementation to reduce environmental impacts of broiler and pig production. a review. Front Vet Sci 2021;8:689259. https://doi.org/10.3389/fvets.2021.689259.Search in Google Scholar PubMed PubMed Central
60. Coban, HB, Demirci, A, Patterson, PH, Elias, RJ. Screening of phenylpyruvic acid producers and optimization of culture conditions in bench scale bioreactors. Bioproc Biosyst Eng 2014;37:2343–52. https://doi.org/10.1007/s00449-014-1212-7.Search in Google Scholar PubMed
61. Koppe, L, De Oliveira, MC, Fouque, D. Ketoacid analogues supplementation in chronic kidney disease and future perspectives. Nutrients 2019;11:1–20. https://doi.org/10.3390/nu11092071.Search in Google Scholar PubMed PubMed Central
62. Harper, AE. Methods for assessing amino acid requirements and the effectiveness of α keto acid analogs as substitutes for amino acids. Am J Clin Nutr 1978;31:1678–87. https://doi.org/10.1093/ajcn/31.9.1678.Search in Google Scholar PubMed
63. Hidalgo, FJ, Delgado, RM, Zamora, R. Intermediate role of α-keto acids in the formation of Strecker aldehydes. Food Chem 2013;141:1140–6. https://doi.org/10.1016/j.foodchem.2013.03.068.Search in Google Scholar PubMed
64. Montazeri, N, Oliveira, ACM, Himelbloom, BH, Leigh, MB, Crapo, CA. Chemical characterization of commercial liquid smoke products. Food Sci Nutr 2013;1:102–15. https://doi.org/10.1002/fsn3.9.Search in Google Scholar PubMed PubMed Central
65. Gobbetti, M, De Angelis, M, Di Cagno, R, Mancini, L, Fox, PF. Pros and cons for using non-starter lactic acid bacteria (NSLAB) as secondary/adjunct starters for cheese ripening. Trends Food Sci Technol 2015;45:167–78. https://doi.org/10.1016/j.tifs.2015.07.016.Search in Google Scholar
66. Law, BA. Controlled and accelerated cheese ripening: the research base for new technologies. Int Dairy J 2001;11:383–98. https://doi.org/10.1016/s0958-6946(01)00067-x.Search in Google Scholar
67. Yvon, M, Rijnen, L. Cheese flavour formation by amino acid catabolism. Int Dairy J 2001;11:185–201. https://doi.org/10.1016/s0958-6946(01)00049-8.Search in Google Scholar
68. Morocco, AP. Cyanides. Crit Care Clin 2005;21:691–705. https://doi.org/10.1016/j.ccc.2005.06.002.Search in Google Scholar PubMed
69. Satpute, R, Hariharakrishnan, J, Bhattacharya, R. Effect of alpha-ketoglutarate and N-acetyl cysteine on cyanide-induced oxidative stress mediated cell death in PC12 cells. Toxicol Ind Health 2010;26:297–308. https://doi.org/10.1177/0748233710365695.Search in Google Scholar PubMed
70. Wu, N, Yang, M, Gaur, U, Xu, H, Yao, Y, Li, D. Alpha-ketoglutarate: physiological functions and applications. Biomol Ther 2016;24:1–8. https://doi.org/10.4062/biomolther.2015.078.Search in Google Scholar PubMed PubMed Central
71. Tatara, MR, Tygesen, MP, Sawa-Wojtanowicz, B, Krupski, W, Majcher, P, Harrison, AP. Bone development: the effect of short-term alpha-ketoglutarate administration on long-term mechanical properties of ribs in ram lambs. Small Rumin Res 2007;67:179–83. https://doi.org/10.1016/j.smallrumres.2005.09.031.Search in Google Scholar
72. Radzki, RP, Bienko, M, Pierzynowski, SG. Anti-osteopenic effect of alpha-ketoglutarate sodium salt in ovariectomized rats. J Bone Miner Metabol 2012;30:651–9. https://doi.org/10.1007/s00774-012-0377-x.Search in Google Scholar PubMed
73. Wullschleger, S, Loewith, R, Hall, MN. TOR signaling in growth and metabolism. Cell 2006;124:471–84. https://doi.org/10.1016/j.cell.2006.01.016.Search in Google Scholar PubMed
74. Di Micco, R, Krizhanovsky, V, Baker, D, d’Adda di Fagagna, F. Cellular senescence in ageing: from mechanisms to therapeutic opportunities. Nat Rev Mol Cell Biol 2021;22:75–95. https://doi.org/10.1038/s41580-020-00314-w.Search in Google Scholar PubMed PubMed Central
75. Zdzisińska, B, Żurek, A, Kandefer-Szerszeń, M. Alpha-ketoglutarate as a molecule with pleiotropic activity: well-known and novel possibilities of therapeutic use. Arch Immunol Ther Exp 2017;65:21–36. https://doi.org/10.1007/s00005-016-0406-x.Search in Google Scholar PubMed PubMed Central
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