Environmental stress as a strategy to enhance rare sugar composition in bacterial polysaccharides: mechanisms, trends, and biotechnological perspectives

Abstract

Rare sugars such as L-fucose, L-rhamnose, and D-altrose possess diverse biological activities and increasing industrial relevance in pharmaceuticals, food, and biomaterials. Microbial exopolysaccharides (EPS) are a renewable and structurally diverse source of these sugars; however, their natural abundance in EPS is often limited. Emerging evidence shows that environmental stress—such as osmotic pressure, pH variation, nutrient limitation, and temperature shifts—can significantly alter EPS composition and promote the incorporation of rare sugars. This review provides a comprehensive overview of the occurrence and biological significance of these uncommon monosaccharides in bacterial polysaccharides. It highlights the influence of environmental stress on microbial metabolism and EPS structure, with emphasis on stress-induced changes in gene expression, sugar nucleotide biosynthesis, and glycosyltransferase regulation. Biotechnological strategies, including stress-optimized fermentation, co-culture systems, metabolic engineering, and synthetic biology, are also discussed as tools to enhance the biosynthesis and incorporation of structurally distinct sugar residues into the polysaccharide matrix. By integrating insights from microbial physiology, metabolic control, and process engineering, this review underscores the potential of environmental stress as a sustainable and versatile approach for producing rare sugar-enriched EPS. Future research opportunities and current knowledge gaps are also addressed, with a focus on systems-level understanding and translational applications.

Keywords

Exopolysaccharides / Environmental stress / Microbial fermentation / Rare sugars / Sugar nucleotide biosynthesis

References

[1] Wen X, Tesfay MA, Ning Y, Lin H, Liu G, Hu H, Xu X, Jiang X, Zhao C, Ren Y, et al. . Green biotechnological synthesis of rare sugars/alcohols: D-allulose, allitol, D-tagatose, L-xylulose, L-ribose. Food Res Int. 2025, 206: 116058

[2] Tomsik P, Soukup T, Cermakova E, Micuda S, Niang M, Sucha L, Rezacova M. L-rhamnose and L-fucose suppress cancer growth in mice. Cent Eur J Biol. 2011, 6(1): 1-9

[3] Adhikari E, Liu Q, Burton C, Mockabee-Macias A, Lester DK, Lau E. L-fucose, a sugary regulator of antitumor immunity and immunotherapies. Mol Carcinog. 2022, 61(5): 439-53

[4] Nguyen H-T, Pham T-T, Nguyen P-T, Le-Buanec H, Rabetafika HN, Razafindralambo HL. Advances in microbial exopolysaccharides: present and future applications. Biomolecules. 2024;14.https://doi.org/10.3390/biom14091162.

[5] Roca C, Alves VD, Freitas F, Reis MAM. Exopolysaccharides enriched in rare sugars: bacterial sources, production, and applications. Front Microbiol. 2015;6.https://doi.org/10.3389/fmicb.2015.00288.

[6] Nguyen P-T, Nguyen T-T, Vo T-N-T, Nguyen T-T-X, Hoang Q-K, Nguyen H-T. Response of Lactobacillus plantarum VAL6 to challenges of pH and sodium chloride stresses. Sci Rep. 2021, 11(1): 1301

[7] Tho NP, Son LT, Tho NT, Cuong BD, Toan HP, Khanh HQ, Thanh NH. Enhancing the production and monosaccharide composition of exopolysaccharides of Lactobacillus plantarum VAL6 by applying thermal stress and increased carbon dioxide concentration. Microbiology. 2021, 90(4): 527-37

[8] Nguyen P-T, Nguyen T-T, Bui D-C, Hong P-T, Hoang Q-K, Nguyen H-T. Exopolysaccharide production by lactic acid bacteria: the manipulation of environmental stresses for industrial applications. AIMS Microbiol. 2020, 6(4): 451-69

[9] Wenninger M, Poulsen M, Larsen M, Hauser N. Recent progress in the synthesis and glycosylation of rare sugars. Synthesis. 2024;57.https://doi.org/10.1055/s-0043-1775405.

[10] Hernandez-Hernandez O, Sabater C, Calvete-Torre I, Doyagüez EG, Muñoz-Labrador AM, Julio-Gonzalez C, de las Rivas B, Muñoz R, Ruiz L, Margolles A, et al. . Tailoring the natural rare sugars D-tagatose and L-sorbose to produce novel functional carbohydrates. NPJ Sci Food. 2024, 8(1): 74

[11] Li R, Yu H, Chen X. Recent progress in chemical synthesis of bacterial surface glycans. Curr Opin Chem Biol. 2020, 58: 121-36

[12] Kononova S, Litvinova E, Vakhitov T, Skalinskaya M, Sitkin S. Acceptive immunity: the role of fucosylated glycans in human host–microbiome interactions. Int J Mol Sci. 2021;22.https://doi.org/10.3390/ijms22083854.

[13] Mistou M-Y, Sutcliffe IC, van Sorge NM. Bacterial glycobiology: rhamnose-containing cell wall polysaccharides in Gram-positive bacteria. FEMS Microbiol Rev. 2016, 40(4): 464-79

[14] Balzaretti S, Taverniti V, Guglielmetti S, Fiore W, Minuzzo M, Ngo Hansel N, Ngere Judith B, Sadiq S, Humphreys Paul N, Laws Andrew P. A novel rhamnose-rich hetero-exopolysaccharide isolated from Lactobacillus paracasei DG activates THP-1 human monocytic cells. Appl Environ Microbiol. 2017, 83(3): e02702-02716

[15] Zheng M, Zheng MC, Kim H, Lupoli TJ. Feedback Inhibition of bacterial nucleotidyltransferases by rare nucleotide l-sugars restricts substrate promiscuity. J Am Chem Soc. 2023, 145(29): 15632-8

[16] Suzuki K, Ogawa D, Kanda T, Fujimori T, Shibayama Y, Rahman A, Ye J, Ohsaki H, Akimitsu K, Izumori K, et al. . Antiproliferative effects of D-allose associated with reduced cell division frequency in glioblastoma. Sci Rep. 2023, 13(1): 19515

[17] Feofanova NA, Bets VD, Borisova MA, Litvinova EA. L-fucose reduces gut inflammation due to T-regulatory response in Muc2 null mice. PLoS ONE. 2022, 17(12): e0278714

[18] Burton C, Bitaraf A, Snyder K, Zhang C, Yoder SJ, Avram D, Du D, Yu X, Lau EK. The functional role of L-fucose on dendritic cell function and polarization. Front Immunol. 2024;15.https://doi.org/10.3389/fimmu.2024.1353570.

[19] Spriha SE, Rahman SM. A review on biological activities of sugars and sugar derivatives. Dhaka Univ J Pharm Sci. 2022, 20(3): 381-94

[20] Concórdio-Reis P, Alves VD, Moppert X, Guézennec J, Freitas F, Reis MAM. Characterization and biotechnological potential of extracellular polysaccharides synthesized by Alteromonas strains isolated from French Polynesia marine environments. Mar Drugs. 2021;19.https://doi.org/10.3390/md19090522.

[21] Mahmoud YAG, El-Naggar ME, Abdel-Megeed A, El-Newehy M. Recent advancements in microbial polysaccharides: synthesis and applications. Polymers. 2021;13.https://doi.org/10.3390/polym13234136.

[22] Xiao M, Ren X, Yu Y, Gao W, Zhu C, Sun H, Kong Q, Fu X, Mou H. Fucose-containing bacterial exopolysaccharides: sources, biological activities, and food applications. Food Chem X. 2022, 13: 100233

[23] Armiento S, Oglio F, Masino A, Iovine A, Trivelli X, Molinaro A, Guerardel Y, Canani RB, De Castro C. The glycocalyx of Lacticaseibacillus paracasei NPB01 presents two different rhamnose-rich polysaccharides with non-equivalent Immunomodulating activities. Carbohydr Polym. 2025;123742.https://doi.org/10.1016/j.carbpol.2025.123742.

[24] Xu X, Peng Q, Zhang Y, Tian D, Zhang P, Huang Y, Ma L, Qiao Y, Shi B. A novel exopolysaccharide produced by Lactobacillus coryniformis NA-3 exhibits antioxidant and biofilm-inhibiting properties in vitro. Food Nutr Res. 2020;64.https://doi.org/10.29219/fnr.v64.3744.

[25] El-Deeb NM, Yassin AM, Al-Madboly LA, El-Hawiet A. A novel purified Lactobacillus acidophilus 20079 exopolysaccharide, LA-EPS-20079, molecularly regulates both apoptotic and NF-κB inflammatory pathways in human colon cancer. Microb Cell Fact. 2018, 17(1): 29

[26] Torres CAV, Marques R, Antunes S, Alves VD, Sousa I, Ramos AM, Oliveira R, Freitas F, Reis MAM. Kinetics of production and characterization of the fucose-containing exopolysaccharide from Enterobacter A47. J Biotechnol. 2011, 156(4): 261-7

[27] Zhang J, Hu T, Ma Y, Ma Y, Sun Q. Characterisation and bioactivity analysis of exopolysaccharides from Lactiplantibacillus plantarum L3. Carbohydr Polym Technol Appl. 2025, 10: 100830

[28] Elmansy EA, Elkady EM, Asker MS, Abdou AM, Abdallah NA, Amer SK. Exopolysaccharide produced by Lactiplantibacillus plantarum RO30 isolated from Romi cheese: characterization, antioxidant and burn healing activity. World J Microbiol Biotechnol. 2022, 38(12): 245

[29] Wang Z, Zhao Y, Jiang Y, Chu W. Prebiotic, antioxidant, and Immunomodulatory properties of acidic exopolysaccharide from marine Rhodotorula RY1801. Front Nutr. 2021;8.https://doi.org/10.3389/fnut.2021.710668.

[30] Llamas I, Amjres H, Mata JA, Quesada E, Béjar V. The potential biotechnological applications of the exopolysaccharide produced by the halophilic bacterium Halomonas almeriensis. Molecules. 2012, 17: 7103-20

[31] Lv H, Teng Q, Chen J, Peng L, Ren Z, Ma L, Yang W, Yu B, Wu Z, Wan C. Probiotic potential of a novel exopolysaccharide produced by Bifidobacterium animalis subsp. Lactis SF. LWT. 2024, 193: 115764

[32] Angelov A, Georgieva A, Petkova M, Bartkiene E, Rocha JM, Ognyanov M, Gotcheva V. On the molecular selection of exopolysaccharide-producing lactic acid bacteria from Indigenous fermented plant-based foods and further fine chemical characterization. Foods. 2023;12.https://doi.org/10.3390/foods12183346.

[33] Vikromvarasiri N, Nakasaki K. Exopolysaccharide production from glycerol by Bacillus sonorensis NTV10 under thermophilic condition. Biomass Convers Bior. 2023, 14: 24295-303

[34] Li F, Hu X, Sun X, Li H, Lu J, Li Y, Bao M. Effect of fermentation pH on the structure, rheological properties, and antioxidant activities of exopolysaccharides produced by Alteromonas australica QD. Glycoconj J. 2022, 39(6): 773-87

[35] Looijesteijn PJ, Van Casteren WHM, Tuinier R, Doeswijk-Voragen CHL, Hugenholtz J. Influence of different substrate limitations on the yield, composition and molecular mass of exopolysaccharides produced by Lactococcus lactis subsp. Cremoris in continuous cultures. J Appl Microbiol. 2000, 89(1): 116-22

[36] Seed KD, Faruque SM, Mekalanos JJ, Calderwood SB, Qadri F, Camilli A. Phase variable O antigen biosynthetic genes control expression of the major protective antigen and bacteriophage receptor in Vibrio cholerae O1. PLoS Pathog. 2012, 8(9): e1002917

[37] Skurska E, Olczak M. Interplay between de Novo and salvage pathways of GDP-fucose synthesis. PLoS ONE. 2024, 19(10): e0309450

[38] Van der Beek SL, Zorzoli A, Çanak E, Chapman RN, Lucas K, Meyer BH, Evangelopoulos D, de Carvalho LPS, Boons G-J, Dorfmueller HC, et al. . Streptococcal dTDP-L-rhamnose biosynthesis enzymes: functional characterization and lead compound identification. Mol Microbiol. 2019, 111(4): 951-64

[39] Pâris A, Rundstadler T, Lafite P. Simultaneous one-pot multienzymatic synthesis and purification of uridine-5’-diphosphate-α-D-glucuronide and uridine-5’-diphosphate-α-D-xylose. Carbohydr Res. 2025;109516.https://doi.org/10.1016/j.carres.2025.109516.

[40] Kimmel SA, Roberts RF, Ziegler GR. Optimization of exopolysaccharide production by Lactobacillus delbrueckii subsp. Bulgaricus RR grown in a semidefined medium. Appl Environ Microbiol. 1998, 64(2): 659-64

[41] Lequeux G, Beauprez J, Maertens J, Van Horen E, Soetaert W, Vandamme E, Vanrolleghem PA. Dynamic metabolic flux analysis demonstrated on cultures where the limiting substrate is changed from carbon to nitrogen and vice versa. Biomed Res Int. 2010, 2010: 621645

[42] Liu X, Wang Z, Xiao J, Zhou X, Xu Y. Osmotic stress tolerance and transcriptome analysis of Gluconobacter oxydans to extra-high titers of glucose. Front Microbiol. 2022;13.https://doi.org/10.3389/fmicb.2022.977024.

[43] Nikel PI, Fuhrer T, Chavarría M, Sánchez-Pascuala A, Sauer U, de Lorenzo V. Reconfiguration of metabolic fluxes in Pseudomonas putida as a response to sub-lethal oxidative stress. ISME J. 2021, 15(6): 1751-66

[44] Aguirre-Ramírez M, Medina G, González-Valdez A, Grosso-Becerra V, Soberón-Chávez G. The Pseudomonas aeruginosa RmlBDAC operon, encoding dTDP-L-rhamnose biosynthetic enzymes, is regulated by the quorum-sensing transcriptional regulator RhlR and the alternative Sigma factor σS. Microbiology. 2012, 158(4): 908-16

[45] Järvinen N, Mäki M, Räbinä J, Roos C, Mattila P, Renkonen R. Cloning and expression of Helicobacter pylori GDP-L-fucose synthesizing enzymes (GMD and GMER) in Saccharomyces cerevisiae. Eur J Biochem. 2001, 268(24): 6458-64

[46] Boels I, Beerthuyzen M, Kosters M, Kaauwen M, Kleerebezem M, De Vos W. Identification and functional characterization of the Lactococcus lactis Rfb operon, required for dTDP-rhamnose biosynthesis. J Bacteriol. 2004, 186: 1239-48

[47] Sadler JC, Brewster RC, Kjeldsen A, González AF, Nirkko JS, Varzandeh S, Wallace S. Overproduction of native and click-able Colanic acid slime from engineered Escherichia coli. JACS Au. 2023, 3(2): 378-83

[48] Marczak M, Żebracki K, Koper P, Horbowicz A, Wójcik M, Mazur A. A new face of the old gene: deletion of the pssA, encoding monotopic inner membrane phosphoglycosyl transferase in Rhizobium leguminosarum, leads to diverse phenotypes that could be attributable to downstream effects of the lack of exopolysaccharide. Int J Mol Sci. 2023;24.https://doi.org/10.3390/ijms24021035.

[49] Schmid J, Heider D, Wendel N, Sperl N, Sieber V. Bacterial glycosyltransferases: challenges and opportunities of a highly diverse enzyme class toward tailoring natural products. Front Microbiol. 2016;7.https://doi.org/10.3389/fmicb.2016.00182.

[50] Meng X, Gangoiti J, Bai Y, Pijning T, Van Leeuwen SS, Dijkhuizen L. Structure–function relationships of family GH70 Glucansucrase and 4,6-α-glucanotransferase enzymes, and their evolutionary relationships with family GH13 enzymes. Cell Mol Life Sci. 2016, 73(14): 2681-706

[51] Le T-S, Nguyen P-T, Nguyen-Ho S-H, Nguyen T-P, Nguyen T-T, Thai M-N, Nguyen-Thi T-U, Nguyen M-C, Hoang Q-K, Nguyen H-T. Expression of genes involved in exopolysaccharide synthesis in Lactiplantibacillus plantarum VAL6 under environmental stresses. Arch Microbiol. 2021, 203(8): 4941-50

[52] Fu C, Xu X, Xie Y, Liu Y, Liu M, Chen A, Blamey JM, Shi J, Zhao S, Sun J. Rational design of GDP-D-mannose Mannosyl hydrolase for microbial L-fucose production. Microb Cell Fact. 2023, 22(1): 56

[53] Li S, Chen F, Li Y, Wang L, Li H, Gu G, Li E. Rhamnose-containing compounds: biosynthesis and applications. Molecules. 2022;27.https://doi.org/10.3390/molecules27165315.

[54] Wan L, Zhu Y, Li W, Zhang W, Mu W. Combinatorial modular pathway engineering for Guanosine 5′-diphosphate-L-fucose production in Recombinant Escherichia coli. J Agric Food Chem. 2020, 68(20): 5668-75

[55] Péant B, LaPointe G, Gilbert C, Danielle A, Ward P, Roy D. Comparative analysis of the exopolysaccharide biosynthesis gene clusters from four strains of Lactobacillus rhamnosus. Microbiology. 2005, 151: 1839-51

[56] Meng J, Young G, Chen J. The Rcs system in enterobacteriaceae: envelope stress responses and virulence regulation. Front Cell Infect Microbiol. 2021;12.https://doi.org/10.3389/fmicb.2021.627104.

[57] Li S, Xu X, Lv X, Liu Y, Li J, Du G, Liu L. Combinatorial metabolic engineering and enzymatic catalysis enable efficient production of Colanic acid. Microorganisms. 2022;10.https://doi.org/10.3390/microorganisms10050877.

[58] Sledjeski DD, Gottesman S. Osmotic shock induction of capsule synthesis in Escherichia coli K-12. J Bacteriol. 1996, 178(4): 1204-6

[59] Jimenez JC, Federle MJ. Quorum sensing in group A Streptococcus. Front Cell Infect Microbiol. 2014;4.https://doi.org/10.3389/fcimb.2014.00127.

[60] Martinez MR, Dias TB, Natov PS, Zachara NE. Stress-induced O-GlcNAcylation: an adaptive process of injured cells. Biochem Soc Trans. 2017, 45(1): 237-49

[61] Thibodeaux CJ, Melançon CEIII, Liu H-w. Natural-product sugar biosynthesis and enzymatic glycodiversification. Angew Chem Int Ed. 2008, 47(51): 9814-59

[62] Wacker M, Feldman MF, Callewaert N, Kowarik M, Clarke BR, Pohl NL, Hernandez M, Vines ED, Valvano MA, Whitfield C, et al. . Substrate specificity of bacterial oligosaccharyltransferase suggests a common transfer mechanism for the bacterial and eukaryotic systems. Proc Natl Acad Sci. 2006, 103(18): 7088-93

[63] Irague R, Tarquis L, André I, Moulis C, Morel S, Monsan P, Potocki-Véronèse G, Remaud-Siméon M. Combinatorial engineering of dextransucrase specificity. PLoS ONE. 2013, 8(10): e77837

[64] Schmid J, Sieber V, Rehm B. Bacterial exopolysaccharides: biosynthesis pathways and engineering strategies. Front Microbiol. 2015;6.https://doi.org/10.3389/fmicb.2015.00496.

[65] Hirakawa H, Kurushima J, Hashimoto Y, Tomita H. Progress overview of bacterial two-component regulatory systems as potential targets for antimicrobial chemotherapy. Antibiotics. 2020;9.https://doi.org/10.3390/antibiotics9100635.

[66] Guo X-P, Sun Y-C. New insights into the non-orthodox two component Rcs phosphorelay system. Front Microbiol. 2017;8.https://doi.org/10.3389/fmicb.2017.02014.

[67] Zhang K, Gao M, Cao C, Zhang M, Ahmad W, Rady A, Aldahmash B, Zhu T, Khan SS, Liu L. Intensification of 2’-fucosyllactose biosynthesis pathway by using a novel fucosyltransferase from Bacillus cereus. Front Bioeng Biotechnol. 2025, 13: 1569597

[68] Rodriguez Ayala F, Bartolini M, Grau R. The stress-responsive alternative Sigma factor SigB of Bacillus subtilis and its relatives: an old friend with new functions. Front Microbiol. 2020;11.https://doi.org/10.3389/fmicb.2020.01761.

[69] Flores N, Escalante A, de Anda R, Báez-Viveros JL, Merino E, Franco B, Georgellis D, Gosset G, Bolívar F. New insights into the role of Sigma factor RpoS as revealed in Escherichia coli strains lacking the phosphoenolpyruvate:carbohydrate phosphotransferase system. J Mol Microbiol Biotechnol. 2007, 14(4): 176-92

[70] Rutherford ST, Bassler BL. Bacterial quorum sensing: its role in virulence and possibilities for its control. Cold Spring Harb Perspect Med. 2012, 2(11): a012427

[71] Zhou L, Zhang Y, Ge Y, Zhu X, Pan J. Regulatory mechanisms and promising applications of quorum sensing-inhibiting agents in control of bacterial biofilm formation. Front Microbiol. 2020;11.https://doi.org/10.3389/fmicb.2020.589640.

[72] Ruhal R, Ghosh M, Kumar V, Jain D. Mutation of putative Glycosyl transferases PslC and PslI confers susceptibility to antibiotics and leads to drastic reduction in biofilm formation in Pseudomonas aeruginosa. Microbiology. 2023;169(9).https://doi.org/10.1099/mic.0.001392.

[73] Sadykov MR, Olson ME, Halouska S, Zhu Y, Fey PD, Powers R, Somerville GA. Tricarboxylic acid cycle-dependent regulation of Staphylococcus epidermidis polysaccharide intercellular adhesin synthesis. J Bacteriol. 2008, 190(23): 7621-32

[74] Ramos A, Boels IC, de Vos WM, Santos H. Relationship between Glycolysis and exopolysaccharide biosynthesis in Lactococcus lactis. Appl Environ Microbiol. 2001, 67(1): 33-41

[75] Singh R, Mailloux RJ, Puiseux-Dao S, Appanna VD. Oxidative stress evokes a metabolic adaptation that favors increased NADPH synthesis and decreased NADH production in Pseudomonas fluorescens. J Bacteriol. 2007, 189(18): 6665-75

[76] Petrovova M, Tkadlec J, Dvoracek L, Streitova E, Licha I. NAD(P)H-hydrate dehydratase—a metabolic repair enzyme and its role in Bacillus subtilis stress adaptation. PLoS ONE. 2014, 9(11): e112590

[77] Jones RA, Shropshire H, Zhao C, Murphy A, Lidbury I, Wei T, Scanlan DJ, Chen Y. Phosphorus stress induces the synthesis of novel glycolipids in Pseudomonas aeruginosa that confer protection against a last-resort antibiotic. ISME J. 2021, 15(11): 3303-14

[78] Rudan Dimlić M, Raić S, Močibob M, Sanader Maršić Ž, Yao Z, Radman M, Stagljar I. Oxidative protein damage negatively affects protein-protein interaction: the case of KRAS-cRAF. Biochem Biophys Res Commun. 2024, 734: 150792

[79] Qiu S, Yang A, Yang X, Li W, Zeng H, Wang Y. Proteome trade-off between primary and secondary metabolism shapes acid stress induced bacterial exopolysaccharide production. Metab Eng. 2024, 91: 254-66

[80] Piette F, D’Amico S, Struvay C, Mazzucchelli G, Renaut J, Tutino M, Danchin A, Leprince P, Feller G. Proteomics of life at low temperatures: trigger factor is the primary chaperone in the Antarctic bacterium Pseudoalteromonas haloplanktis TAC125. Mol Microbiol. 2010, 76: 120-32

[81] Horváth I, Multhoff G, Sonnleitner A, Vígh L. Membrane-associated stress proteins: more than simply chaperones. Biochim Biophys Acta Biomembr. 2008, 1778(7): 1653-64

[82] Lang BJ, Holton KM, Guerrero-Gimenez ME, Okusha Y, Magahis PT, Shi A, Neguse M, Venkatesh S, Nhu AM, Gestwicki JE, et al. . Heat shock protein 72 supports extracellular matrix production in metastatic mammary tumors. Cell Stress Chaperones. 2024, 29(3): 456-71

[83] Wang Y, Branicky R, Noë A, Hekimi S. Superoxide dismutases: dual roles in controlling ROS damage and regulating ROS signaling. J Cell Biol. 2018, 217(6): 1915-28

[84] Huang D, Cheng C-Q, Zhang H-Y, Huang Y, Li S-Y, Huang Y-T, Huang X-L, Pei L-L, Luo Z, Zou L-G, et al. . Heat shock transcription factor-mediated thermal tolerance and cell size plasticity in marine diatoms. Nat Commun. 2025, 16(1): 3404

[85] Krysenko S, Wohlleben W. Role of carbon, nitrogen, phosphate and sulfur metabolism in secondary metabolism precursor supply in Streptomyces spp. Microorganisms. 2024, 12: 1571

[86] Mirończuk A, Rakicka-Pustułka M, Biegalska A, Rymowicz W, Dobrowolski A. A two-stage fermentation process of erythritol production by yeast Y. lipolytica from molasses and glycerol. Bioresour Technol. 2015;198.https://doi.org/10.1016/j.biortech.2015.09.008.

[87] Raj K, Venayak N, Mahadevan R. Novel two-stage processes for optimal chemical production in microbes. Metab Eng. 2020, 62: 186-97

[88] Guérin M, Silva CR, Garcia C, Remize F. Lactic acid bacterial production of exopolysaccharides from fruit and vegetables and associated benefits. Fermentation. 2020;6.https://doi.org/10.3390/fermentation6040115.

[89] Skurska E, Szulc B, Maszczak-Seneczko D, Wiktor M, Wiertelak W, Makowiecka A, Olczak M. Incorporation of fucose into glycans independent of the GDP-fucose transporter SLC35C1 preferentially utilizes salvaged over de Novo GDP-fucose. J Biol Chem. 2022, 298(8): 102206

[90] Wang W, Zhang F, Wen Y, Hu Y, Yuan Y, Wei M, Zhou Y. Cell-free enzymatic synthesis of GDP-L-fucose from mannose. AMB Express. 2019, 9(1): 74

[91] Fulda S, Gorman AM, Hori O, Samali A. Cellular stress responses: cell survival and cell death. Int J Cell Biol. 2010, 2010: 214074

[92] Nguyen T-D, Duong H-N, Nguyen T-P, Nguyen P-T, Nguyen H-H, Nguyen T-T, Pham H-G, Truong D-H, Nguyen H-T. Antibiotic potential and metabolic modulation of Bacillus velezensis VTRNT 01 in response to bacterial elicitors. World J Microbiol Biotechnol. 2025, 41(3): 102

[93] Peng W, Guo X, Xu X, Zou D, Zou H, Yang X. Advances in polysaccharide production based on the co-culture of microbes. Polymers. 2023;15.https://doi.org/10.3390/polym15132847.

[94] Dragosits M, Mattanovich D. Adaptive laboratory evolution– principles and applications for biotechnology. Microb Cell Fact. 2013, 12(1): 64

[95] Sun T, Jiang H, Xu X, Ma Y, Liang X, Wang R, Gu Y, Li S, Qiu Y, Sun D, et al. . Adaptive laboratory evolution of Naematelia aurantialba under high temperature for efficient production of exopolysaccharide. Int J Biol Macromol. 2024, 263: 130425

[96] Senanayake D, Ramarao-Milne P, Pandey G, Hlaing MM, Chandrapala J, Torley PJ, Terefe NS. Genomic insights into exopolysaccharide biosynthesis pathways in novel Lactiplantibacillus plantarum and Leuconostoc mesenteroides strains. LWT. 2025, 225: 117863

[97] Pérez-Burgos M, García-Romero I, Jung J, Schander E, Valvano MA, Søgaard-Andersen L. Characterization of the exopolysaccharide biosynthesis pathway in Myxococcus xanthus. J Bacteriol. 2020, 202(19): e00335-20

[98] Casillo A, Lanzetta R, Parrilli M, Corsaro MM. Exopolysaccharides from marine and marine extremophilic bacteria: structures, properties, ecological roles and applications. Mar Drugs. 2018;16.https://doi.org/10.3390/md16020069.

[99] Chistoserdova L. Functional metagenomics: recent advances and future challenges. Biotechnol Genet Eng Rev. 2010, 26: 335-52

[100] Alam K, Abbasi MN, Hao J, Zhang Y, Li A. Strategies for natural products discovery from uncultured microorganisms. Molecules. 2021;26.https://doi.org/10.3390/molecules26102977.

[101] Nelson J, Boulton R, Knoesen A. Redox potential and its control in research and commercial wine fermentations. Fermentation. 2025;11.https://doi.org/10.3390/fermentation11010009.

[102] Poeker SA, Lacroix C, de Wouters T, Spalinger MR, Scharl M, Geirnaert A. Stepwise development of an in vitro continuous fermentation model for the murine caecal microbiota. Front Microbiol. 2019;10.https://doi.org/10.3389/fmicb.2019.01166.

[103] Zhao Z-T, Ding J, Pang J, Bao M-Y, Luo G, Wang B-Y, Liu B-F, Zhang L-Y, Ren N-Q, Yang S. Pretreatments of lignocellulosic biomass for biohydrogen biorefinery: recent progress, techno-economic feasibility and prospectives. Crit Rev Environ Sci Technol. 2025;1–27.https://doi.org/10.1080/10643389.2025.2484892.

[104] Crowe SA, Liu Y, Zhao X, Scheller HV, Keasling JD. Advances in engineering nucleotide sugar metabolism for natural product glycosylation in Saccharomyces cerevisiae. ACS Synth Biol. 2024, 13(6): 1589-99

[105] Anderson LA, Islam MA, Prather KLJ. Synthetic biology strategies for improving microbial synthesis of green biopolymers. J Biol Chem. 2018, 293(14): 5053-61

[106] Li J, Wang B-X, Zhang J, Han N, Liu S-T, Geng W-J, Jia S-R, Li Y-R, Gan Q, Han P-P. A newly discovered glycosyltransferase gene UGT88A1 affects growth and polysaccharide synthesis of Grifola frondosa. Appl Microbiol Biotechnol. 2024, 108(1): 246

[107] Hoffmeister D, Wilkinson B, Foster G, Sidebottom PJ, Ichinose K, Bechthold A. Engineered urdamycin glycosyltransferases are broadened and altered in substrate specificity. Chem Biol. 2002, 9(3): 287-95

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