Food and Fermentation Industries >

2025 , Vol. 51 >Issue 22: 397 - 405

DOI: https://doi.org/10.13995/j.cnki.11-1802/ts.042595

Research progress and challenges in biosynthesis of uridine diphosphate-sugars

  • LI Xinyun ,
  • SUN Qiuyan ,
  • FENG Xudong ,
  • LI Chun
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  • 1(Key Laboratory of Medical Molecule Science and Pharmaceutical Engineering, Ministry of Industry and Information Technology, Institute of Biochemical Engineering, School of Chemistry and Chemical Engineering, Beijing Institute of Technology, Beijing 102488, China)
    2(Key Lab for Industrial Biocatalysis, Ministry of Education, Department of Chemical Engineering, Tsinghua University, Beijing 100084, China)

Received date: 2025-03-04

  Revised date: 2025-05-02

  Online published: 2025-12-15

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Abstract

Uridine diphosphate (UDP)-sugars, among the most prevalent nucleotide sugar donors, play critical roles in biological processes such as glycosylation, cell wall synthesis, and cellular signaling.These compounds hold significant potential for applications in pharmaceuticals, food additives, and biomaterials.Despite progress in enzymatic and microbial synthesis approaches, persistent challenges include low catalytic efficiency, limited substrate availability, product feedback inhibition, and imbalanced metabolic flux distribution.Recent advances in enzymatic and microbial synthesis of UDP-sugars have been systematically reviewed, with a focus on identifying technical bottlenecks across different methodologies.Key limitations involve inefficient enzyme-substrate interactions in vitro and metabolic competition in microbial systems, which hinder scalable production.Future efforts should prioritize high-throughput enzyme screening, protein engineering, and the development of synthetic biology tools to optimize pathway enzymes and regulatory elements.Concurrently, dynamic metabolic control strategies and modular pathway engineering are essential to balance precursor allocation and minimize inhibitory effects.Integrating these approaches could establish robust biosynthetic platforms for sustainable UDP-sugar production, thereby accelerating the industrial-scale manufacturing of glycosylated compounds.

Key words： uridine diphosphate (UDP)-sugars; glycosylation; enzyme catalysis; metabolic engineering; microbial cell factory

Cite this article

LI Xinyun , SUN Qiuyan , FENG Xudong , LI Chun . Research progress and challenges in biosynthesis of uridine diphosphate-sugars[J]. Food and Fermentation Industries, 2025 , 51(22) : 397 -405 . DOI: 10.13995/j.cnki.11-1802/ts.042595

References

[1] RAI A, UMASHANKAR S, RAI M, et al.Coordinate regulation of metabolite glycosylation and stress hormone biosynthesis by TT8 in Arabidopsis[J].Plant Physiology, 2016, 171(4):2499-2515.
[2] HE M Y, ZHOU X X, WANG X.Glycosylation:Mechanisms, biological functions and clinical implications[J].Signal Transduction and Targeted Therapy, 2024, 9(1):194.
[3] LEE C E, KIM T, NILO-POYANCO R, et al.Genomic signatures of specialized metabolism in plants[J].Science, 2014, 344(6183):510-513.
[4] THOMAS D, RATHINAVEL A K, RADHAKRISHNAN P.Altered glycosylation in cancer:A promising target for biomarkers and therapeutics[J].Biochimica et Biophysica Acta (BBA)-Reviews on Cancer, 2021, 1875(1):188464.
[5] ZOU Y, SONG Y, YANG W J, et al.Galactose-installed photo-crosslinked pH-sensitive degradable micelles for active targeting chemotherapy of hepatocellular carcinoma in mice[J].Journal of Controlled Release, 2014, 193:154-161.
[6] HUANG F C, EFFENBERGER I, FISCHER T, et al.Comparative physicochemical and biochemical characterization of small-molecule glucosides[J].Journal of Agricultural and Food Chemistry, 2022, 70(50):15972-15980.
[7] REXER T, LAAF D, GOTTSCHALK J, et al.Advances in Glycobiotechnology[M].Cham:Springer International Publishing, 2021.
[8] WAGNER K G, BACKER A I.International Review of Cytology[M].New York:Academic Press, 1992.
[9] ZHANG X L, SHENG W H, LI K, et al.Substrate specificity of the galactokinase from the human gut symbiont Akkermansia muciniphila ATCC BAA-835[J].Enzyme and Microbial Technology, 2020, 139:109568.
[10] KALCKAR H M.Biochemical mutations in man and microorganisms[J].Science, 1957, 125(3238):105-108.
[11] WANG J J, GREENWAY H, LI S S, et al.Facile and stereo-selective synthesis of UDP-α-D-xylose and UDP-β-L-arabinose using UDP -sugar pyrophosphorylase[J].Frontiers in Chemistry, 2018, 6:163.
[12] ZHANG Y Y, TANG B, DU G C.Self-induction system for cellulase production by cellobiose produced from glucose in Rhizopus stolonifer[J].Scientific Reports, 2017, 7:10161.
[13] ZHAO L T, MA Z B, WANG Q, et al.Highly efficient production of UDP-glucose from sucrose via the semirational engineering of sucrose synthase and a cascade route design[J].Journal of Agricultural and Food Chemistry, 2023, 71(33):12549-12557.
[14] CHEN J, YU Y, GAO J J, et al.UDP-glucose dehydrogenase:The first-step oxidation is an NAD+-dependent bimolecular nucleophilic substitution reaction (SN2)[J].International Journal of Biological Sciences, 2019, 15(2):341-350.
[15] LI Y, SUN Y F, REN G X, et al.Functional characterization and substrate promiscuity analysis of UDP-glucose dehydrogenases from licorice (Glycyrrhiza uralensis)[J].Journal of Molecular Structure, 2022, 1265:133355.
[16] WANG Y J, LI X Y, WEI J J, et al.Mechanism of sugar ring contraction and closure catalyzed by UDP -d-apiose/ UDP -d-xylose synthase (UAXS)[J].Journal of Chemical Information and Modeling, 2022, 62(3):632-646.
[17] LI Z M, CHEN R P, WEN Y F, et al.Comprehensive analysis of the UDP-glucuronate decarboxylase (UXS) gene family in tobacco and functional characterization of NtUXS16 in Golgi apparatus in Arabidopsis[J].BMC Plant Biology, 2023, 23(1):551.
[18] FUSHINOBU S.Molecular evolution and functional divergence of UDP-hexose 4-epimerases[J].Current Opinion in Chemical Biology, 2021, 61:53-62.
[19] SCHÄPER S, WENDT H, BAMBERGER J, et al.A bifunctional UDP-sugar 4-epimerase supports biosynthesis of multiple cell surface polysaccharides in Sinorhizobium meliloti[J].Journal of Bacteriology, 2019, 201(10):e00801-18.
[20] ZHANG S, WANG Y Y, CUI Z R, et al.Functional characterization of a flavonol 3-O-rhamnosyltransferase and two UDP-rhamnose synthases from Hypericum monogynum[J].Plant Physiology and Biochemistry, 2023, 197:107643.
[21] ZOU Y, XUE M Y, WANG W J, et al.One-pot three-enzyme synthesis of UDP-Glc, UDP-Gal, and their derivatives[J].Carbohydrate Research, 2013, 373:76-81.
[22] ZHANG L, GAO Y N, LIU X F, et al.Mining of sucrose synthases from Glycyrrhiza uralensis and their application in the construction of an efficient UDP-recycling system[J].Journal of Agricultural and Food Chemistry, 2019, 67(42):11694-11702.
[23] BÜLTER T, ELLING L.Enzymatic synthesis of UDP-galactose on a gram scale[J].Journal of Molecular Catalysis B:Enzymatic, 2000, 8(4-6):281-284.
[24] MAHOUR R, LEE J W, GRIMPE P, et al.Cell-free multi-enzyme synthesis and purification of uridine diphosphate galactose[J].ChemBioChem, 2022, 23(2):e202100361.
[25] LI Y J, CHEN Q, LIU S Y, et al.Efficient one-pot synthesis of uridine diphosphate galactose employing a trienzyme system[J].Journal of Agricultural and Food Chemistry, 2024, 72(7):3644-3653.
[26] JIANG N, DILLON F M, SILVA A, et al.Rhamnose in plants - from biosynthesis to diverse functions[J].Plant Science, 2021, 302:110687.
[27] WANG S S, ZHANG J B, WEI F Y, et al.Facile synthesis of sugar nucleotides from common sugars by the cascade conversion strategy[J].Journal of the American Chemical Society, 2022, 144(22):9980-9989.
[28] PEI J J, CHEN A N, SUN Q, et al.Construction of a novel UDP-rhamnose regeneration system by a two-enzyme reaction system and application in glycosylation of flavonoid[J].Biochemical Engineering Journal, 2018, 139:33-42.
[29] GOTTSCHALK J, BLASCHKE L, AßMANN M, et al.Integration of a nucleoside triphosphate regeneration system in the one-pot synthesis of UDP-sugars and hyaluronic acid[J].ChemCatChem, 2021, 13(13):3074-3083.
[30] SHI J M, WU T T, ZHOU H, et al.Substrate promiscuities of a bacterial galactokinase and a glucose-1-phosphate uridyltransferase enable xylose salvaging[J].Green Chemistry, 2022, 24(9):3717-3722.
[31] SUN Q Y, GUO F, REN S C, et al.Construction of a UDP-arabinose regeneration system for efficient Arabinosylation of pentacyclic triterpenoids[J].ACS Synthetic Biology, 2023, 12(8):2463-2474.
[32] MAHOUR R, KLAPPROTH J, REXER T F T, et al.Establishment of a five-enzyme cell-free cascade for the synthesis of uridine diphosphate N-acetylglucosamine[J].Journal of Biotechnology, 2018, 283:120-129.
[33] EISELE A, ZAUN H, KUBALLA J, et al.In vitro one-pot enzymatic synthesis of hyaluronic acid from sucrose and N-acetylglucosamine:Optimization of the enzyme module system and nucleotide sugar regeneration[J].ChemCatChem, 2018, 10(14):2969-2981.
[34] FISCHÖDER T, WAHL C, ZERHUSEN C, et al.Repetitive batch mode facilitates enzymatic synthesis of the nucleotide sugars UDP-Gal, UDP-GlcNAc, and UDP-GalNAc on a multi-gram scale[J].Biotechnology Journal, 2019, 14(4):boit.201800386.
[35] LI S, WANG S S, WANG Y Q, et al.Gram-scale production of sugar nucleotides and their derivatives[J].Green Chemistry, 2021, 23(7):2628-2633.
[36] TAN H.A simplified method for the preparation of pure UDP[14C]glucose[J].Biochimica et Biophysica Acta (BBA) General Subjects, 1979, 582(3):543-547.
[37] CHUNG S K, RYU S I, LEE S B.Characterization of UDP-glucose 4-epimerase from Pyrococcus horikoshii:Regeneration of UDP to produce UDP-galactose using two-enzyme system with trehalose[J].Bioresource Technology, 2012, 110:423-429.
[38] SONG H B, ZHAO G H, ZHANG M, et al.Optimization of the UDP-Xyl biocatalytic synthesis from Crassostrea gigas by orthogonal design method[J].Protein Expression and Purification, 2022, 190:106002.
[39] LIU Q L, LIU Y, LI G, et al.De novo biosynthesis of bioactive isoflavonoids by engineered yeast cell factories[J].Nature Communications, 2021, 12:6085.
[40] KANG Y J, QIAN Z L, YU H S, et al.Programmable biosynthesis of plant-derived 4′-deoxyflavone glycosides by an unconventional yeast consortium[J].Small Methods, 2024, 8(8):2301371.
[41] XU Y M, WANG X L, ZHANG C Y, et al.De novo biosynthesis of rubusoside and rebaudiosides in engineered yeasts[J].Nature Communications, 2022, 13:3040.
[42] LIU S K, LI D, QIN Z J, et al.Enhancing glycosylation of flavonoids by engineering the uridine diphosphate glucose supply in Escherichia coli[J].Journal of Agricultural and Food Chemistry, 2023, 71(46):17842-17851.
[43] KOIZUMI S, ENDO T, TABATA K, et al.Large-scale production of UDP-galactose and globotriose by coupling metabolically engineered bacteria[J].Nature Biotechnology, 1998, 16(9):847-850.
[44] LIAO Y X, LAO C W, WU J Y, et al.High-yield synthesis of lacto-N-neotetraose from glycerol and glucose in engineered Escherichia coli[J].Journal of Agricultural and Food Chemistry, 2024, 72(10):5325-5338.
[45] ZHOU X J, ZHANG X X, WANG D, et al.Efficient biosynthesis of salidroside via artificial in vivo enhanced UDP-glucose system using cheap sucrose as substrate[J].ACS Omega, 2024, 9(20):22386-22397.
[46] PEI J J, SUN Q, ZHAO L G, et al.Efficient biotransformation of luteolin to isoorientin through adjusting induction strategy, controlling acetic acid, and increasing UDP-glucose supply in Escherichia coli[J].Journal of Agricultural and Food Chemistry, 2019, 67(1):331-340.
[47] GU N, QIU C, ZHAO L G, et al.Enhancing UDP-rhamnose supply for rhamnosylation of flavonoids in Escherichia coli by regulating the modular pathway and improving NADPH availability[J].Journal of Agricultural and Food Chemistry, 2020, 68(35):9513-9523.
[48] AN T, LIN G Y, LIU Y, et al.De novo biosynthesis of anticarcinogenic icariin in engineered yeast[J].Metabolic Engineering, 2023, 80:207-215.
[49] ZHAO C L, LI X M, GUO L, et al.Reprogramming metabolic flux in Escherichia coli to enhance chondroitin production[J].Advanced Science, 2024, 11(10):2307351.
[50] WANG D, WANG J H, SHI Y S, et al.Elucidation of the complete biosynthetic pathway of the main triterpene glycosylation products of Panax notoginseng using a synthetic biology platform[J].Metabolic Engineering, 2020, 61:131-140.
[51] LIU Y Z, ZHAO X X, GAN F, et al.Complete biosynthesis of QS-21 in engineered yeast[J].Nature, 2024, 629(8013):937-944.
[52] CROWE S A, ZHAO X X, GAN F, et al.Engineered Saccharomyces cerevisiae as a biosynthetic platform of nucleotide sugars[J].ACS Synthetic Biology, 2024, 13(4):1215-1224.
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