Microbial hyaluronic acid production

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Microbial hyaluronic acid production refers to the process by which microorganisms, such as bacteria and yeast, are utilized in fermentation to synthesize hyaluronic acid (HA).[1] HA is used in a wide range of medical, cosmetic, and biological products because of its high moisture retention and viscoelasticity qualities.[2] HA had originally been extracted from rooster combs in limited quantities.[3] However, challenges such as low yields, high production costs, and ethical issues associated with animal-derived HA has driven the development of microbial production methods for HA.[4]

Although there are other methods for instance chemical synthesis and modification, chemoenzymatic synthesis, enzymatic synthesis; microbial fermentation has been preferred to produce HA because of economical advantages.[5]

Bacterial production[edit]

Some bacteria, like Streptococcus, develop an extracellular capsule that contains HA. This capsule functions as a molecular mimic to elude the host's immune system during the infection process in addition to providing adherence and protection.[6] Streptococcus zooepidemicus was used for first commercially HA fermentation, and that is most used bacteria since provides high yields although it is a pathogen microorganism.[7]

Encoding of HA production is carried out by hasA, hasB, hasC, hasD and hasE genes in S. zooepidemicus.[8]

Genes and their functions HA production in S. zooepidemicus
Gene Enzyme Function Reference
hasA Hyaluronic acid synthase HA synthesis and

transport

[9]
hasB UDP-glucose dehydrogenase UDP-GlcA

biosynthesis

[10][11]
hasC UDP-glucose pyrophosphorylase UDP-GlcA

biosynthesis

[12]
hasD Acetyltransferase and

pyrophosphorylase (bifunctional)

UDP-GlcNAc

biosynthesis

[13]
hasE Phosphoglucoisomerase UDP-GlcNAc

biosynthesis

[13]

Genetically modified producers were developed such as Kluysveromyces  lactis,[14]  Lactococcus  lactis,[15] Bacillus  subtilis,[16] Escherichia  coli,[17]  and Corynebacterium glutamicum[18][19] because of S. zooepidemicus’s pathogeny.

Biological process[edit]

Intracellular factors[edit]

Metabolism[edit]

Intermediates are used from  pathways  essential  to  support cell  growth,  such  as  the  production  of  organic  acids,  polysaccharides during the HA production.[20] HA is not an essential metabolite, and it competes other metabolites to attend the carbon flux in the cell.[4] Reduction potential of S. zooepidemicus may have a role in hyaluronic acid production, because 2 NAD+ are consumed during the synthesis of one monomer. Although NAD+ does not control HA synthesis when NADH oxidase over-expressed,[21] it has a big role in biomass formation.

Some studies showed that balanced intracellular concentration of precursors and their fluxes balanced provides higher molecular weight such as UDP-acetylglucosamine concentration.[22][23] Enzymes such as hyaluronidase,[24] β-glucuronidase[25] of S. zooepidemicus decrease yield of HA. HA concentration is increased by deletion of associated genes of these enzymes.[24][25]

On the other hand, some enzymes induce HA production like sucrose-6-phosphatate hydrolase,[26] and hyaluronan synthase.[27] Using combined approaches with these two type enzymes is a good strategy for high yield HA production.[20]

Membrane[edit]

HA is produced around the cell, serving as a barrier against the host immune system by the bacteria. Only 8% of HA remains as attached the cell when cells arrived stationary phase. Biosurfactants such as sodium dodecyl sulfate (SDS) are used to gain this product.[28] Hyaluronan synthase, that is a membrane-binding enzyme, is one of the factors that reduces the production of HA. Hyaluronan synthase limits hyaluronic acid production by affecting cell morphology.[28]

Environmental factors[edit]

pH[edit]

Organic acids formed during HA production by S. zooepidemicus cause pH to decrease[20] Although HA production without pH control is cheaper, it prefers since provides high hyaluronic acid yields..[29][30]

Temperature[edit]

HA production is affected regarding to yield and molecular weight by temperature.[31] HA production increases while bacterial cells are growing above 37°C. However, HA yield decreases while molecular weight is higher with fermentation under 32°C.[30]

See also[edit]

References[edit]

  1. ^ Serra M, Casas A, Toubarro D, Barros AN, Teixeira JA (February 2023). "Microbial Hyaluronic Acid Production: A Review". Molecules. 28 (5): 2084. doi:10.3390/molecules28052084. PMC 10004376. PMID 36903332.
  2. ^ Sze JH, Brownlie JC, Love CA (June 2016). "Biotechnological production of hyaluronic acid: a mini review". 3 Biotech. 6 (1): 67. doi:10.1007/s13205-016-0379-9. PMC 4754297. PMID 28330137.
  3. ^ Ciriminna R, Scurria A, Pagliaro M (2021). "Microbial production of hyaluronic acid: the case of an emergent technology in the bioeconomy". Biofuels, Bioproducts and Biorefining. 15 (6): 1604–1610. doi:10.1002/bbb.2285. ISSN 1932-104X.
  4. ^ a b Chong BF, Blank LM, Mclaughlin R, Nielsen LK (January 2005). "Microbial hyaluronic acid production". Applied Microbiology and Biotechnology. 66 (4): 341–351. doi:10.1007/s00253-004-1774-4. PMID 15599518.
  5. ^ Shikina EV, Kovalevsky RA, Shirkovskaya AI, Toukach PV (2022). "Prospective bacterial and fungal sources of hyaluronic acid: A review". Computational and Structural Biotechnology Journal. 20: 6214–6236. doi:10.1016/j.csbj.2022.11.013. PMC 9676211. PMID 36420162.
  6. ^ Wessels MR, Moses AE, Goldberg JB, DiCesare TJ (October 1991). "Hyaluronic acid capsule is a virulence factor for mucoid group A streptococci". Proceedings of the National Academy of Sciences of the United States of America. 88 (19): 8317–8321. Bibcode:1991PNAS...88.8317W. doi:10.1073/pnas.88.19.8317. PMC 52499. PMID 1656437.
  7. ^ Torres-Acosta MA, Castaneda-Aponte HM, Mora-Galvez LM, Gil-Garzon MR, Banda-Magaña MP, Marcellin E, et al. (2021-07-21). "Comparative Economic Analysis Between Endogenous and Recombinant Production of Hyaluronic Acid". Frontiers in Bioengineering and Biotechnology. 9: 680278. doi:10.3389/fbioe.2021.680278. PMC 8334870. PMID 34368093.
  8. ^ Zhang Y, Luo K, Zhao Q, Qi Z, Nielsen LK, Liu H (April 2016). "Genetic and biochemical characterization of genes involved in hyaluronic acid synthesis in Streptococcus zooepidemicus". Applied Microbiology and Biotechnology. 100 (8): 3611–3620. doi:10.1007/s00253-016-7286-1. PMID 26758299.
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  11. ^ Chen J, Gao J, Yu Y, Yang S (May 2019). "A hyaluronan-based polysaccharide peptide generated by a genetically modified Streptococcus zooepidemicus". Carbohydrate Research. 478: 25–32. doi:10.1016/j.carres.2019.04.005. PMID 31042589.
  12. ^ Crater DL, Dougherty BA, van de Rijn I (December 1995). "Molecular characterization of hasC from an operon required for hyaluronic acid synthesis in group A streptococci. Demonstration of UDP-glucose pyrophosphorylase activity". The Journal of Biological Chemistry. 270 (48): 28676–28680. doi:10.1074/jbc.270.48.28676. PMID 7499387.
  13. ^ a b Blank LM, Hugenholtz P, Nielsen LK (July 2008). "Evolution of the hyaluronic acid synthesis (has) operon in Streptococcus zooepidemicus and other pathogenic streptococci". Journal of Molecular Evolution. 67 (1): 13–22. Bibcode:2008JMolE..67...13B. doi:10.1007/s00239-008-9117-1. PMID 18551332.
  14. ^ V Gomes AM, Netto JH, Carvalho LS, Parachin NS (August 2019). "Heterologous Hyaluronic Acid Production in Kluyveromyces lactis". Microorganisms. 7 (9): 294. doi:10.3390/microorganisms7090294. PMC 6780701. PMID 31466214.
  15. ^ Jeeva P, Shanmuga Doss S, Sundaram V, Jayaraman G (June 2019). "Production of controlled molecular weight hyaluronic acid by glucostat strategy using recombinant Lactococcus lactis cultures". Applied Microbiology and Biotechnology. 103 (11): 4363–4375. doi:10.1007/s00253-019-09769-0. PMID 30968163.
  16. ^ Westbrook AW, Ren X, Moo-Young M, Chou CP (May 2018). "Application of hydrocarbon and perfluorocarbon oxygen vectors to enhance heterologous production of hyaluronic acid in engineered Bacillus subtilis". Biotechnology and Bioengineering. 115 (5): 1239–1252. doi:10.1002/bit.26551. PMID 29384194.
  17. ^ Lai ZW, Teo CH (2019). "Cloning and expression of hyaluronan synthase (hasA) in recombinant Escherichia coli BL21 and its hyaluronic acid production in shake flask culture". Malaysian Journal of Microbiology. doi:10.21161/mjm.190444. ISSN 2231-7538.
  18. ^ Hoffmann J, Altenbuchner J (September 2014). "Hyaluronic acid production with Corynebacterium glutamicum: effect of media composition on yield and molecular weight". Journal of Applied Microbiology. 117 (3): 663–678. doi:10.1111/jam.12553. PMID 24863652.
  19. ^ Karami M, Shahraky MK, Ranjbar M, Tabandeh F, Morshedi D, Aminzade S (January 2021). "Preparation, purification, and characterization of low-molecular-weight hyaluronic acid". Biotechnology Letters. 43 (1): 133–142. doi:10.1007/s10529-020-03035-4. PMID 33131008.
  20. ^ a b c Harth ML, Furlan FF, Horta AC (2024-03-27). "Microbial hyaluronic acid production in the 21 century: a roadmap toward high production, tailored molecular weight". Observatório de la Economía Latinoamericana. 22 (3): e3913. doi:10.55905/oelv22n3-185. ISSN 1696-8352.
  21. ^ Chong BF, Nielsen LK (January 2003). "Amplifying the cellular reduction potential of Streptococcus zooepidemicus". Journal of Biotechnology. 100 (1): 33–41. doi:10.1016/S0168-1656(02)00239-0. PMID 12413784.
  22. ^ Badle SS, Jayaraman G, Ramachandran KB (July 2014). "Ratio of intracellular precursors concentration and their flux influences hyaluronic acid molecular weight in Streptococcus zooepidemicus and recombinant Lactococcus lactis". Bioresource Technology. 163: 222–227. Bibcode:2014BiTec.163..222B. doi:10.1016/j.biortech.2014.04.027. PMID 24814248.
  23. ^ Jagannath S, Ramachandran K (2010). "Influence of competing metabolic processes on the molecular weight of hyaluronic acid synthesized by Streptococcus zooepidemicus". Biochemical Engineering Journal. 48 (2): 148–158. doi:10.1016/j.bej.2009.09.003. ISSN 1369-703X.
  24. ^ a b Pourzardosht N, Rasaee MJ (June 2017). "Improved Yield of High Molecular Weight Hyaluronic Acid Production in a Stable Strain of Streptococcus zooepidemicus via the Elimination of the Hyaluronidase-Encoding Gene". Molecular Biotechnology. 59 (6): 192–199. doi:10.1007/s12033-017-0005-z. PMID 28500482.
  25. ^ a b Krahulec J, Krahulcová J (July 2006). "Increase in hyaluronic acid production by Streptococcus equi subsp. zooepidemicus strain deficient in beta-glucuronidase in laboratory conditions". Applied Microbiology and Biotechnology. 71 (4): 415–422. doi:10.1007/s00253-005-0173-9. PMID 16292534.
  26. ^ Zhang X, Wang M, Li T, Fu L, Cao W, Liu H (December 2016). "Construction of efficient Streptococcus zooepidemicus strains for hyaluoronic acid production based on identification of key genes involved in sucrose metabolism". AMB Express. 6 (1): 121. doi:10.1186/s13568-016-0296-7. PMC 5125315. PMID 27896786.
  27. ^ Zakeri A, Rasaee MJ, Pourzardosht N (December 2017). "Enhanced hyluronic acid production in Streptococcus zooepidemicus by over expressing HasA and molecular weight control with Niscin and glucose". Biotechnology Reports. 16: 65–70. doi:10.1016/j.btre.2017.02.007. PMC 5727345. PMID 29296591.
  28. ^ a b Duan XJ, Yang L, Zhang X, Tan WS (April 2008). "Effect of oxygen and shear stress on molecular weight of hyaluronic acid". Journal of Microbiology and Biotechnology. 18 (4): 718–724. PMID 18467866.
  29. ^ Amado IR, Vázquez JA, Pastrana L, Teixeira JA (2017). "Microbial production of hyaluronic acid from agro-industrial by-products: Molasses and corn steep liquor". Biochemical Engineering Journal. 117: 181–187. Bibcode:2017BioEJ.117..181A. doi:10.1016/j.bej.2016.09.017. hdl:10261/140221.
  30. ^ a b Liu J, Wang Y, Li Z, Ren Y, Zhao Y, Zhao G (October 2018). "Efficient production of high-molecular-weight hyaluronic acid with a two-stage fermentation". RSC Advances. 8 (63): 36167–36171. Bibcode:2018RSCAd...836167L. doi:10.1039/C8RA07349J. PMC 9088804. PMID 35558483.
  31. ^ Li Y, Li G, Zhao X, Shao Y, Wu M, Ma T (June 2019). "Regulation of hyaluronic acid molecular weight and titer by temperature in engineered Bacillus subtilis". 3 Biotech. 9 (6): 225. doi:10.1007/s13205-019-1749-x. PMC 6529495. PMID 31139540.
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