Wikipedia

Microbial hyaluronic acid production

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

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Some bacteria, like Streptococcus, develop an extracellular capsule that contains HA.[6] 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.[7] 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.[8]

Encoding of HA production is carried out by hasA, hasB, hasC, hasD and hasE genes in S. zooepidemicus.[9]

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

transport

[10]
hasB UDP-glucose dehydrogenase UDP-GlcA

biosynthesis

[11][12]
hasC UDP-glucose pyrophosphorylase UDP-GlcA

biosynthesis

[13]
hasD Acetyltransferase and

pyrophosphorylase (bifunctional)

UDP-GlcNAc

biosynthesis

[14]
hasE Phosphoglucoisomerase UDP-GlcNAc

biosynthesis

[14]

Genetically modified producers were developed such as Kluysveromyces  lactis,[15]  Lactococcus  lactis,[16] Bacillus  subtilis,[17] Escherichia  coli,[18]  and Corynebacterium glutamicum[19][20] because of S. zooepidemicus’s pathogeny.

Biological process

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Intracellular factors

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Metabolism

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Intermediates are used from  pathways  essential  to  support cell  growth,  such  as  the  production  of  organic  acids,  polysaccharides during the HA production.[21] 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,[22] 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.[23][24] Enzymes such as hyaluronidase,[25] β-glucuronidase[26] of S. zooepidemicus decrease yield of HA. HA concentration is increased by deletion of associated genes of these enzymes.[25][26]

On the other hand, some enzymes induce HA production like sucrose-6-phosphatate hydrolase,[27] and hyaluronan synthase.[28] Using combined approaches with these two type enzymes is a good strategy for high yield HA production.[21]

Membrane

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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.[29] 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.[29]

Environmental factors

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pH

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Organic acids formed during HA production by S. zooepidemicus cause pH to decrease[21] Although HA production without pH control is cheaper, it prefers since provides high hyaluronic acid yields..[30][31]

Temperature

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HA production is affected regarding to yield and molecular weight by temperature.[32] 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.[31]

Aeration

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Although S. zooepidemicus is an aerotolerant anaerobe, hyaluronic acid production is affected by oxygen because NADH/NAD+ balance of cells changes with oxygen amount. Controlling oxygen during the cultivation via agitation rate provides increase both HA yield and molecular weight.[33]

Culture Media Components

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The carbon source is one of the media components that has effects on production of microbial HA.[21] Although the glucose[34][35] is most used one as a carbon source for the HA production; molasses,[36] sucrose,[37] and maltose[33] are used for microbial production.

HA production needs also many amino acids in the culture media therefore nitrogen source concentration has a key.[38]

See also

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References

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  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.
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  6. ^ How is Hyaluronic Acid Powder Made, Stanford Chemicals Company, 2024.9.10
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