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]
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]
Aeration
[edit]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.[32]
Culture Media Components
[edit]The carbon source is one of the media components that has effects on production of microbial HA.[20] Although the glucose[33][34] is most used one as a carbon source for the HA production; molasses,[35] sucrose,[36] and maltose[32] are used for microbial production.
HA production needs also many amino acids in the culture media therefore nitrogen source concentration has a key.[37]
See also
[edit]References
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