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]

Contents

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

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
GeneEnzymeFunctionReference
hasAHyaluronic acid synthaseHA synthesis and

transport

 [9]
hasBUDP-glucose dehydrogenaseUDP-GlcA

biosynthesis

 [10] [11]
hasCUDP-glucose pyrophosphorylaseUDP-GlcA

biosynthesis

 [12]
hasDAcetyltransferase and

pyrophosphorylase (bifunctional)

UDP-GlcNAc

biosynthesis

 [13]
hasEPhosphoglucoisomeraseUDP-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

Intracellular factors

Metabolism

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

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

pH

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

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

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

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

Related Research Articles

<i>Streptococcus</i> Genus of bacteria

Streptococcus is a genus of gram-positive coccus or spherical bacteria that belongs to the family Streptococcaceae, within the order Lactobacillales, in the phylum Bacillota. Cell division in streptococci occurs along a single axis, so as they grow, they tend to form pairs or chains that may appear bent or twisted. This differs from staphylococci, which divide along multiple axes, thereby generating irregular, grape-like clusters of cells. Most streptococci are oxidase-negative and catalase-negative, and many are facultative anaerobes.

<span class="mw-page-title-main">Chymosin</span> Class of enzymes

Chymosin or rennin is a protease found in rennet. It is an aspartic endopeptidase belonging to MEROPS A1 family. It is produced by newborn ruminant animals in the lining of the abomasum to curdle the milk they ingest, allowing a longer residence in the bowels and better absorption. It is widely used in the production of cheese.

<i>Aspergillus niger</i> Species of fungus

Aspergillus niger is a mold classified within the Nigri section of the Aspergillus genus. The Aspergillus genus consists of common molds found throughout the environment within soil and water, on vegetation, in fecal matter, on decomposing matter, and suspended in the air. Species within this genus often grow quickly and can sporulate within a few days of germination. A combination of characteristics unique to A. niger makes the microbe invaluable to the production of many acids, proteins and bioactive compounds. Characteristics including extensive metabolic diversity, high production yield, secretion capability, and the ability to conduct post-translational modifications are responsible for A. niger's robust production of secondary metabolites. A. niger's capability to withstand extremely acidic conditions makes it especially important to the industrial production of citric acid.

<i>Lactococcus</i> Genus of bacteria

Lactococcus is a genus of lactic acid bacteria that were formerly included in the genus Streptococcus Group N1. They are known as homofermenters meaning that they produce a single product, lactic acid in this case, as the major or only product of glucose fermentation. Their homofermentative character can be altered by adjusting environmental conditions such as pH, glucose concentration, and nutrient limitation. They are gram-positive, catalase-negative, non-motile cocci that are found singly, in pairs, or in chains. The genus contains strains known to grow at or below 7˚C.

<i>Lactococcus lactis</i> Species of bacterium

Lactococcus lactis is a gram-positive bacterium used extensively in the production of buttermilk and cheese, but has also become famous as the first genetically modified organism to be used alive for the treatment of human disease. L. lactis cells are cocci that group in pairs and short chains, and, depending on growth conditions, appear ovoid with a typical length of 0.5 - 1.5 µm. L. lactis does not produce spores (nonsporulating) and are not motile (nonmotile). They have a homofermentative metabolism, meaning they produce lactic acid from sugars. They've also been reported to produce exclusive L-(+)-lactic acid. However, reported D-(−)-lactic acid can be produced when cultured at low pH. The capability to produce lactic acid is one of the reasons why L. lactis is one of the most important microorganisms in the dairy industry. Based on its history in food fermentation, L. lactis has generally recognized as safe (GRAS) status, with few case reports of it being an opportunistic pathogen.

<span class="mw-page-title-main">Glycosaminoglycan</span> Polysaccharides found in animal tissue

Glycosaminoglycans (GAGs) or mucopolysaccharides are long, linear polysaccharides consisting of repeating disaccharide units. The repeating two-sugar unit consists of a uronic sugar and an amino sugar, except in the case of the sulfated glycosaminoglycan keratan, where, in place of the uronic sugar there is a galactose unit. GAGs are found in vertebrates, invertebrates and bacteria. Because GAGs are highly polar molecules and attract water; the body uses them as lubricants or shock absorbers.

<span class="mw-page-title-main">Hyaluronidase</span> Class of enzymes

Hyaluronidases are a family of enzymes that catalyse the degradation of hyaluronic acid. Karl Meyer classified these enzymes in 1971, into three distinct groups, a scheme based on the enzyme reaction products. The three main types of hyaluronidases are two classes of eukaryotic endoglycosidase hydrolases and a prokaryotic lyase-type of glycosidase.

<span class="mw-page-title-main">Gluconic acid</span> Chemical compound

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<span class="mw-page-title-main">Hyaluronic acid</span> Anionic, nonsulfated glycosaminoglycan

Hyaluronic acid, also called hyaluronan, is an anionic, nonsulfated glycosaminoglycan distributed widely throughout connective, epithelial, and neural tissues. It is unique among glycosaminoglycans as it is non-sulfated, forms in the plasma membrane instead of the Golgi apparatus, and can be very large: human synovial HA averages about 7 million Da per molecule, or about 20,000 disaccharide monomers, while other sources mention 3–4 million Da.

<i>Streptococcus mutans</i> Species of bacterium

Streptococcus mutans is a facultatively anaerobic, gram-positive coccus commonly found in the human oral cavity and is a significant contributor to tooth decay. It is part of the "streptococci", an informal general name for all species in the genus Streptococcus. The microbe was first described by James Kilian Clarke in 1924.

<span class="mw-page-title-main">Xylanase</span> Any of a class of enzymes that degrade the polysaccharide xylan into xylose

Endo-1,4-β-xylanase is any of a class of enzymes that degrade the linear polysaccharide xylan into xylose, thus breaking down hemicellulose, one of the major components of plant cell walls:

<span class="mw-page-title-main">Lactic acid bacteria</span> Order of bacteria

Lactobacillales are an order of gram-positive, low-GC, acid-tolerant, generally nonsporulating, nonrespiring, either rod-shaped (bacilli) or spherical (cocci) bacteria that share common metabolic and physiological characteristics. These bacteria, usually found in decomposing plants and milk products, produce lactic acid as the major metabolic end product of carbohydrate fermentation, giving them the common name lactic acid bacteria (LAB).

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<span class="mw-page-title-main">HAS2</span> Protein-coding gene in the species Homo sapiens

Hyaluronan synthase 2 is an enzyme that in humans is encoded by the HAS2 gene.

<span class="mw-page-title-main">HAS1</span> Protein-coding gene in the species Homo sapiens

Hyaluronan synthase 1 is an enzyme that in humans is encoded by the HAS1 gene.

<i>Streptococcus zooepidemicus</i> Species of bacterium

Streptococcus zooepidemicus is a Lancefield group C streptococcus that was first isolated in 1934 by P. R. Edwards, and named Animal pyogens A. It is a mucosal commensal and opportunistic pathogen that infects several animals and humans, but most commonly isolated from the uterus of mares. It is a subspecies of Streptococcus equi, a contagious upper respiratory tract infection of horses, and shares greater than 98% DNA homology, as well as many of the same virulence factors.

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n produced by certain types of bacteria. While cellulose is a basic structural material of most plants, it is also produced by bacteria, principally of the genera Komagataeibacter, Acetobacter, Sarcina ventriculi and Agrobacterium. Bacterial, or microbial, cellulose has different properties from plant cellulose and is characterized by high purity, strength, moldability and increased water holding ability. In natural habitats, the majority of bacteria synthesize extracellular polysaccharides, such as cellulose, which form protective envelopes around the cells. While bacterial cellulose is produced in nature, many methods are currently being investigated to enhance cellulose growth from cultures in laboratories as a large-scale process. By controlling synthesis methods, the resulting microbial cellulose can be tailored to have specific desirable properties. For example, attention has been given to the bacteria Komagataeibacter xylinus due to its cellulose's unique mechanical properties and applications to biotechnology, microbiology, and materials science.

<span class="mw-page-title-main">Lancefield grouping</span> System for classifying streptococci bacteria

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<span class="mw-page-title-main">Industrial microbiology</span> Branch of biotechnology

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References

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