Genetic basis for hyper production of hyaluronic acid in natural and engineered microorganisms

Abstract

Hyaluronic acid, or HA, is a rigid and linear biopolymer belonging to the class of the glycosaminoglycans, and composed of repeating units of the monosaccharides glucuronic acid and N-acetylglucosamine. HA has multiple important functions in the human body, due to its properties such as bio-compatibility, lubricity and hydrophilicity, it is widely applied in the biomedical, food, health and cosmetic fields. The growing interest in this molecule has motivated the discovery of new ways of obtaining it. Traditionally, HA has been extracted from rooster comb-like animal tissues. However, due to legislation laws HA is now being produced by bacterial fermentation using Streptococcus zooepidemicus, a natural producer of HA, despite it being a pathogenic microorganism. With the expansion of new genetic engineering technologies, the use of organisms that are non-natural producers of HA has also made it possible to obtain such a polymer. Most of the published reviews have focused on HA formulation and its effects on different body tissues, whereas very few of them describe the microbial basis of HA production. Therefore, for the first time this review has compiled the molecular and genetic bases for natural HA production in microorganisms together with the main strategies employed for heterologous production of HA.

Hyaluronic Acid in the 3^rd Millennium

“…Despite the extraction protocols were improved over the years, this methodology was always hampered by several technical limitations which led to the production of highly polydispersed HA (MW ≥ 10 6 Da) with low yield [1,46]. This was due to the polymer intrinsic polydispersity, its low concentration in the tissues, and its uncontrolled degradation caused by the endogenous HYAL and the harsh isolation conditions [46,49]. Additional disadvantages of animal-derived HA were represented by the risk of biological contamination -presence of proteins, nucleic acids and viruses-and by the high purification costs [46,49,124].…”

“…infected by the Chlorovirus [49,83]-, yeasts such as Cryptococcus neoformans- [49] and molluscs [84]. However, it is not found in fungi, plants and insects [85].…”

“…The first production process applied at an industrial scale consisted in HA extraction from animal sources, such as bovine vitreous and rooster combs [46,49,124]. Despite the extraction protocols were improved over the years, this methodology was always hampered by several technical limitations which led to the production of highly polydispersed HA (MW ≥ 10 6 Da) with low yield [1,46].…”

“…This was due to the polymer intrinsic polydispersity, its low concentration in the tissues, and its uncontrolled degradation caused by the endogenous HYAL and the harsh isolation conditions [46,49]. Additional disadvantages of animal-derived HA were represented by the risk of biological contamination -presence of proteins, nucleic acids and viruses-and by the high purification costs [46,49,124]. Therefore, alternative methodologies for the industrial production of HA have been developed.…”

“…Hyaluronan is widely diffused in nature: it is present in humans, animals -such as, rabbits, bovines, roosters-, bacteria -such as Streptococcus equi, Streptococcus zooepidermicus, Streptococcus equisimilis, Streptococcus pyogenes, Streptococcus uberis, Pasteurella multocida- [49,[80][81][82], algae -such as the green algae Chlorella sp. infected by the Chlorovirus [49,83]-, yeasts such as Cryptococcus neoformans- [49] and molluscs [84].…”