Biochemistry of Hyaluronan

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Abstract
Hyaluronan (hyaluronic acid) is a linear polysaccharide formed from disaccharide units containing N-acetylglucosamine and glucuronic acid. It is ubiquitously distributed in the organism but is found in the highest concentrations in soft connective tissues. The molecular weight of hyaluronan is usually in the order of 106 to 107. Due to hydrogen bonding, the chain is rather stiff and the molecule behaves in solution as an extended, randomly kinked coil. Molecules of hyaluronan start to entangle already at concentrations of > 1 g/l and form a continuous polymer network. Some of the functions of the polysaccharide have been connected with the unique physical chemical characteristics of the network such as its Theological properties, flow resistance, osmotic pressure, exclusion properties and filter effect. Hyaluronan is synthesized in the cell membrane by adding monosaccharides to the reducing end of the chain. The precursors are UDP-glucuronic acid and UDP-N-acetylglucosamine. The polysaccharide grows out from the cell surface and it can be shown that fibroblasts, for exampel, surround themselves with a coat of hyaluronan. The rate of biosynthesis is regulated by various factors, such as growth factors, hormones, inflammatory mediators, etc. The responsible enzyme, hyaluronan synthase, is a phosphoprotein and the regulation of the synthetic rate is apparently via phosphorylation. The hyaluronan is at least partly carried by lymph flow from the tissues. Part of the material is taken up and degraded in the lymph nodes. Another part is carried to the general circulation and taken up in the endothelial cells in the liver sinusoids. These cells have specific receptors for hyaluronan, which also recognize chondroitin sulphate. The uptake in the liver of high-molecular weight hyaluronan is very efficient and its normal halt-life in serum is only in the order of 2 to 5 min. The polysaccharide is rapidly degraded in the lysosomes to low-molecular weight products, lactate and acetate. The total turnover of hyaluronan in serum is in the order of 10–100 mg/24 h. The normal concentration of hyaluronan in serum is > 100 μg/l with a mean of 30–40 μg/l. High serum levels have been noted in liver cirrhosis (impaired uptake in the liver) and rheumatoid arthritis (increased synthesis in the tissues). Hyaluronan has been shown to interact specifically with certain proteins and cell surfaces. It binds to proteoglycans in cartilage and other tissues and fills an important structural role in the organization of the extra-cellular matrix. Several authors report interactions with granulocytes. macrophages. immune cells, etc. and a regulation of the function of these cells has been implied.