Biosynthesis of hyaluronic acid

6-phosphate to hexosamines. L-Glutamine can donate nitrogen for this conversion, but ammonia cannot. No added cofactor is required for this hexosamine synthesis from n-glucose 6-phosphate. 

D-Glucose appears to be incorporated as a unit into both the D-glucos-amine and D-glucuronate units of hyaluronate. 

Radioactivity introduced into hyaluronate by uridine diphosphate V-acetyl-D-glucosamine labeled with acetyl-l-C in a homogenate of Rous chicken-wing sarcoma (free from nucleoside-triphosphoric acid) is 

Uridine-5-triphosphoric acid - - iV-acetyl-D-glucosamine 1-phosphate 

L-Glutamine donates nitrogen for hexosamine synthesis in Neurospora crassa and for the n-glucosamine units of hyaluronate in streptococci. Of twenty-three amino acids (and ammonium chloride) tested with group A streptococci, L-glutamine was the only consistent nitrogen-donor for 

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Cifonelli The Biosynthesis of Hyaluronic Acid by Group A Streptococcus. IV. Role of Glucosone as an Intermediate in the Synthesis of Glucosamine. J. biol. Chemistry 216, 549 (1955)-... 

Yu H, Stephanopoulos G (2008) Metabolic engineering of Escherichia coli for biosynthesis of hyaluronic acid. Metab Eng 10 24—32... 

With hyaluronic acid, much of the informative work on its biosynthesis has accrued from studies with bacteria. Group A hemolytic streptococci have long been known (K6) to produce hyaluronic acid identical with that present in mammalian connective tissues. The participation of uridine nucleotides in the biosynthesis of hyaluronic acid is now well... 

GNAc-6-phosphate -> GNAc-l-phosphate Fig. 1. Possible mechanism of biosynthesis of hyaluronic acid. 

H7. Hedberg, H., and Moritz, U., Biosynthesis of hyaluronic acid in tissue cultures of human synovial membrane. Proc. Soc. Exptl. Biol. Med. 98, 80-84 (1958). 

Hyalm onate is produced both by animals and bacteria. It was first obtained by Meyer and Palmer from the vitreous humor of cattle eyes. Since then, it has been isolated from many sources, such as Wharton s jellyconnective tissue, skin, cock s comb, synovial fluid, Rous sarcoma, myxoedemal fluids, and encapsulated strains of hemolytic streptococci. Aerobacter aerogenes may also produce hyaluronate. Group A streptococci have been principally used for the investigation of the biosynthesis of hyaluronic acid. 

Examples of the use of induced biosynthetic effects for the deduction of the processes involved include the use of puromycin and cyclohexi-mide. These compounds, according to experiments with other systems, inhibit protein synthesis. Thus the inhibition of biosynthesis of hyaluronic acid and dermatan sulfate in human fibroblast cultures (M13, M16), of hyaluronic acid in synovial cells (S31), and of chondroitin sulfate (HI) led to the conclusion that the synthesis of protein acceptor is necessary for the polysaccharide chain initiation. Comparison of the effects of 1-butanol on the biosynthesis of chick cartilage chondroitin sulfate and streptococcal hyaluronic acid led to the suggestion that binding of Mg + ions and the uridine diphosphate moiety results in stabilization of the spatial arrangement of the specific enzymes (S47, T4). 

In the biosynthesis of hyaluronic acid by group A streptococci, no lipid intermediates appear to be involved. Chain elongation of the hyaluronic acid proceeds by the alternate addition of monosaccharides from UDP-sugars by a membrane-bound synthase system followed by the release of completed hyaluronic acid chains. 

Roseman S., Moses F.E., Ludowieg J., Dorfman A. (1953) The biosynthesis of hyaluronic acid by group A Streptococcus. Utilization of 1-C 14-glucose. Journal of Biological Chemistry, 203, 213-225. 

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