Regulatory aspects of glycosaminoglycan biosynthesis.
The control of glycosaminoglycan biosynthesis was investigated by studying the kinetic and regulatory properties of some enzymes involved in the formation of UDP-sugar precursors: UDP-N-acetylglucosamine 4'-epimerase, catalyzing the interconversion of hexosamine precursors and UDP-glucose dehydrogenase and UDP-glucose 4'-epimerase, utilizing UDP-glucose for the formation of uronic acid and galactose precursors. The study was carried out in tissues with different glycosaminoglycan production: bovine cornea, producing both chondroitin sulfate and keratan sulfate, and newborn-pig epiphysial-plate cartilage, producing mostly chondroitin sulfate. The biosynthesis of hexosamine precursors appeared to be regulated by the value of the NAD/NADH ratio. This control mechanism regulated also the activities of both UDP-glucose dehydrogenase and UDP-glucose 4'-epimerase and, therefore, it could correlate the biosynthesis of glycosaminoglycan precursors with the redox activity of the cell. At the level of UDP-glucose utilization two other control mechanisms were demonstrated: the different affinities of UDP-glucose dehydrogenase and UDP-glucose 4'-epimerase for UDP-glucose in tissues with different glycosaminoglycan production and the cellular concentration of UDP-xylose. This sugar-nucleotide inhibited UDP-glucose dehydrogenase, but did not affect the UDP-glucose 4'-epimerase activity; therefore, and increase of its cellular concentration may result in a decreased chondroitin sulfate synthesis and in an increased keratan sulfate formation.
D000818:Animals; D000831:Animals, Newborn; D002237:Carbohydrate Dehydrogenases / Q000378:metabolism*; D002238:Carbohydrate Epimerases / Q000378:metabolism*; D002356:Cartilage / Q000201:enzymology*; D002417:Cattle; D002478:Cells, Cultured; D003315:Cornea / Q000201:enzymology*; D005347:Fibroblasts / Q000201:enzymology; D006025:Glycosaminoglycans / Q000096:biosynthesis*; D006706:Homeostasis; D006801:Humans; D007700:Kinetics; D012867:Skin / Q000201:enzymology; D013552:Swine; D014534:UDPglucose 4-Epimerase / Q000378:metabolism; D014533:Uridine Diphosphate Glucose Dehydrogenase / Q000378:metabolism*
D006025:Glycosaminoglycans; D002237:Carbohydrate Dehydrogenases; D014533:Uridine Diphosphate Glucose Dehydrogenase; D002238:Carbohydrate Epimerases; C023223:UDP-N-acetylglucosamine 4-epimerase; D014534:UDPglucose 4-Epimerase