Enzymic pathways of hyaluronan catabolism.

The enzymic degradation of hyaluronan in mammalian tissues takes place in two phases, encompassing breakdown of the polysaccharide to its monosaccharide constituents and subsequent utilization of the monosaccharide products. Degradation to the monosaccharide components is effected by the concerted action of three enzymes, hyaluronidase, beta-D-glucuronidase and beta-N-acetyl-D-hexosaminidase. The relative contributions of hyaluronidase and the two exoglycosidases to the physiological catabolism of hyaluronan are not yet known but consideration of the kinetic properties of the three enzymes clearly indicates that hyaluronidase is best suited for the initial attack on the polysaccharide, inasmuch as its Km for hyaluronan is 1000- to 10,000-fold lower than that estimated for beta-D-glucuronidase. Recent investigations in the authors' laboratories have been focused on the catabolism of hyaluronan and other complex carbohydrates in liver, since the sinusoidal endothelial cells in this organ are the main sites for degradation of circulating hyaluronan. Assay of ten lysosomal hydrolases in isolated rat liver cells showed considerably higher activities in Kupffer cells and endothelial cells than in hepatocytes for nine of the enzymes, including beta-D-glucuronidase and beta-N-acetyl-D-hexosaminidase. The activity of N-acetylglucosamine-6-phosphate deacetylase, a key enzyme in the metabolism of the N-acetylglucosamine released by the lysosomal degradation of hyaluronan and other complex carbohydrates, has also been determined. High deacetylase activities were observed in both Kupffer cells and endothelial cells but, surprisingly, virtually no activity was detected in hepatocytes. This finding implies that N-acetylglucosamine cannot be degraded in hepatocytes and must be largely reutilized in the synthesis of new macromolecules. Further studies of the enzymes involved in hyaluronan degradation and N-acetylglucosamine utilization in the liver are under way.