Hyaluronan catabolism: a new metabolic pathway.
A new pathway of intermediary metabolism is described involving the catabolism of hyaluronan. The cell surface hyaluronan receptor, CD44, two hyaluronidases, Hyal-1 and Hyal-2, and two lysosomal enzymes, beta-glucuronidase and beta-N-acetylglucosaminidase, are involved. This metabolic cascade begins in lipid raft invaginations at the cell membrane surface. Degradation of the high-molecular-weight extracellular hyaluronan occurs in a series of discreet steps generating hyaluronan chains of decreasing sizes. The biological functions of the oligomers at each quantum step differ widely, from the space-filling, hydrating, anti-angiogenic, immunosuppressive 10(4)-kDa extracellular polymer, to 20-kDa intermediate polymers that are highly angiogenic, immuno-stimulatory, and inflammatory. This is followed by degradation to small oligomers that can induce heat shock proteins and that are anti-apoptotic. The single sugar products, glucuronic acid and a glucosamine derivative are released from lysosomes to the cytoplasm, where they become available for other metabolic cycles. There are 15 g of hyaluronan in the 70-kg individual, of which 5 g are cycled daily through this pathway. Some of the steps in this catabolic cascade can be commandeered by cancer cells in the process of growth, invasion, and metastatic spread.
Stern
Robert
R
Department of Pathology, School of Medicine, University of California, San Francisco, 513 Parnassus Avenue, S-564, San Francisco, CA 94143-0511, USA. rstern@itsa.ucsf.edu
D000818:Animals; D017209:Apoptosis / Q000276:immunology / Q000502:physiology; D005944:Glucosamine / Q000276:immunology / Q000378:metabolism; D020723:Glucuronic Acid / Q000276:immunology / Q000378:metabolism; D006026:Glycoside Hydrolases / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D018960:Hyaluronan Receptors / Q000276:immunology / Q000378:metabolism*; D006820:Hyaluronic Acid / Q000276:immunology / Q000378:metabolism*; D008247:Lysosomes / Q000378:metabolism*; D021962:Membrane Microdomains / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D009081:Mucolipidoses / Q000378:metabolism; D009369:Neoplasms / Q000276:immunology / Q000378:metabolism; D018919:Neovascularization, Physiologic / Q000276:immunology / Q000502:physiology
D018960:Hyaluronan Receptors; D020723:Glucuronic Acid; D006820:Hyaluronic Acid; D006026:Glycoside Hydrolases; D005944:Glucosamine