title: Hyaluronan catabolism: a new metabolic pathway.
abstract: 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.
authors.affiliation: 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
authors.forename: Robert
authors.initials: R
authors.lastname: Stern
mesh_terms: 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
chemical_list: D018960:Hyaluronan Receptors; D020723:Glucuronic Acid; D006820:Hyaluronic Acid; D006026:Glycoside Hydrolases; D005944:Glucosamine