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Glycobiology Advance Access published online on November 4, 2009
Glycobiology, doi:10.1093/glycob/cwp174
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© The Author 2009. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oxfordjournals.org

Identification of human hyaluronidase-4 as a novel chondroitin sulfate hydrolase that preferentially cleaves the galactosaminidic linkage in the trisulfated tetrasaccharide sequence

Tomoyuki Kaneiwa, Shuji Mizumoto, Kazuyuki Sugahara and Shuhei Yamada{dagger}

Laboratory of Proteoglycan Signaling and Therapeutics, Hokkaido University Graduate School of Life Science, Sapporo 001-0021

{dagger} To whom correspondence may be addressed: Laboratory of Proteoglycan Signaling and Therapeutics, Graduate School of Life Science, Hokkaido University, Nishi 11-choume, Kita 21-jo, Kita-ku, Sapporo, Hokkaido 001-0021, Japan. Tel.: 81-(11)-706-9055; Fax: 81-(11)-706-9055; E-mail: tjohej{at}sci.hokudai.ac.jp

Received on September 5, 2009; accepted on November 1, 2009

Human hyaluronidases have been considered to be the enzymes acting at the initial step in the catabolism of chondroitin sulfate (CS) in vivo. However, human hyaluronidase-1 digests CS more slowly than hyaluronan (HA), and its preferred substrate is HA rather than CS. We have identified a chondroitin hydrolase in Caenorhabditis elegans, which effectively degrades chondroitin but depolymerizes HA to a much lesser extent (Kaneiwa T, Yamada S, Mizumoto S, Montaño AM, Mitani S, Sugahara K. 2008. J Biol Chem. 283:14971–14979), suggesting the existence of CS-specific endoglycosidases in mammalian systems. In this study, human hyaluronidase-4 was demonstrated to be a CS-specific endo-β-N-acetylgalactosaminidase. This is the first demonstration of a CS hydrolase in higher organisms. The specificity of a purified recombinant form of the enzyme was investigated in detail through the characterization of degradation products. The best substrate of the CS hydrolase was the galactosaminidic linkage in the sequence of a trisulfated tetrasaccharide GlcUA(2-O-sulfate)-GalNAc(6-O-sulfate)-GlcUA-GalNAc(4-O- or 6-O-sulfate), where GlcUA and GalNAc represent D-glucuronic acid and N-acetyl-D-galactosamine, respectively. The disaccharide unit on the nonreducing side, GlcUA(2-O-sulfate)-GalNAc(6-O-sulfate) (D unit), is rich in shark fin cartilage CS-D among various CS isoforms. CS hydrolase will be a useful tool for investigating CS-specific functions in tissues and cells. In addition, it may well be applicable to the treatment of acute spinal cord injuries as in the case of, or instead of, the bacterial CS lyase which has been used for recent clinical trials.

Key words: chondroitin sulfate / glycosaminoglycan / hyaluronan / hyaluronidase / sulfated oligosaccharide


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