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Originally published In Press as doi:10.1074/jbc.M508930200 on August 22, 2005

J. Biol. Chem., Vol. 280, Issue 44, 37204-37216, November 4, 2005
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Characterization of a Human Core-specific Lysosomal {alpha}1,6-Mannosidase Involved in N-Glycan Catabolism*

Chaeho Park{ddagger}§, Lu Meng{ddagger}, Leslie H. Stanton§, Robert E. Collins§, Steven W. Mast{ddagger}, Xiaobing Yi{ddagger}, Heather Strachan{ddagger}§, and Kelley W. Moremen{ddagger}§1

From the {ddagger}Complex Carbohydrate Research Center and the §Department of Biochemistry and Molecular Biology, University of Georgia, Athens, Georgia 30602

In humans and rodents, the lysosomal catabolism of core Man3GlcNAc2 N-glycan structures is catalyzed by the concerted action of several exoglycosidases, including a broad specificity lysosomal {alpha}-mannosidase (LysMan), core-specific {alpha}1,6-mannosidase, {beta}-mannosidase, and cleavage at the reducing terminus by a di-N-acetylchitobiase. We describe here the first cloning, expression, purification, and characterization of a novel human glycosylhydrolase family 38 {alpha}-mannosidase with catalytic characteristics similar to those established previously for the core-specific {alpha}1,6-mannosidase (acidic pH optimum, inhibition by swainsonine and 1,4-dideoxy-1,4-imino-D-mannitol, and stimulation by Co2+ and Zn2+). Substrate specificity studies comparing the novel human {alpha}-mannosidase with human LysMan revealed that the former enzyme efficiently cleaved only the {alpha}1-6mannose residue from Man3GlcNAc but not Man3GlcNAc2 or other larger high mannose oligosaccharides, indicating a requirement for chitobiase action before {alpha}1,6-mannosidase activity. In contrast, LysMan cleaved all of the {alpha}-linked mannose residues from high mannose oligosaccharides except the core {alpha}1-6mannose residue. {alpha}1,6-Mannosidase transcripts were ubiquitously expressed in human tissues, and expressed sequence tag searches identified homologous sequences in murine, porcine, and canine databases. No expressed sequence tags were identified for bovine {alpha}1,6-mannosidase, despite the identification of two sequence homologs in the bovine genome. The lack of conservation in 5'-flanking sequences for the bovine {alpha}1,6-mannosidase genes may lead to defective transcription similar to transcription defects in the bovine chitobiase gene. These results suggest that the chitobiase and {alpha}1,6-mannosidase function in tandem for mammalian lysosomal N-glycan catabolism.

Received for publication, August 12, 2005 , and in revised form, August 22, 2005.

* This work was supported by National Institutes of Health Research Grants GM47533, CA91295, and RR05351 (to K. W. M.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

1 To whom correspondence should be addressed. Tel.: 706-542-1705; Fax: 706-542-1759; E-mail: moremen{at}uga.edu.


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