| Species-specific differences in the processing of acid α-glucosidase are due to the amino acid identity at position 201. | |
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MedLine Citation:
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PMID: 21963446 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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Acid α-glucosidase (GAA) is a lysosomal enzyme that hydrolyzes glycogen to glucose. Deficiency of GAA causes Pompe disease. Mammalian GAA is synthesized as a precursor of ~110,000Da that is N-glycosylated and targeted to the lysosome via the M6P receptors. In the lysosome, human GAA is sequentially processed by proteases to polypeptides of 76-, 19.4-, and 3.9-kDa that remain associated. Further cleavage between R(200) and A(204) inefficiently converts the 76-kDa polypeptide to the mature 70-kDa form with an additional 10.4-kDa polypeptide. GAA maturation increases its affinity for glycogen by 7-10 fold. In contrast to human GAA, processing of bovine and hamster GAA to the 70-kDa form is more rapid. A comparison of sequences surrounding the cleavage site revealed human GAA contains histidine at 201 while other species contain hydrophobic amino acids at position 201 in the otherwise conserved sequence. Recombinant human GAA (rhGAA) containing the H201L substitution was expressed in 293T cells by transfection. Pulse chase experiments in 293T cells expressing rhGAA with or without the H201L substitution revealed rapid processing of rhGAA(H201L) but not rhGAA(WT) to the 70-kDa form. Similarly, when GAA precursor was endocytosed by human Pompe fibroblasts rhGAA(H201L) but not rhGAA(WT) was rapidly converted to the 70-kDa mature GAA. These studies indicate that the amino acid at position 201 influences the rate of conversion of 76-kDa GAA to 70-kDa GAA. The GAA sequence rather than the lysosomal protease environment explains the predominance of the 76-kDa form in human tissues. |
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Authors:
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Rodney J Moreland; Sheri Higgins; Anqiang Zhou; Peter Vanstraten; Robert D Cauthron; Michael Brem; Beverly J McLarty; Mariko Kudo; William M Canfield |
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Publication Detail:
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Type: JOURNAL ARTICLE Date: 2011-9-22 |
Journal Detail:
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Title: Gene Volume: - ISSN: 1879-0038 ISO Abbreviation: - Publication Date: 2011 Sep |
Date Detail:
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Created Date: 2011-10-3 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 7706761 Medline TA: Gene Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Copyright Information:
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Copyright © 2011. Published by Elsevier B.V. |
Affiliation:
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Genzyme Corporation, 49 New York Ave, Framingham, Massachusetts 01701, USA; Siwa Biotech Corporation, Oklahoma City, Oklahoma, USA. |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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