| Bioinformatic and biochemical studies point to AAGR-1 as the ortholog of human acid alpha-glucosidase in Caenorhabditis elegans. | |
| | |
MedLine Citation:
|
PMID: 20349118 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
|
Human acid alpha-glucosidase (GAA, EC 3.2.1.20) is a lysosomal enzyme that belongs to the glycoside hydrolase family 31 (GH31) and catalyses the hydrolysis of alpha-1,4- and alpha-1,6-glucosidic linkages at acid pH. Hereditary deficiency of GAA results in lysosomal glycogen storage disease type II (GSDII, Pompe disease). The aim of this study was to assess GH31 proteins in Caenorhabditis elegans (C. elegans) to identify the ortholog of human GAA. Bioinformatic searches for GAA ortholog in C. elegans genome revealed four acid alpha-glucosidase-related (aagr-1-4) genes. Multiple sequence alignment of AAGRs with other GH31 proteins demonstrated their evolutionary conservation. Phylogenetic analyses suggested clustering of AAGR-1 and -2 with acid-active and AAGR-3 and -4 with neutral-active GH31 enzymes. In order to prove the AAGRs' predicted alpha-glucosidase activity, we performed RNA interference of all four aagr genes. The impact on the alpha-glucosidase activity was evaluated at pH 4.0 (acid) and pH 6.5 (neutral), with or without the inhibitor acarbose. AAGR-1 and -2 expressed acidic alpha-glucosidase activity; on the contrary, AAGR-3 not -4 represented the predominant neutral alpha-glucosidase activity in C. elegans. Similar results were obtained in each of aagr-1 and -4 deletion mutants. Moreover, based on our structural models of AAGRs and these biochemical experiments, we hypothesize that the enzymatic sensitivity of AAGR-2 and human maltase-glucoamylase to the inhibitor acarbose is associated with a tyrosine residue in the GH31 active site, whereas acarbose resistance of AAGR-1 and human GAA is associated with the corresponding tryptophane in the active site. Acid-active AAGR-1 may thus represent the ortholog of human GAA in C. elegans. |
| | |
Authors:
|
Jakub Sikora; Jana Urinovská; Filip Majer; Helena Poupetová; Jitka Hlavatá; Marta Kostrouchová; Jana Ledvinová; Martin Hrebícek |
Related Documents
:
|
6820168 - The pericardium as a source of prostacyclin in the dog, ox and rat. 17419638 - Efficiency of natural phenolic compounds regenerating alpha-tocopherol from alpha-tocop... 20347318 - New aromatic monoesters of alpha-aminoaralkylphosphonic acids as inhibitors of aminopep... 10933888 - Essential role of trehalose in the synthesis and subsequent metabolism of corynomycolic... 3432318 - Acceptability by rats of aqueous solutions of amino acid analogues. 15613978 - Folic acid improves baroreceptor sensitivity in hypertension. |
Publication Detail:
|
Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2010-03-27 |
Journal Detail:
|
Title: Molecular and cellular biochemistry Volume: 341 ISSN: 1573-4919 ISO Abbreviation: Mol. Cell. Biochem. Publication Date: 2010 Aug |
Date Detail:
|
Created Date: 2010-07-26 Completed Date: 2010-12-06 Revised Date: - |
Medline Journal Info:
|
Nlm Unique ID: 0364456 Medline TA: Mol Cell Biochem Country: Netherlands |
Other Details:
|
Languages: eng Pagination: 51-63 Citation Subset: IM |
Affiliation:
|
1st Faculty of Medicine, Institute of Inherited Metabolic Disorders, Charles University in Prague, Ke Karlovu 2, Prague 2, Czech Republic. jakub.sikora@lf1.cuni.cz |
Export Citation:
|
APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
|
Acarbose
/
pharmacology Animals Caenorhabditis elegans Proteins / antagonists & inhibitors, chemistry, genetics* Catalytic Domain Computational Biology / methods Humans Phylogeny Sequence Alignment alpha-Glucosidases / antagonists & inhibitors, chemistry, genetics* |
| Chemical | |
Reg. No./Substance:
|
0/Caenorhabditis elegans Proteins; 56180-94-0/Acarbose; EC 3.2.1.20/Aagr-1 protein, C elegans; EC 3.2.1.20/GAA protein, human; EC 3.2.1.20/alpha-Glucosidases |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
Previous Document: Regucalcin and metabolic disorders: osteoporosis and hyperlipidemia are induced in regucalcin transg...
Next Document: Identification, characterization, and expression of a unique secretory lipase from the human pathoge...