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PMID:20349118

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Citation

Sikora, J, Urinovská, J, Majer, F, Poupetová, H, Hlavatá, J, Kostrouchová, M, Ledvinová, J and Hrebícek, M (2010) Bioinformatic and biochemical studies point to AAGR-1 as the ortholog of human acid alpha-glucosidase in Caenorhabditis elegans. Mol. Cell. Biochem. 341:51-63

Abstract

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.

Links

PubMed Online version:10.1007/s11010-010-0436-3

Keywords

Acarbose/pharmacology; Animals; Caenorhabditis elegans Proteins/antagonists & inhibitors; Caenorhabditis elegans Proteins/chemistry; Caenorhabditis elegans Proteins/genetics; Catalytic Domain; Computational Biology/methods; Humans; Phylogeny; Sequence Alignment; alpha-Glucosidases/antagonists & inhibitors; alpha-Glucosidases/chemistry; alpha-Glucosidases/genetics

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

CAEEL:Q19004

located_in

GO:0005764: lysosome

ECO:0000250: sequence similarity evidence used in manual assertion

UniProtKB:P10253

C

Seeded From UniProt

complete

CAEEL:Q19004

enables

GO:0004558: alpha-1,4-glucosidase activity

ECO:0000315: mutant phenotype evidence used in manual assertion

WB:WBVar00093472

F

Seeded From UniProt

complete

CAEEL:Q19004

involved_in

GO:0005980: glycogen catabolic process

ECO:0000315: mutant phenotype evidence used in manual assertion

WB:WBVar00093472

P

Seeded From UniProt

complete

CAEEL:Q20239

located_in

GO:0005764: lysosome

ECO:0000250: sequence similarity evidence used in manual assertion

UniProtKB:P10253

C

Seeded From UniProt

complete

CAEEL:Q20239

enables

GO:0004558: alpha-1,4-glucosidase activity

ECO:0000315: mutant phenotype evidence used in manual assertion

F

Seeded From UniProt

complete

CAEEL:Q20239

involved_in

GO:0005980: glycogen catabolic process

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

CAEEL:Q21750

located_in

GO:0005764: lysosome

ECO:0000250: sequence similarity evidence used in manual assertion

UniProtKB:P10253

C

Seeded From UniProt

complete

CAEEL:Q21750

enables

GO:0004558: alpha-1,4-glucosidase activity

ECO:0000315: mutant phenotype evidence used in manual assertion

F

Seeded From UniProt

complete

CAEEL:Q21750

involved_in

GO:0005980: glycogen catabolic process

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

CAEEL:Q9U3F8

located_in

GO:0005764: lysosome

ECO:0000250: sequence similarity evidence used in manual assertion

UniProtKB:P10253

C

Seeded From UniProt

complete

CAEEL:Q9U3F8

enables

GO:0004558: alpha-1,4-glucosidase activity

ECO:0000315: mutant phenotype evidence used in manual assertion

F

Seeded From UniProt

complete

CAEEL:Q9U3F8

involved_in

GO:0005980: glycogen catabolic process

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete


See also

References

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