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Background  Human α-galactosidase A (α-GAL) and α-N-acetylgalactosaminidase (α-NAGA) are presumed to share a common ancestor. Deficiencies of these enzymes cause two well-characterized human lysosomal storage disorders (LSD) – Fabry (α-GAL deficiency) and Schindler (α-NAGA deficiency) diseases.  Caenorhabditis elegans  was previously shown to be a relevant model organism for several late endosomal/lysosomal membrane proteins associated with LSDs. The aim of this study was to identify and characterize  C. elegans  orthologs to both human lysosomal luminal proteins α-GAL and α-NAGA.    Results  BlastP searches for orthologs of human α-GAL and α-NAGA revealed a single  C. elegans  gene (R07B7.11) with homology to both human genes (α- ga lactosidase and α- N - a cetylgalactosaminidase) –  gana-1 . We cloned and sequenced the complete  gana-1  cDNA and elucidated the gene organization.  Phylogenetic analyses and homology modeling of GANA-1 based on the 3D structure of chicken α-NAGA, rice α-GAL and human α-GAL suggest a close evolutionary relationship of GANA-1 to both human α-GAL and α-NAGA.  Both α-GAL and α-NAGA enzymatic activities were detected in  C. elegans  mixed culture homogenates. However, α-GAL activity on an artificial substrate was completely inhibited by the α-NAGA inhibitor, N-acetyl-D-galactosamine.  A GANA-1 :: GFP fusion protein expressed from a transgene, containing the complete  gana-1  coding region and 3 kb of its hypothetical promoter, was not detectable under the standard laboratory conditions. The GFP signal was observed solely in a vesicular compartment of coelomocytes of the animals treated with Concanamycin A (CON A) or NH 4 Cl, agents that increase the pH of the cellular acidic compartment.  Immunofluorescence detection of the fusion protein using polyclonal anti-GFP antibody showed a broader and coarsely granular cytoplasmic expression pattern in body wall muscle cells, intestinal cells, and a vesicular compartment of coelomocytes.  Inhibition of  gana-1  by RNA interference resulted in a decrease of both α-GAL and α-NAGA activities measured in mixed stage culture homogenates but did not cause any obvious phenotype.    Conclusions  GANA-1 is a single  C. elegans  ortholog of both human α-GAL and α-NAGA proteins. Phylogenetic, homology modeling, biochemical and GFP expression analyses support the hypothesis that GANA-1 has dual enzymatic activity and is localized in an acidic cellular compartment.

bmc cell biology

Characterization of gana-1, a Caenorhabditis elegans gene encoding a single ortholog of vertebrate alpha-galactosidase and alpha-N-acetylgalactosaminidase.