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Fabry disease (FD) is caused by a defective α-galactosidase A (α-GAL A) enzyme responsible for breaking down globotriaosylceramide (Gb 3 ). To develop affordable therapeutics, more effort is needed to obtain insights into the underlying mechanism of FD and understanding human α-GAL A structure and function in related animal models. We adopted  C. elegans  as a model to elucidate the sequence and 3D structure of its GANA-1 enzyme and compared it to human α-GAL A. We constructed GANA-1 3D structure by homology modelling and validated the quality of the predicted GANA-1 structure, followed by computational docking of human ligands. The GANA-1 protein shared sequence similarities up to 42.1% with the human α-GAL A  in silico  and had dual active sites. GANA-1 homology modelling showed that 11 out of 13 amino acids in the first active site of GANA-1 protein overlapped with the human α-GAL A active site, indicating the prospect for substrate cross-reaction. Computational molecular docking using human ligands like Gb 3  (first pocket) ,  4-nitrophenyl-α-D-galactopyranoside (second pocket), α-galactose (second pocket), and N-acetyl-D-galactosamine (second pocket) showed negative binding energy. This revealed that the ligands were able to bind within both GANA-1 active sites, mimicking the human α-GAL A and α-NAGA enzymes. We identified human compounds with adequate docking scores, predicting robust interactions with the GANA-1 active site. Our data suggested that the  C. elegans  GANA-1 enzyme may possess structural and functional similarities to human α-GAL A, including an intrinsic capability to metabolize Gb 3  deposits. Communicated by Ramaswamy H. Sarma

Identification of dual active sites in Caenorhabditis elegans GANA-1 protein: an ortholog of the human α-GAL a and α-NAGA enzymes