Helminths (parasitic worms) secrete a range of proteins, some of which are known to modulate human host immune responses as a means to avoid expulsion from the host. Immunomodulatory abilities of helminth proteins are investigated by researchers to better understand their immunotherapeutic potential. Among the top 100 most abundant secreted proteins of the flat worm Schistosoma japonicum (S. japonicum), is the cytoplasmic asparaginyl tRNA synthetase (SJAsnRS). Overproduction of this enzyme relative to the other 19 aminoacyl-tRNA synthetase of S. japonicum led us to suspect the protein possessed a novel immunomodulatory function, similar to the asparaginyl tRNA synthetases in human and filarial nematodes. To explore structure-function relationships, we have determined the three-dimensional solution structure of the N terminus of SJAsnRS. The protein consists of 110 amino acids and was recombinantly expressed and isotopically labelled. Heteronuclear triple resonance experiments were used to assign the chemical shifts and CYANA used to determine the structure. We compared the structure to the N terminus of the B. malayi and human cytoplasmic AsnRS, each with their own unique immunomodulatory properties. Our comparisons indicate important evolutionary differences in three eukaryotic enzymes whose primary functions are all the aminoacylation of tRNA- asparagine. The observed structural differences may indicate the basis for different secondary immune responses induced by each enzyme. These findings suggest an interesting evolutionary pattern in the structures of tRNA synthetases of human parasites to act as novel immunomodulatory agents.