The overall structure of the enzyme, based on crystallization from "E. coli", consists of 16 alpha helices which connect to 20 beta strands by turns and loops. There are four main domains: N, A, B, and C. Each domain has a central beta sheet with an alpha helix on at least one side. The N, A, and C domains are clustered together, while the B domain is slightly separated from the others and connected to them by two hinge regions. The active site is between the NAC group and the B domain. The A and B domains appear to facilitate ATP binding, while the N and C domains confer substrate specificity. The N domain is very similar to that of glycinamide ribonucleotide transformylase. Although the orientation of the B domains varies, the structure of GARS is very similar across organisms. Furthermore, the gene has been sequenced in many organisms, and "E. coli" shows between 41 and 52% identity with the GARS sequences of "B. subtilis", "S. cerevisiae", "D. melanogaster", and "D. pseudobscura". Human GARS-AIRS-GART has been shown to be most similar to that of mice, chimpanzees, and cows. Among the amino acids that are identical in "B. subtilus", "S. cerevisiae", "D. melanogaster", and "D. pseudobscura", almost a third are glycine and proline, which suggests that they play an important role in proper folding of the protein. In addition to similar structure across species, GARS as a whole has a very similar structure to D-alanine:D-alanine ligase, biotin carboxylase, and glutathione synthetase. All of these enzymes have an ATP binding domain classified as ATP-grasp domains. In humans, the gene that codes for GARS-AIRS-GART is on chromosome 21, and individuals with Down Syndrome have higher purine levels, which has been correlated with mental retardation. Thus, studies have been conducted to investigate its involvement in Down Syndrome. It has been found that GARS is expressed for longer in individuals with Down Syndrome than in unaffected individuals. In unaffected individuals, GARS is highly expressed in the cerebellum before birth but is barely expressed by three weeks after birth. In individuals with Down Syndrome, GARS expression continues until at least seven weeks after birth. This suggests that GARS may be a main contributor to the development of Down Syndrome.