The Growth of ADA2♦

♦ See referenced article, J. Biol. Chem. 2010, 285, 12367–12377

Humans have two known adenosine deaminase enzymes: ADA1 and ADA2. The function of ADA1 is to decrease intracellular levels of adenosine, an important signaling molecule, but one that is toxic at higher concentrations. In contrast, ADA2 is expressed extracellularly and has not only deaminase activity but also cytokine-like growth factor activity. In this Paper of the Week, Anton Zavialov and colleagues report the crystal structures of native ADA2 and ADA2 bound to the transition state analogue coformycin and provide insights into the structural basis of the catalytic/signaling activity of this protein. Although the catalytic domain of ADA2 is similar to that of ADA1, there are large differences in the arrangement of the substrate binding pockets. In addition, the structure revealed two novel and ADA2-specific domains that mediate dimerization (ADA1 is a monomer) and binding to cell surface receptors that probably respond to ADA2's growth factor activity. Extensive glycosylation, a conserved disulfide bond, and a signal peptide confirm that ADA2 is specifically designed for the extracellular environment. These structural differences account for the differing affinities of ADA1 and ADA2 for substrates and inhibitors, differences that can be exploited for rational design of ADA2-targeting drugs that can modulate its activity up or down for clinical use. For example, ADA2 inhibition may be helpful in treating lymphomas, whereas ADA2 stimulation may boost the immune systems of immunocompromised individuals.

Superposition of the ADA2 and ADA1 structures to highlight their differences. ADA2 is shown in magenta except for the putative receptor-binding domain (pink) and hairpin SH1-SH2 (red); ADA1 is in yellow except for the β2-α2 loop (green). The coformycin molecule in the ADA2 catalytic site is shown as spheres.