Phosphoaspartate-forming catalytic residue

The phosphoaspartate-forming catalytic residue is a highly conserved structural motif essential for the function of several enzyme superfamilies, most notably the P-type ATPases and the Haloacid Dehalogenase (HAD) superfamily (Kuhlbrandt, 2004). In these enzymes, a specific aspartate residue acts as a nucleophile to attack a phosphate group—typically from ATP—forming a covalent, high-energy anhydride bond known as a phosphoaspartate intermediate (Burroughs et al., 2006). This intermediate is a transient state in the catalytic cycle; its formation and subsequent hydrolysis drive the large-scale conformational changes required for the active transport of ions like sodium, potassium, and calcium across cell membranes (Toyoshima et al., 2000). In prokaryotes, this mechanism is also central to two-component signaling systems, where the phosphorylation of an aspartate in a response regulator protein modulates downstream gene expression (Stock et al., 2000). Because these residues are fundamental to the activity of critical transporters, they are the primary sites of action for several major drug classes. For instance, cardiac glycosides like digoxin inhibit the Na+/K+-ATPase by binding to the E2-P state of the enzyme, while proton pump inhibitors like omeprazole target the H+/K+-ATPase, effectively halting the catalytic cycle to treat acid-related disorders (Shin et al., 2009).

Other names

Catalytic aspartatePhosphoaspartate intermediate siteAspartyl phosphate intermediateP-type ATPase phosphorylation siteEnzyme catalytic aspartate residues forming phosphoaspartate intermediates

Inhibition of the catalytic cycle by stabilizing specific conformational states (e.g., the E2-P state in P-type ATPases) or by preventing the formation and subsequent hydrolysis of the covalent phosphoaspartate intermediate.