Atp Inhibition Couples Guanylyl Cyclase A And B To Cellular Energy Status

Homodimeric and heterodimeric guanylyl cyclases (GCs) regulate numerous biologic functions by catalyzing the synthesis of cGMP in response to peptide or gaseous ligands, respectively. Atrial natriuretic peptide (NP) and C‐type NP reduce the Km for GC‐A and GC‐B, respectively, by a process that requires ATP binding to a high affinity allosteric activation site in the catalytic domain with an EC50 of ~0.1 mM. Here, we show that higher physiologic concentrations of ATP inhibit GC‐A and GC‐B by binding a low affinity site with an IC50 of ~2 mM in the catalytic domain. Unlike activation, inhibition neither required the 2'ribosyl OH group of ATP nor CNP. The inhibition was mixed type and was observed with ATP and ADP but not AMP. Inhibition was competitive with the product, pyrophosphate but not the substrate, GTP. We suggest that changes in cellular ATP concentrations couple GC activity to the energy status of the cell by binding the pyrophosphate site.