Inhibition of adenylosuccinase by adenylophosphonopropionate and related compounds.

Adenylosuccinase from muscle, liver and yeast is strongly inhibited by the substrate analogue adenylophosphonopropionate (N6-(DL-1-carboxy-2-phosphonoethyl)-adenosine 5'-monophosphate). The inhibition is freely reversible and of the competitive type, with apparent K1 values between 5.4 and 86 nM depending on the source of enzyme. Ratios of Km/K1 with adenylosuccinate as substrate fall in the range of 44 to 1350. Comparison of four carboxyl analogues of adenylosuccinate with the corresponding phosphonate analogues shows that the phosphonates are much better inhibitors. Adenylosuccinate analogues in which the beta-carboxyl is replaced by other functional groups are much poorer inhibitors. The exceptionally high affinity of adenylosuccinase for adenylophosphonopropionate appears to involve the dianion of the phosphonate group.