Inhibition of adenylosuccinase by adenylophosphonopropionate and related compounds

Abstract

Adenylosuccinase (EC 4.3.2.2) from [rat] 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 Ki values between 5.4-86 nM depending on the source of enzyme. Ratios of Km/Ki with adenylosuccinate as substrate fall in the range of 44-1350. Comparison of 4 carboxyl analogs of adenylosuccinate with the corresponding phosphonate analogs shows that the phosphonates are much better inhibitors. Adenylosuccinate analogs 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.