Structure and substrate-binding mechanism, of human Ap4A hydrolase

Abstract

Asymmetric diadenosine 5′,5‴-P1,P 4-tetraphosphate (Ap4A) hydrolases play a major role in maintaining homeostasis by cleaving the metabolite diadenosine tetraphosphate (Ap4A) back into ATP and AMP. The NMR solution structures of the 17-kDa human asymmetric Ap4A hydrolase have been solved in both the presence and absence of the product ATP. The adenine moiety of the nucleotide predominantly binds in a ring stacking arrangement equivalent to that observed in the x-ray structure of the homologue from Caenorhabditis elegans. The binding site is, however, markedly divergent to that observed in the plant/pathogenic bacteria class of enzymes, opening avenues for the exploration of specific therapeu..