Roles for nucleotide phosphatases in sulfate assimilation and skeletal disease

Abstract

Sulfur is an essential element to all kingdoms of life and is used in essential cellular processes including the synthesis of sulfur-containing amino acids, maintenance of cellular redox states, and incorporation into various metabolites. Inorganic sulfate, the most abundant source of environmental sulfur, is metabolized into two commonly formed nucleotide precursors: adenosine 5’-phosphosulfate (APS) and 3’-phosphoadenosine 5’-phosphosulfate (PAPS). Donation of activated sulfur occurs through a broad range of enzymatic reactions many of which consume PAPS thereby producing 3’-phosphoadenosine 5’-phosphate (PAP). Two classes of 3’-nucleotide phosphatases then hydrolyze PAP into 5’-AMP: one is evolutionarily conserved from bacteria to man and localizes to the cytoplasmic compartment, while the other is restricted to a subset of eukaryotes and is active within the Golgi lumen. Interestingly, both classes of 3’-nucleotidase are members of a structurally conserved family of lithium-inhibited phosphatases that are targets of the drug in a variety of organisms. In this review we provide an overview of sulfur assimilation and the broad regulatory roles that 3’-nucleotidases play in processes ranging from halotolerance to glycosaminoglycan sulfation. In addition, we discuss recent plant and animal studies that emphasize roles for 3’-nucleotidase function in developmental biology, physiology, and in a rare subset of human patients with skeletal abnormalities.