Computational Modeling of Human 3’-Phosphoadenosine 5’-Phosphosulfate Synthase

Abstract

Listen

Translate article

The sulfur nucleotide PAPS (3’-phosphoadenosine 5’-phosphosulfate) is the universal sulfuryl donor of the cell. In mammals 3’-phosphoadenosine 5’-phosphosulfate Synthase (PAPSS), using ATP, converts biochemically inert inorganic sulfate to the metabolically active PAPS. It is a bi-functional enzyme and catalyzes the formation of PAPS in two sequential steps. In the first step, inorganic sulfate reacts with ATP to form APS and pyrophosphate. The resulting phosphoric-sulfuric anhydride bond has high energy that is the chemical basis of sulfate activation. The second step is catalyzed by the kinase domain of PAPSS and involves the reaction of APS with ATP to form PAPS and ADP. The proper function of PAPSS is essential for normal physiology in the human being. PAPSS deficiency in human results in osteochondrodysplasias or defective cartilage and bone metabolism as evidenced in the clinical condition of the recessively inherited, spondyloepimetaphyseal dysplasia (SEMD). Using a combination of homology modeling, molecular dynamics simulations and computational chemistry methods we try to understand how the three dimensional structure of PAPSS determines the enzyme function, focusing on the roles of specific amino acid residues/overall structures on the dynamics of the enzyme in aqueous solution and the related quaternary arrangements of the enzyme. Finally, we aim to predict/describe enzymatic reactions in three-dimensional space and to explore the reaction coordinate through the lens of molecular dynamics simulations.