PAPSS2

PAPSS2, or 3'-phosphoadenosine 5'-phosphosulfate synthase 2, is a cytosolic bifunctional enzyme in humans that catalyzes the production of 3'-phosphoadenosine-5'-phosphosulfate (PAPS), the universal sulfate donor used by sulfotransferases. The enzyme carries two activities in one polypeptide: ATP sulfurylase activity converts inorganic sulfate and ATP to adenosine-5'-phosphosulfate (APS) and pyrophosphate, and APS kinase activity converts APS to PAPS. PAPSS2 belongs to a small family of related enzymes, with PAPSS1 as a closely related isoform.

PAPSS2 provides the sulfate donor required for sulfation reactions that modify a wide range of molecules, including glycosaminoglycans, proteoglycans, proteins, and lipids. Sulfation of glycosaminoglycans such as chondroitin sulfate and dermatan sulfate is particularly important for the structure and function of the extracellular matrix in cartilage and other connective tissues. Because sulfation affects proteoglycan function and signaling pathways, PAPSS2 activity is important for skeletal development and joint integrity. The enzyme is expressed in many tissues but shows prominent expression in cartilage and skeletal tissues, where sulfation demand is high.

Genetic and clinical aspects: mutations in PAPSS2 have been associated with skeletal disorders, most notably autosomal recessive spondyloepimetaphyseal dysplasia and related skeletal phenotypes. Affected individuals may present with short stature, platyspondyly, metaphyseal changes, and early-onset joint issues. Research in model systems supports a role for PAPSS2 in proper sulfation and skeletal development, and reduced PAPS production can disrupt proteoglycan sulfation and extracellular matrix organization.

PAPSS2 operates alongside PAPSS1, and together they contribute to the cellular capacity for sulfation. The gene is conserved across vertebrates, and further study continues to clarify its tissue-specific regulation and contribution to cartilage biology and skeletal pathology.