Allosteric regulation of prostaglandin endoperoxide H2 synthases

Prostaglandin Endoperoxide H₂ Synthases (PGHS-1 and PGHS-2), also referred to as cyclooxygenases (COX-1 and COX-2), are homodimeric enzymes that oxygenate arachidonic acid (AA) to generate Prostaglandin H₂ (PGH₂), the precursor to prostaglandins, prostacyclin, and thromboxane. The homodimeric enzymes behave as conformational heterodimers comprised of allosteric (E_allo) and catalytic (E_cat) subunits. During catalysis, only the E_cat subunit actively oxygenates AA to PGH₂. Different ligands bind to E_allo to allosterically modulate the oxygenation of AA in E_cat. Biochemical studies and functional characterizations have provided compelling evidence for asymmetry between subunits of the homodimer centered at the dimer interface. However, the structural transitions responsible for mediating intersubunit communication remain elusive. This review summarizes the pivotal experiments that have shaped our current understanding of the mechanisms underlying the allosteric modulation of PGHS-1 and PGHS-2. An ensemble-based structural model, derived from one-dimensional fluorine nuclear magnetic resonance spectroscopy, is presented to provide a framework of the conformational landscapes associated with the regulation of PGHS function.