# Allosteric regulation of prostaglandin endoperoxide H2 synthases

## TL;DR

This review explains how prostaglandin synthases use allosteric regulation to control the production of important signaling molecules like prostaglandins.

## Contribution

The paper presents an ensemble-based structural model from NMR data to explain allosteric modulation in PGHS enzymes.

## Key findings

- PGHS enzymes function as conformational heterodimers with distinct allosteric and catalytic subunits.
- Ligand binding to the allosteric subunit modulates catalytic activity through intersubunit communication.
- NMR-based models reveal conformational landscapes linked to enzyme regulation.

## Abstract

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 (Eallo) and catalytic (Ecat) subunits. During catalysis, only the Ecat subunit actively oxygenates AA to PGH2. Different ligands bind to Eallo to allosterically modulate the oxygenation of AA in Ecat. 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.