Prostaglandin-endoperoxide synthase 1 (COX-1) (PTGS1)

Prostaglandin-endoperoxide synthase 1 (PTGS1), widely known as Cyclooxygenase-1 (COX-1), is a key enzyme in the arachidonic acid cascade, responsible for the synthesis of prostaglandin H2 [8, 12]. While most non-steroidal anti-inflammatory drugs (NSAIDs) directly and competitively inhibit the cyclooxygenase active site, paracetamol (acetaminophen) is believed to inhibit PTGS1 through an indirect mechanism involving its bioactive metabolites [6, 15]. Specifically, paracetamol is deacetylated to p-aminophenol, which is then conjugated with arachidonic acid by fatty acid amide hydrolase (FAAH) in the central nervous system to form N-arachidonoylphenolamine (AM404) [3, 5, 11]. AM404 has been shown to inhibit the activity of both COX-1 and COX-2, contributing to the central analgesic and antipyretic effects of paracetamol [2, 24]. Furthermore, paracetamol itself can act as a reducing co-substrate at the enzyme's peroxidase site, effectively lowering the peroxide tone required for cyclooxygenase activation [10, 18]. This unique mode of action, particularly the involvement of CNS-specific metabolites like AM404, distinguishes paracetamol from traditional NSAIDs and explains its minimal peripheral anti-inflammatory and anti-platelet effects [10, 19].

Other names

Cyclooxygenase-1COX-1PGH synthase 1Prostaglandin G/H synthase 1Prostaglandin H2 synthase 1

Indirect inhibition via the metabolite AM404 (N-arachidonoylphenolamine), which is formed in the CNS and inhibits COX-1/2 activity; also acts as a reducing agent at the peroxidase site of the enzyme.