Expression and selective inhibition of the constitutive and inducible forms of human cyclo-oxygenase.

Article Details

Citation

Gierse JK, Hauser SD, Creely DP, Koboldt C, Rangwala SH, Isakson PC, Seibert K

Expression and selective inhibition of the constitutive and inducible forms of human cyclo-oxygenase.

Biochem J. 1995 Jan 15;305 ( Pt 2):479-84.

PubMed ID
7832763 [ View in PubMed
]
Abstract

The enzyme cyclo-oxygenase catalyses the oxygenation of arachidonic acid, leading to the formation of prostaglandins. Recently two forms of cyclo-oxygenase have been described: a constitutive (COX-1) enzyme present in most cells and tissues, and an inducible (COX-2) isoenzyme observed in many cells in response to pro-inflammatory cytokines. Constitutive and inducible forms of human cyclo-oxygenase (hCOX-1 and hCOX-2) were cloned and expressed in insect cells, utilizing a baculovirus expression system. hCOX-1 had a specific activity of 18.8 mumol of O2/mg with a Km of 13.8 microM for arachidonate and Vmax. of 1500 nmol of O2/nmol of enzyme, whereas hCOX-2 had a specific activity of 12.2 mumol of O2/mg with a Km of 8.7 microM for arachidonate and a Vmax. of 1090 nmol of O2/nmol of enzyme. Indomethacin inhibited both hCOX-1 and hCOX-2, whereas NS-398 and Dup-697 selectively inhibited hCOX-2. Both NS-398 and Dup-697 exhibited time-dependent inactivation of hCOX-2, as did indomethacin on both enzymes. The competitive inhibitor of hCOX-1, mefenamic acid, also displayed competitive inhibition of hCOX-2. These results demonstrate the ability to generate selective non-steroidal anti-inflammatory drugs (NSAIDs), which could provide useful improvement therapeutically in the treatment of chronic inflammatory disease.

DrugBank Data that Cites this Article

Drug Targets
DrugTargetKindOrganismPharmacological ActionActions
Mefenamic acidProstaglandin G/H synthase 1ProteinHumans
Unknown
Inhibitor
Details
Mefenamic acidProstaglandin G/H synthase 2ProteinHumans
Yes
Inhibitor
Details