Cyclooxygenases are enzymes that catalyze the formation of prostanoids. Cyclooxygenases are of two types: COX-1 & COX-2.

1. CycloOXygenase 2 (COX 2)
BY Mehwish Nawaz

2. Cyclooxygenases (COX)
• Cyclooxygenases (COXs) are enzymes that catalyze the formation of
Prostanoids ( prostaglandins, thromboxanes and prostacyclins).
• Cyclooxygenases are also known as Prostaglandins H Synthase.
• This enzyme converts arachidonic acid, a fatty acid in cell membranes,
into prostaglandins, modified fatty acids attached to a ring of five
carbons.
• Prostaglandins (PGs) are hormone-like bioactive substances involved
in many physiological and pathological processes

3. Biosynthesis of Prostanoids

4. Types of COX enzyme
Conversation of Arachidonic acid to Prostaglandins is mediated by
Cyclo-oxygenases which are of two types COX 1 and COX 2.
1. COX 1 : Constitutive , activated by physiologic stimuli.
2. COX 2 : Inducible by Pro-inflammatory stimuli.
COX-1 and COX-2 are very similar in structure (60- 65% of the
sequence is conserved), however they are expressed in different parts of
the body.

5. Actions of Cyclooxygenases

6. Cyclooxygenase site, where arachidonic acid is converted into the
hydroperoxy endoperoxide ProstaGlandin G2 (PGG2).
Heme site with peroxidase activity, responsible for the conversion of PGG2
to PGH2.
• Which is then converted into prostanoids (PGD2, PGF2α PGE2,
thromboxane A2, PGI2) by specific isomerase enzymes
Active sites of COX

8. COX 2
• COX 2 is an Inducible enzyme that acts to speed up the production of
certain chemical messengers, called prostaglandins that play a key role
in promoting inflammation.
• COX-2 is located in macrophages, leukocytes and fibroblasts.
Structural Domains of COX 2
• N-terminal epidermal growth factor (EGF)
• A Membrane Binding Domain (MBD)
• A large C-terminal globular catalytic domain

9. Structure of COX 2

10. Pathway of COX enzymes

11. Prostaglandins produced by COX 2
• PGE2
• PGI2
• PGD2
• These prostaglandins are produced by COX 2 and gives signal for pain and
inflammation.
• Their production is stimulated by inflammatory cytokines and growth
factors.

12. MECHANISM OF ACTION OF
PROSTAGLANDINS VIA cAMP PATHWAY
Prostaglandin I2 (PGI2,
prostacyclin).
It causes relaxation of
vascular smooth muscle
and inhibits platelet
aggregation.

13. MECHANISM OF ACTION OF
PROSTAGLANDINS VIA IP3/DAG PATHWAY

14. Non-Steroidal Anti-Inflammatory Drugs
(NSAIDs)
• NSAIDs produce anti-inflammatory, anti-pyretic and analgesic effects.
• Finding ways of reducing pain and inflammation are key roles of
NSAIDs
• The mechanism of these drugs is due to their binding ability to the
active sites of COX , preventing the catalysis of Arachidonic acid to
prostaglandins

15. NSAIDs
• NSAIDs binds irreversibly to COX enzymes and inhibit their action i.e
the conversion of Arachidonic acid to the prostaglandins.
• NSAIDs acetylates the actives site of COX enzyme which causes
inhibition.
• Some examples of NSAIDs are:
• Aspirin
• Ibuprofen
• Piroxicam etc
• Aspirin irreversibly inactivates both COX 1 and COX 2 by acetylation of
a specific Serine residues.

16. Side effects of NSAIDs
Aspirin and other similar NSAIDs lead to excessive production of
stomach acid as well as ulceration and gastrointestinal bleeding.
NSAIDs can prolong the bleeding time
NSAIDs can increase blood pressure.
These all side effects are due to the inhibition of COX1’s house
keeping role.

17. Selective drug targeting of COX 2
• Selective drug targeting of COX 2 becomes possible by focusing on
Hydrophilic side pocket present in COX 2.

18. Categories of NSAIDs
NSAIDS can be divided into the
following categories:
Non-selective COX inhibitor (Aspirin,
Naproxen, ibuprofen and piroxicam).
Selective COX-2 inhibitors (meloxicam,
Celecoxib and diclofenac).

19. COX 2 Inhibitors (COXIBs)
• As COX 2 has role in inflammation and pyrexia. So it is desirous to
inhibit COX-2. There are different types of drugs that are used to
inhibit COX-2 enzyme.
• COX-2 inhibitors (COXIBs) are a special category of NSAIDs that
target only COX-2 enzymes.

20. Chemical structures of COXIBs

21. Celecoxib
• Since aspirin is nonselective to both
COX1 and COX2 it shows duel effects
• Celecoxib shows selectivity to COX2
thus inhibiting only the inflammatory
prostaglandins and not the COX1 house
keeping prostaglandins

22. Why is Celecoxib selective to COX 2?

23. Different mechanisms through which the COX-
2-derived prostaglandins are involved in the
carcinogenesis

24. The mechanisms by which COX-2
contributes to cancer
Activation of
carcinogens
Prostaglandins
and Apoptosis
Prostaglandins
and increased
invasiveness
Prostaglandins
and
Angiogenesis
Prostaglandins
and cell
proliferation