CO2

1
CO2
or
CO2


COO-
2
AcCoA
CO2
or
CO2


3
prostaglandins
Prostaglandin H2 Synthase
4
NSAIDS nonsteroidal anti inflamatory drugs
inhibit formation of prostaglandins involved in
fever, pain and inflammation
5
Synthesis of prostaglandins from arachidonic
acid the cyclic pathway
What
Prostaglandins and related compounds are "local
hormones" that are synthesized from the
polyunsaturated fatty acid arachidonate. They
have specific effects on target cells close to
their site of formation. They are rapidly
degraded, so they are not transported to distal
sites within the body. Prostaglandins and related
compounds are collectively known as eicosanoids.
They are produced from arachidonic acid, a
20-carbon polyunsaturated fatty acid 
(5,8,11,14-eicosatetraenoic acid).
How
Prostaglandin receptors Prostaglandins and
related compounds are transported out of the
cells that synthesize them. Most affect other
cells by interacting with plasma membrane
G-protein coupled receptors. Depending on the
cell type, the activated G protein may stimulate
or inhibit formation of cAMP, or may activate a
phosphatidylinositol signal pathway leading to
intracellular Ca release.
Effects
They have roles in inflammation, fever,
regulation of blood pressure, blood clotting,
control of reproductive processes and tissue
growth, and regulation of the sleep/wake cycle.
6
Synthesis of prostaglandins
Prostaglandin H2 Synthase is a heme-containing
dioxygenase, bound to endoplasmic reticulum
membranes. (A dioxygenase incorporates O2 into
a substrate.) PGH2 Synthase exhibits two
catalytic activities, Cyclooxygenase and
Peroxidase. The enzyme expressing both
activities is sometimes referred to as
Cyclooxygenase, abbreviated COX.
7
COX-1 vs COX-2

• COX-1 is constitutively expressed at low levels
  in many cell types. COX-1 is essential for
  maintaining the integrity of the gastrointestinal
  epithelium.
• COX-2 expression is stimulated by growth factors,
  cytokines, and endotoxins. Inflammation is
  associated with up-regulation of COX-2 and
  increased formation of prostaglandins. COX-2
  levels increase in inflammatory disease states
  such as arthritis. Increased expression of COX-2
  is seen in some cancer cells. Angiogenesis (blood
  vessel development) essential to tumor growth
  requires COX-2. Overexpression of COX-2 leads to
  increased expression of VEGF (vascular
  endothelial growth factor).

8
NSAIDS nonsteroidal anti inflamatory drugs
inhibit formation of prostaglandins involved in
fever, pain and inflammation

• Ibuprofen and related compounds act by blocking
  the hydrophobic channel by which arachidonate
  enters the Cyclooxygenase active site.

• Aspirin acetylates a serine residue, near the
• Cyclooxygenase active site. This prevents binding
  
• of arachidonate. The inhibition by aspirin is
• irreversible. 

9
More selective COX-2 inhibitors have been
developed, e.g., Celebrex and Vioxx. COX-2
inhibitors are anti-inflammatory and block pain,
but are less likely to cause the gastric toxicity
that often accompanies chronic use of less
specific NSAIDs.  
10

Synthesis of ketone bodies
CoASH
HMGCoA synthase
bhydroxy bmethyl glutaryl CoA HMGCoA
Succinyl CoA
acetoacetate
Succinate
OH
CH3C-
acetone
H
CoA
Acetoacetyl CoA
bhydroxy butyrate
11
Liver
blood
tissue
2 AcCoA
FFA
Acetone
AcAcCoA
AcAc
AcAc
AcAc
b-hydroxybutyrate
b-hydroxybutyrate
b-hydroxybutyrate
12
Effect of activity of circulating ketone bodies
2
X
X
non-athelete
KB (mM)
1
running
X
athelete
X
X
X
X
before activity
X
X
X
X
X
1
2
3
Time (hours)