Download COO - UTSC

COO-
COO-
CH2
C O
CH2
CH2
COO-
COO-
COO-
AcCoA
CH2
HOC COOCH2
COO-
CO2
COOC O
CH3
CO2
O
CH3C-SCoA
or
COOC O
+
CH2
COO-
COO-
COO-
HC OH
C O
CH2
CH2
COO-
COO-
O
CH3C-SCoA
COOCH2
HOC COO-
CH2
COO-
COO-
C O
CH2
COO-
+
O
CH3C-SCoA
COO-
COO-
CH2
C O
CH2
CH2
COO-
COO-
CO2
COOC O
CH3
CO2
O
CH3C-SCoA
or
AcCoA
COOCH2
COO-
CH2
HOC COOCH2
COO-
COO-
COO-
HC OH
C O
CH2
CH2
COO-
COOCOO-
C O
+
COO-
CH2
HOC COOCH2
COO-
O
CH3C-SCoA
COOC O
CH2
COO-
+
O
CH3C-SCoA
prostaglandins
Prostaglandin H2 Synthase
NSAIDS: nonsteroidal anti inflamatory drugs inhibit formation of
prostaglandins involved in fever, pain and inflammation
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 Gprotein 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.
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.
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).
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.
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.
Synthesis of
ketone bodies
O
CH3C-SCoA
+
O
CH3C-SCoA
O
O
O
CH3C-CH2C-SCoA
CH3C-SCoA
CoASH HMGCoA synthase
OH O
bhydroxy bmethyl glutaryl CoA -OOCCH2C-CH2C-SCoA
HMGCoA
CH3
O
CH3C-SCoA
O
O
acetoacetate CH3C-CH2C-O-
Succinyl CoA
Succinate
O
CH3C-CH3
acetone
OH O
CH3C-CH2C-OH
bhydroxy butyrate
O
O
CH3C-CH2C-SCoA
CoA
Acetoacetyl CoA
O
2 CH3C-SCoA
Liver
blood
tissue
2 AcCoA
FFA
Acetone
AcAc
b-hydroxybutyrate
AcAc
b-hydroxybutyrate
AcAcCoA
AcAc
b-hydroxybutyrate
Effect of activity of circulating ketone bodies
2
X
X
non-athelete
[KB]
1
(mM)
running
X
athelete
X
X
X
X
X
X
1
X
X
2
Time (hours)
X
before activity
3