Fatty Acid Synthesis:

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Fatty Acid Synthesis Not exactly the reverse of
Fatty Acid Breakdown Takes place in the
cytoplasm Primarily in liver and adipose
tissue.
First step
Acetyl CoA Carboxylase
O
O
O
CoA
CoA
CO2, Biotin
S
HO
S
CH2
CH3
Malonyl CoA
Acetyl CoA
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After Malonyl CoA, there are no further soluble
intermediates. The remaining synthesis is
catalyzed by a single multi-functional complex,
Fatty Acid synthase. Head to Tail Dimeric
complex Intermediates remain attached to a
subunit of the synthase, ACP (acyl carrier
protein), via a phosphopantatheinate moiety
(like in Coenzyme A)
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The reactions that occur in the FAS complex
(b-reduction) are similar to Fatty Acid
degradation in that they are cyclical, but the
result is the addition of two carbons in
each cycle
b -oxidation oxidation -
hydration - oxidation - thiolysis b-reduction
condensation-reduction-dehydration-reduction
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Reaction 1 condensation
CE
Keto Acyl Synthase (CE)
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Keto-Acyl Reductase
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b-hydroxy- dehydratase
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Enoyl Reductase
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Fatty Acid Synthase Dimeric multiprotein complex
that contains all the enzymatic activities
necessary for FA synthesis, except Acetyl-CoA
carboxylase -- produces palmitic acid (160)
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b-
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Translocation
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Source of Acetyl CoA for Fatty Acid Synthesis
Glucose
CO2
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Regulation of Fatty Acid Synthesis
1) Allosteric
Long chain FAs
Citrate

-
Acetyl CoA Carboxylase
O
O
O
CoA
CoA
CO2, Biotin
S
HO
S
CH2
Malonyl CoA
Acetyl CoA
Also Malonyl CoA inhibits Carnitine Acyl
Transferase I
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2) Hormonal regulation
Glucagon
Insulin
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The Liver is the major site of Fatty Acid
synthesis and the major fatty acids produced in
the liver are palmitoleic acid (161) and
stearic acid (180)
Transport from Liver to tissues. Release Newly
synthesized FAs are condensed into
triacylglycerols. These TAGs are complexed into
VLDL particles and released to the circulation
Uptake Insulin stimulates the release of
lipoprotein lipase by Adipose cells. Cleavage
by the lipase releases the FAs, which are taken
up, reincorporated into TAGs and stored (Fat).
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Elongation and Desaturation of Fatty Acids
Both processes occur in the ER Elongation
occurs by steps similar to those catalyzed by FA
synthase (ie b-reduction). EXCEPT that 1)Fatty
Acyl-CoA (not ACP) is the substrate for
condensation with malonyl-CoA 2) Catalyzed by
individual ER localized enzymes, not a single
multiprotein complex
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Desaturation Uses molecular Oxygen (O2) as the
electron acceptor and leads to the oxidation of
both the Fatty Acid (introduction of the double
bond) and NADH
(181)
(180)
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The combination of action by the elongases and
the desaturase can generate more complex
polyunsaturated FAs
Eg. Start w/ palmitic acid (160)
desaturate
w7 unsaturated FA
Palmitoleic acid (161 D9)
elongate
181 D11
desaturate
182 D8 D11
elongate
202 D10 D13
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The combination of action by the elongases and
the desaturase can generate more complex
polyunsaturated FAs
Eg. Start w/ palmitic acid (160)
or Start w/ palmitic acid (180)
desaturate
desaturate
Palmitoleic acid (161 D9)
Oleic acid (181 D9)
elongate
w9 unsaturated FA
181 D11
desaturate
182 D8 D11
elongate
202 D10 D13
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Essential Fatty Acids
O
9
2
4
6
8
1
3
5
7
OH
Linoleic Acid 182 D9, D12
O
9
2
4
6
8
1
3
5
7
OH
Linolenic Acid 183 D9, D12, D15
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O
6
3
1
5
2
4
OH
Linoleic Acid 182 D9, D12 w6 unsaturated
fatty acid
O
1
3
2
OH
Linolenic Acid 183 D9, D12, D15 w3
unsaturated fatty acid
Obtained from Plant oils, Fish oils.
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Linoleic Acid
(204 D5, D8, D11, D14)
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Prostaglandins and Leukotrienes A large family
of bioactive lipids. Act as paracrine/autocrine
hormones Very short half lives In general
regulate local inflammation but each molecule has
specific effects eg. Prostaglandin E2 -
vasodilator Prostaglandin F2 -
vasoconstriction Prostacyclin (PGI2) -
vasodilator / inhibits platelet aggregation
Thromboxane A2 - vasoconstrictor /
stimulates platelet aggregation Different
prostaglandins are made by different cell
types. eg. Thromboxane A2 is made in platelets
Prostacyclin is produced by vascular
endothelial cells
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Structures of a few different arachidonic acid
derivatives
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Categorization of Prostaglandins I Letter
designation is based on the configuration of the
ring in the molecule
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Eicosanoids are classified into three series
based on their precursor fatty acid
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Prostagandin biosynthesis pathways are a
common drug target.
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The cyclooxygenase reaches into the membrane to
act on arachidonic acid
Crystal structure of the cyclooxygenase
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The oxidation of arachidonic acid takes place in
a hydrophobic channel within the cyclooxygenase
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The cyclooxygenase is a target for many
common non-steroidal anti-inflammatory drugs.
e.g Aspirin Ibuprofen Acetominophen
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Fatty Acids Key points
Fatty Acid Breakdown -Pathways of release by
Adipose cells/Uptake in Liver -b-oxidation
cycle -Metabolic energy derived from saturated
unsaturated FAs -Differences for VLCFAs -Ketone
Bodies Normal Pathological states
Fatty Acid Synthesis -Regulation of Acetyl CoA
carboxylase -Steps in palmitate synthesis by FA
synthase -Transport of Acetyl CoA to the
cytosol -Essential FAs -Pathways of release by
Liver/uptake by Adipose