


Since carbohydrate storage reserves are limited, excess carbohydrates should be converted to fats
Fatty acid synthesis is regulated but total capacity of fat storage is not
Although it may seem that fatty acid synthesis is a complete reversal of fatty acid degradation, the pathways differ in the enzymes involved, acyl group carriers, stereochemistry of the intermediates, electron carriers, intracellular location and regulation

Synthesis Degradation
Intermediates
Site
Enzymes
Redox
Coenzymes
Linked to SH in Proteins Linked to CoASH
(Acyl Carrier Proteins)
Cytosol Mitochondria
Components of Single Peptide Separate Polypeptides
NADP
+
/ NADPH NAD
+
/ NADH


3 MAJOR PROCESSES
1. Biosynthesis of Palmitate from acetyl CoA
2. Chain elongation from Palmitate
3. Desaturation


Occurs in the cytosol

Synthesis starts with acetyl CoA

Problem:
 acetyl CoA produced in the mitochondria

Acetyl CoA cannot traverse the mitochondrial membrane

Solution:

Citrate as carrier of acetate groups via the
TRICARBOXYLATE TRANSPORT SYSTEM

CH
3
COSCoA + ATP + HCO
3
-
Acetyl CoA
O
2
CCH
2
+ ADP + P
Malonyl CoA i
+ H +
• Committed step in fatty acid synthesis
• Reaction is irreversible
• Regulation of acetyl CoA carboxylase activity: by palmitoyl CoA by citrate (feed-forward allosteric activation) by insulin by epinephrine and glucagon
• Malonyl CoA inhibits carnitine acyl transferase I
• Blocks beta oxidation


Activation of acetyl CoA and malonyl CoA
AT
CH
3
COSCoA CH
3
CO-S-ACP
Acetyl ACP
MAT
O
2
CCH
2
COSCoA O
2
CCH
2
CO-S-ACP
Malonyl ACP
ACP = Acyl carrier protein
MAT = Malony/acetyl-CoA-ACP transacylase

CH
3
(CH
2
)
13
CH
2
COSCoA Palmitoyl CoA
CH
3
COSCoA
Thiolase
CH
3
(CH
2
)
13
CH
2
COCH
2
COSCoA
NADH + H +
Dehydrogenase
NAD +
L Configuration
OH
CH
3
(CH
2
)
13
CH
2
CCH
2
COSCoA
H

Occurs in the mitochondria and endoplasmic reticulum

OH
CH
3
(CH
2
)
13
CH
2
CCH
2
COSCoA
H - H
2
O
Hydratase
H
CH
3
(CH
2
)
13
CH
2
C=CCOSCoA
NADPH + H +
H
Dehydrogenase
NADP
+
CH
3
(CH
2
)
13
CH
2
CH
2
CH
2
COSCoA
Stearoyl CoA






The most common monosaturated fatty acids in animal lipids are oleic acid 18:c1 Δ 9 and palmitoleic acid
16:c1 Δ 9 (from strearate and palmitate, respectively)
Synthesized by fatty acyl-CoA desaturase
Both Stearoyl CoA and NADH will undergo two-electron oxidations in this reaction. The overall electron transfer involves a flavin-dependent cytochrome b
5 reductase
Three desaturating systems are present: Δ9, Δ6, Δ5
All three are subject to complex hormonal control.
Activities are enhanced by insulin

CH
3
(CH
2
)
7
9
C=C(CH
2
)
7
CO
2
H
Plants: Further unsaturation occurs primarily in this region
H H
Oleic acid
(18:1  9 )
Animals: Further unsaturation occurs primarily in this region
12 9
CO
2
H
Linoleic acid (18:2  9, 12 ) ω-6
Essential dietary fatty acids in mammals
15 12 9
CO
2
H
Linolenic acid (18:3 9, 12, 15 ) ω-3


These EFA are further desaturated and elongated after ingestion to form arachidonic acid which is the precursor of a class of compounds called eicosanoids.

Eicosanoids include 2 important classes of metabolic regulators (prostaglandins and thromboxanes)

CO
2
H
Eicosapentaenoic acid (20:5 5, 8, 11, 14, 17 )
 -3 double bond
Docahexaenoic acid (22:6 4, 7, 10, 13, 16, 19 )
CO
2
H

 both are derived from α-linolenic acid (ALA)
Conversion of ALA to DHA and EPA is more efficient in women than men




Insulin – stimulate glucose entry into cells. This upregulates glycolysis and pyruvate dehydrogenase reaction, which provide acetyl-CoA for fatty acid synthesis. Activates pyruvate dehydrogenase complex by stimulating its dephosphorylation.
Another site of regulation is the transfer of acetyl units from the mitochondrial matrix to the cytosol.
Acetyl-CoA carboxylase – phosphorylated form is inactive
 polymerization is inhibited by low levels of long chain fatty acyl-CoA (feedback inhibition). Insulin lowers the levels of fatty acyl-CoA


Synthesis is controlled by the availability of reducing equivalents (NADPH). NADPH comes from both the transport of citrate out of mitochondria and pentose phosphate pathway.

The PPP is controlled through inhibition by
NADPH of glucose-6-phosphate dehydrogenase and 6-phosphogluconate dehydrogenase.