1. FATTY ACID BIOSYNTHESIS

2. Fatty ACID SYNTHESIS
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

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

4. FATTY ACID SYNTHESIS 3 MAJOR PROCESSES
1. Biosynthesis of Palmitate from acetyl CoA
2. Chain elongation from Palmitate
3. Desaturation

5. BIOSYNTHESIS of palmitate
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

6. TRICARBOXYLATE SHUTTLE SYSTEM

7. BIOSYNTHESIS OF PALMITATE
CH3COSCoA + ATP + HCO O2CCH2COSCoA
Acetyl CoA
Carboxylase
+ ADP + Pi + H+
Malonyl CoA
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

8. BIOSynthesis of palmitate
Activation of acetyl CoA and malonyl CoA
CH3COSCoA CH3CO-S-ACP
-O2CCH2COSCoA O2CCH2CO-S-ACP AT
MAT
Acetyl ACP
Malonyl ACP
ACP = Acyl carrier protein
MAT = Malony/acetyl-CoA-ACP transacylase

10. Chain elongation CH3(CH2)13CH2COSCoA CH3(CH2)13CH2COCH2COSCoA
Palmitoyl CoA
CH3(CH2)13CH2COCH2COSCoA
CH3(CH2)13CH2CCH2COSCoA OH
NADH + H+
NAD+
Thiolase
Dehydrogenase
L- Configuration
CH3COSCoA
Occurs in the mitochondria and endoplasmic reticulum H

11. CHAIN elongation CH3(CH2)13CH2CCH2COSCoA CH3(CH2)13CH2C=CCOSCoAOH H
CH3(CH2)13CH2C=CCOSCoA
- H2O
Hydratase
CH3(CH2)13CH2CH2CH2COSCoA
Stearoyl CoA
NADPH + H+
NADP+
Dehydrogenase

12. DESAturation
The most common monosaturated fatty acids in animal lipids are oleic acid 18:c1Δ9 and palmitoleic acid 16:c1Δ9 (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 b5 reductase
Three desaturating systems are present: Δ9, Δ6, Δ5
All three are subject to complex hormonal control. Activities are enhanced by insulin

13. desaturation CH3(CH2)7C=C(CH2)7CO2H H Oleic acid
Plants: Further unsaturation
occurs primarily in this region
Animals: Further unsaturation
(18:19) 9
Linoleic acid (18:29, 12) ω-6
Linolenic acid (18:39, 12, 15) ω-3
Essential dietary
fatty acids in mammals

14. DESATURATION
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)

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

17. CONTROL
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

18. CONTROL
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.