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FATTY ACID BIOSYNTHESIS

FATTY ACID BIOSYNTHESIS. 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

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FATTY ACID BIOSYNTHESIS

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  1. FATTY ACID BIOSYNTHESIS

  2. 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 Fatty ACID SYNTHESIS

  3. SYNTHESIS vs DEGRADATION 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

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

  5. 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 BIOSYNTHESIS of palmitate

  6. TRICARBOXYLATE SHUTTLE SYSTEM

  7. BIOSYNTHESIS OF PALMITATE Acetyl CoA Carboxylase + ADP + Pi + H+ CH3COSCoA + ATP + HCO3- - O2CCH2COSCoA MalonylCoA • Committed step in fatty acid synthesis • Reaction is irreversible • Regulation of acetyl CoAcarboxylase activity: • by palmitoylCoA • by citrate (feed-forward allosteric activation) • by insulin • by epinephrine and glucagon • MalonylCoA inhibits carnitineacyltransferase I • Blocks beta oxidation

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

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

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

  11. 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-CoAdesaturase • Both StearoylCoA and NADH will undergo two-electron oxidations in this reaction. The overall electron transfer involves a flavin-dependent cytochrome b5reductase • Three desaturating systems are present: Δ9, Δ6, Δ5 • All three are subject to complex hormonal control. Activities are enhanced by insulin DESAturation

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

  13. 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) DESATURATION

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

  15. Insulin – stimulate glucose entry into cells. This upregulatesglycolysis and pyruvatedehydrogenase reaction, which provide acetyl-CoA for fatty acid synthesis. Activates pyruvatedehydrogenase complex by stimulating its dephosphorylation. • Another site of regulation is the transfer of acetyl units from the mitochondrial matrix to the cytosol. • Acetyl-CoAcarboxylase – 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 CONTROL

  16. 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. CONTROL

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