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De novo synthesis of fatty acids (Biosynthesis of fatty acids)
The document outlines the processes of fatty acid synthesis and oxidation, highlighting the roles of various intermediates, enzymes, and coenzymes involved in these metabolic pathways. It describes the conversion of dietary carbohydrates and proteins to fatty acids, the significance of acetyl-CoA and malonyl-CoA in synthesis, and the regulation mechanisms that control fatty acid metabolism. Key steps and enzymes in the synthesis of palmitic acid, the major fatty acid produced, are detailed along with regulatory short-term and long-term controls impacting fatty acid synthesis.
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Comparison of beta-oxidation (mitochondria) and fatty acid synthesis (cytoplasm); Key enzymes and coenzymes involved.
Dietary sources provide fatty acids; surplus carbohydrates and proteins convert to fatty acids for storage.
Process occurs in cytoplasm via extramitochondrial pathway; main product is palmitic acid from acetyl CoA and NADPH.
Fatty acid synthesis occurs in stages, starting with Acetyl CoA transport and NADPH production from citrate.
Acetyl CoA converts to malonyl CoA via acetyl CoA carboxylase, a critical regulatory enzyme requiring ATP and biotin.
Multienzyme complex with seven activities for fatty acid synthesis; includes acyl carrier protein (ACP) and their functions.
Transfer of acetyl and malonyl groups; elongation of fatty acid chain with steps including condensation, reduction, and dehydration.
Fatty acid elongation completed through repeated cycles; each cycle adds 2 carbons, ending with palmitate via thioesterase.
Summary of palmitate synthesis outlines relationship of acetyl CoA, malonyl CoA, NADPH, ATP, and intermediate production.
Overview of control mechanisms regulating fatty acid synthesis including short-term and long-term factors.
Allosteric regulation by citrate stimulating acetyl CoA carboxylase; role of phosphorylation affecting enzyme activity.
Induction/repression of enzyme synthesis during varying dietary conditions; affects overall fatty acid synthesis efficiency.
Provides contact details for further inquiries and links for more presentations related to biochemistry.
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De novo synthesis of fatty acids (Biosynthesis of fatty acids)
- 2. Differenceinthetwopathways Site Mitochondria Cytoplasm Intermediates Presentas CoA derivatives Covalently linked to SH group of ACP Enzymes Present as independent proteins Multienzyme complex Sequential units 2 carbon units split off as acetyl CoA 2 carbon units added, as 3 carbon malonyl CoA Co-enzymes NAD+ & FAD are reduced NADPH used as reducing power Beta-oxidation Fatty acid synthesis
- 3. The majority offatty acids required for the body is supplied by the diet. Fatty acids are synthesized whenever there is caloric excess in the diet. Excess amount of carbohydrate & protein from the diet can be converted to fatty acids & stored as triacylglycerols.
- 4. 4 The sites ofFatty acid synthesis are…
- 5. It takes placein cytoplasm of the cell. It is referred to as extramitochondrial or cytoplasmic fatty acid synthase system. The major fatty acid synthesized de novo is palmitic acid, the 16C saturated fatty acid. Source of carbon atoms-Acetyl CoA Source of reducing equivalents-NADPH Source of energy-ATP.
- 6. Steps in fattyacids synthesis The fatty acids synthesis occurs in following stages....
- 7. Production (transport) ofAcetyl CoA & NADPH. Acetyl CoA is produced in the mitochondria by… However, mitochondria is not permeable for acetyl CoA. So, an alternate arrangement is made for the transfer of acetyl CoA to cytosol in the form of citrate.
- 8. Acetyl CoA condenseswith oxaloacetate in mitochodria to form citrate. Citrate is free transpoted to cytosol. Here it is cleaved by citrate lyase to acetyl CoA and oxaloacetate. Oxaloacetate in the cytosol is converted to malate. Malate dehydrogenase convert malate to pyruvate with production of NADPH and CO2. Transport of acetyl CoA from mitochondria to cytosol is coupled with production of NADPH and CO2. both of them are utilized for FA synthesis.
- 9. Acetyl-CoA Acetyl-CoA HMP shunt pyruvate pyruvate oxaloacetate CitrateCitrate Oxaloacetate Malate Glucose AAs Fatty acids Fattyacid CoASH NAD+ NADH+H NADP+ NADPH+H Citrate lyase Citrate synthase Malate DH Malic enzyme P. carboxylasePDH Transport of Acetyl CoA & NADPH. Mitochondrial matrix
- 10. Formation of MalonylCoA Acetyl CoA is carboxylated to malonyl CoA by acetyl CoA carboxylase. ATP dependent and Biotin is required for CO2 fixation. Acetyl CoA carboxylase is the regulatory enzyme in this pathway. Malonyl-CoA CO2 ADP+Pi CH3-C-SCoA O = Acetyl-CoA -OOC-CH2-C-SCoA O = ATP, BiotinAcetyl CoA carboxylase
- 11. • It isa polypeptide containing seven enzyme activities & acyl carrier protein (ACP) unit. • it is dimer composed of 2 identical monomer units. • Each monomer is identical having all 7 enzyme activity of fatty acid synthase. • ACP-segment contain a 4-phosphopantetheine gr. This provide sulfhydryl (-SH) group to which the growing fatty acid chain is attached. • Thus, the function of ACP in FA synthesis is analogous to coenzyme A in fatty acid oxidation. • One more –SH group is contributed by a specific cysteine recidue of 3-ketoacyl synthase. • Both –SH groups participate in fatty acid synthesis. • 2 functional subunit of FAS independently operate & two synthesize fatty acids simultaneously. Fatty acid synthase multienzyme complex
- 12. Fatty acid synthase multienzymecomplex Ketoacyl synthase Acetyl transacylase Malonyl transacylase Dehydratase Enoyl reductase Ketoacyl reductase ACP Thioesterase Dehydratase Enoyl reductase Ketoacyl reductase ACPThioesterase Ketoacyl synthase Acetyl transacylaseMalonyl transacylase Cys Cys 4’-phospho- pantetheine 4’-phospho- pantetheine SH SH SH SH Subunit division Releasing enzyme
- 13. Reactions of fattyacid synthase complex The 2 “C” fragment of acetyl CoA is transferred to ACP of FAS, by the enzyme acetyl tranacylase. Acetyl unit is then transferred to cysteine –SH of the enzyme. Thus ACP site falls vacant. The enzyme malonyl transacylase transfer malonate from malonyl CoA to ACP to form acetyl-malonyl enzyme. Now fatty acid synthase has two group attached to it. An acetyl group to cysteine –SH and malonyl group at ACP-SH. Enzyme complex is now ready for chain elongation process It done by following four steps……
- 14. Condensation acetyl gr. whichis attached to cys-SH is condenses with malonyl gr Attached to ACP to form β-Ketoacyl-ACP by losing CO2 which was added by carboxylase. This reaction is catalysed by ketoacyl synthase. Reduction Ketoacyl reductase reduces ketoacyl group to hydroxyacyl group. The reducing equivalents are supplied by NADPH. Dehydration β-hydroxyacyl-ACP undergoes dehydration by the enzyme dehydratase to form enoyl-ACP. Reduction enoyl-ACP reduced by the enzyme enoyl reductase to acyl-ACP. Here second molecule of NADPH is used. At the end of this reaction 4 ”C” atom butyryl group is formed.
- 15. • The carbonchain attached to ACP is transferred to cys-SH • the reaction of 2-6 are repeated 6 times. • Each time, the fatty acid is elongated by 2 “C” unit. • At the end of 7 cycles, a 16 carbon fatty acid (saturated) is formed at ACP. • The enzyme thioesterase separates palmitate from fatty acid synthase. • This complete fatty acid synthesis.
- 16. Malonyl-CoA CH3-C-SCoA O = Acetyl-CoA -OOC-CH2-C-SCoA O = CoA-SH ACP SH Cys SH ACPS Cys SH -C-CH3 O = ACP SH Cys S -C-CH3 O =ACP S Cys S-C-CH3 O = -C-CH2-COO- O = Acylmalonyl- enzyme Acetyl S-enzyme Acetyl S-ACP Fatty acid synthase CoA-SH 1 2 Malonyl trasacylase Acetyl CoA trasacylase Transfer of acetyl to cys
- 17. Acylmalonyl-enzyme CO2 ACP S Cys SH-C-CH3 O = -C-CH2 O = β-Ketoacyl-ACP NADP+ NADPH+H+ ACPS Cys SH -CH-CH3 OH - -C-CH2 O = β-Hydroxyacyl-ACP β-Ketoacyl reductase H2O ACP S Cys SH =CH-CH3 OH --C-CH O = Trans-enoyl-ACP β-hydroxyacyl dehydratase 3 4 5 β-Ketoacyl synthatase
- 18. ACP S Cys SH =CH-CH3 OH - -C-CH O = NADP+ NADPH+H+ Enoylreductase ACP S Cys SH -CH2-CH3-C-CH2 O =Acyl-ACP Trans-enoyl-ACP ACP SH Cys S -CH2-CH3-C-CH2 O = Acyl-S-enzyme Transfer of C chain to cys-SH ACP S Cys SH -CH2-CH3-C-(CH2)13 O = Acyl-ACP ACP SH Cys SH CH3-CH2 -(CH2)13-COO- palmitateThioesterase 6 more Cycles Of reac. 2-6 6
- 19. Summary of β-oxidationof palmitoyl CoA Palmitoyl-coA CO-S-coA CH3 1 2 3 4 5 6 7 8 9 10121416 15 13 11 1 acetyl coA + 7 Malonyl coA = 8 Acetyl-coA CH3-CO-SCoA 14 NADPH+H+ 7 Cycles of Fatty acid synthesis 7 ATP 7 ADP+Pi 14 NADP+ 6 H2O
- 20. •Two type ofcontrol mechanism regulate the fatty acid synthesis…… Regulation of fatty acid synthesis
- 21. Short-term Control Mechanism •Short-termcontrol mechanism by…
- 22. Allosteric regulation Theconc. of citrate in the cytosol is most imp. short term regulator. Citrate stimulates acetyl CoA carboxylase, which catalyzes formation of malonyl CoA(rate limiting step). The level of citrate is high when both acetyl CoA & ATP are abundant. The effect of citrate on carboxylase is opposes by palmitoyl CoA palmitoyl CoA also inhibits the transfer of citrate from mitochondria to cytosol and G6PD which generate NADPH
- 23. •Allosteric regulation • Theactivity of acetyl CoA carboxylase is also controlled by phosphorylation. • Phosphorylated enzyme is inactive. • Dephosphorylated enzyme is active. • Glucagon & epinephrine stimulate phosphorylation. • Insulin stimulate dephosphorylation.
- 24. Insulin phosphatase Acetyl CoA carboxylase (inactive) Acetyl CoA carboxylase (active) Protein kinase Glucagon,Epinephrine ATPADP P - + Malonyl-CoA Acetyl-CoA Glucose Citrate palmitate Palmitoyl CoA NADPH - - + G6PD Covalent modification Allosteric regulation Pentose phosphate pathway
- 25. • It exertsits effect slowly. • It is by induction and repression of the enzyme synthesis. • This involves change in the gene expression which controls the rate of synthesis of these enzymes. • The production of enzyme of FAS is stimulated in liver when carbohydrate and ATP are available. • And it is decreased during starvation, diabetes. LONG TERM CONTROL MECHANISM + High fat diet Starvation DM - All the enzymes of fatty acid synthesis High carbohydrate diet
- 26. 27 of 75 Contactno. – 07418831766 E mail – [email protected] For more presentation visit - http://www.slideshare.net/ashokktt Asst. Professor Dept. of Biochemistry, Dhanalakshmi Srinivasan Medical College, Perambalur