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Synthesis of fatty acids
This document summarizes the synthesis of fatty acids. Fatty acids are synthesized from acetyl-CoA, which is derived mostly from glucose and amino acids. Fatty acid synthesis occurs in the cytosol through a multi-enzyme complex called fatty acid synthase. The process involves repeated cycles of reactions that add two-carbon units from malonyl-CoA to an growing fatty acid chain. Triglycerides are then formed from fatty acids and stored in adipose tissue as an energy source. The synthesis is regulated by enzymes like acetyl-CoA carboxylase in response to energy levels.
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Overview of fatty acid synthesis by R. C. Gupta from the Department of Biochemistry in India.
Fatty acids synthesize from acetyl CoA, primarily from glucose and amino acids, with energy storage as lipids.Acetyl CoA serves for energy in citric acid cycle or is converted into fatty acids for storage.
Triglycerides are the main form of stored lipids in adipose tissue, providing energy during caloric insufficiency.
Synthesis includes extramitochondrial, mitochondrial, and microsomal pathways, primarily relying on acetyl CoA.
Key enzymes, including acetyl CoA carboxylase, NADPH requirement, and the multi-enzyme complex (MEC) involvement.
MEC comprises two identical subunits with various catalytic activities for simultaneous fatty acid synthesis.
The cycle involves binding malonyl groups, synthesizing butyryl, continues until producing palmitate.
MEC cannot lengthen acyl chains beyond 16 carbons; palmitate is split off for use.
Acetyl CoA, generated from pyruvate, moves to the cytosol for fatty acid synthesis.
Mainly from HMP shunt, with other minor pathways using isocitrate and malate for NADPH.
Fatty acids elongate through mitochondrial and microsomal pathways, using malonyl CoA for carbon.
Metabolism adjusts depending on energy levels; acetyl CoA carboxylase is a key regulatory enzyme.
Insulin induces acetyl CoA carboxylase synthesis; higher enzyme levels boost fatty acid synthesis.
PUFAs are essential, sourced from diet; humans synthesize monounsaturated fatty acids via desaturase system.
Arachidonic acid is synthesized from linoleic acid using desaturase, highlighting dietary PUFA requirements.
Dietary needs for w-6 and w-3 PUFAs are in a rough ratio of 10:1.
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Synthesis of fatty acids
- 1. Synthesis of FattyAcids R. C. Gupta Professor and Head Department of Biochemistry National Institute of Medical Sciences Jaipur, India
- 2. Fatty acids aresynthesized from acetyl CoA Acetyl CoA for fatty acid synthesis comes mostly from glucose and amino acids The capacity to store glucose and amino acids is limited
- 3. An average adultcan store 125-150 gm glycogen and 5-6 kg protein In terms of energy, this is less than 25,000 kcal However, the capacity to store lipids is huge When calorie intake exceeds its utilization, the excess energy is stored as lipids
- 4. Glucose is oxidizedto pyruvate by glycolysis Pyruvate is converted into acetyl CoA by oxidative decarboxylation Carbon skeletons of many amino acids are converted into acetyl CoA
- 5. If there isneed for energy, acetyl CoA is oxidized in citric acid cycle If energy is not required, acetyl CoA is converted into fatty acids Fatty acids are esterified with glycerol to form triglycerides
- 6. Triglycerides are themajor storage form of lipids They are stored in adipose tissue In times of caloric insufficiency, stored triglycerides are broken down The fatty acids released are used as a source of energy
- 7. Synthesis of fattyacids The pathways for synthesis of saturated fatty acids are: Extramitochondrial fatty acid synthesis Mitochondrial fatty acid synthesis Microsomal fatty acid synthesis
- 8. Extra-mitochondrial fatty acidsynthesis occurs in cytosol It results in de novo synthesis of fatty acids from acetyl CoA The other two pathways only elongate the pre-existing fatty acids
- 9. A pathway forthe synthesis of mono- unsaturated fatty acids is present in endoplasmic reticulum However, polyunsaturated fatty acids can't be synthesized in human beings, and must be provided in diet
- 10. This pathway ispresent in many tissues e.g. liver, kidneys, mammary glands, adipose tissue, lungs, brain etc The basic building block is acetyl CoA which is the source of all the carbon atoms of the fatty acid being synthesized Extramitochondrial fatty acids synthesis
- 11. NADPH is requiredas a reductant Carbon dioxide and biotin are required for a carboxylation reaction ATP is required as a source of energy for the carboxylation reaction The carboxylation reaction is catalysed by acetyl CoA carboxylase
- 12. All the otherenzymes required in the pathway are present in the form of a multi-enzyme complex (MEC) The MEC is made up of two identical subunits MEC is also known as fatty acid synthase (FAS)
- 13. Each subunit ofMEC/FAS contains an acyl carrier protein (ACP) and seven different catalytic activities The ACP is not a separate protein; it is just a domain in the subunit Seven different catalytic activities are also present in seven domains
- 14. ACP contains 4'-phosphopantetheineas a prosthetic group 4'-Phosphopantetheine has got a free sulphydryl (–SH) group Intermediates of fatty acid synthesis are bound to the –SH group of ACP
- 15. The enzymatic activities present ineach subunit are: Acyl transferase (AT) Malonyl transferase (MT) Condensing enzyme (CE) b-Ketoacyl reductase (KR) Dehydratase (DH) Enoyl reductase (ER) Thio esterase (TE)
- 16. AT, MT andCE of one subunit and KR, DH, ER, TE and ACP of the other subunit form one functional unit There are two functional units in each MEC The two functional units synthesize two fatty acid molecules simultaneously
- 17. CE has gota cysteine residue; its ‒SH group binds an acetyl (or acyl) group ACP has also got a ‒SH group in its prosthetic group which is flexible ACP moves the growing acyl chain from one catalytic site of MEC to another
- 20. Malonyl CoA transfersits malonyl group to ACP of one functional unit of MEC Acetyl CoA transfers its acetyl group to CE of one functional unit of MEC Subsequent reactions leading to the synthesis of fatty acid occur on the MEC
- 21. Malonyl group isdecarboxylated and condensed with acetyl group This reaction is catalysed by CE The product is a b-ketoacyl group, bound to –SH group of ACP The –SH group of CE becomes free
- 23. The b-ketoacyl groupis reduced to b-hydroxyacyl group The reaction is catalysed by KR The reducing equivalents are provided by NADPH
- 25. The –OH groupattached to b-carbon and an –H atom from a-carbon atom are removed as water The reaction is catalysed by DH The b-hydroxyacyl group is converted into an a, b-unsaturated acyl (enoyl) group
- 27. The double bondbetween the a- and b- carbon atoms is reduced to a single bond The reducing equivalents are provided by NADPH This reaction is catalysed by ER The product is a butyryl group
- 29. The butyryl groupis transferred to the –SH group of CE This completes one cycle of reactions The 2-carbon acetyl group has been converted into a 4-carbon butyryl group
- 31. Another cycle beginswith the binding of a malonyl group to ACP Two carbon atoms are added to the butyryl group by the end of the cycle These cycles continue until the acyl group is converted into a palmityl group
- 32. The MEC isincapable of increasing the length of the acyl chain beyond 16 carbon atoms Palmitate is hydrolytically split off the multi-enzyme complex by thio esterase
- 34. Acetyl CoA requiredfor fatty acid synthesis is obtained mostly from pyruvate Pyruvate, formed mainly from glucose, is converted into acetyl CoA in mitochondria When the cells have sufficient energy, acetyl CoA is used for fatty acid synthesis
- 35. While acetyl CoAis formed in mitochondria, fatty acid synthesis occurs in cytosol Acetyl CoA has to move out of mitochondria for fatty acid synthesis But mitochondrial membrane is not permeable to acetyl CoA
- 36. Acetyl CoA combineswith oxaloacetate to form citrate Citrate comes out of the mitochondria It is cleaved into oxaloacetate and acetyl CoA by ATP-citrate lyase
- 38. NADPH used infatty acid synthesis comes mainly from HMP shunt Two other minor sources are: Extramitochondrial oxidation of isocitrate Oxidative decarboxylation of malate
- 39. Extramitochondrial oxidation ofisocitrate uses NADP+ as a coenzyme It is catalysed by cytosolic isocitrate dehydrogenase Isocitrate a-Ketoglutarate + CO2 NADP+ NADPH + H+
- 40. Malate Pyruvate +CO2 NADP+ NADPH + H+ Oxidative decarboxylation of malate also uses NADP+ as a coenzyme It is catalysed by cytosolic malic enzyme
- 41. This is aminor pathway for elongation of medium-chain fatty acids It is just a reversal of b-oxidation pathway except for one reaction a, b-Unsaturated acyl CoA is reduced by a different enzyme Mitochondrial synthesis (elongation) of fatty acids
- 43. This is themajor pathway for elongation of fatty acids Two carbon atoms are added to the carboxyl end of a pre-existing fatty acid in one cycle Microsomal synthesis (elongation) of fatty acids
- 44. The carbon atomsfor elongation are provided by malonyl CoA NADPH is required as a reductant Each cycle involves four reactions
- 46. This pathway alsoconverts long-chain fatty acids into very long-chain fatty acids Very long-chain fatty acids are required in brain for the synthesis of sphingolipids
- 47. Metabolism of fattyacids is regulated according to availability of energy During energy abundance, synthesis of fatty acids in increased and their oxidation is decreased The reverse occurs during caloric insufficiency Regulation of fatty acid synthesis
- 48. Acetyl CoA carboxylaseis the regulatory enzyme of fatty acid synthesis It catalyses the committed step of the pathway which is also the rate-limiting step Acetyl CoA is regulated by allosteric mechanism and covalent modification
- 49. Citrate and palmitoylCoA are allosteric regulators of acetyl CoA carboxylase Citrate is the allosteric activator of the enzyme Palmitoyl CoA is the allosteric inhibitor of the enzyme
- 50. Concentration of citrateis high in times of caloric sufficiency Citrate activates acetyl CoA carboxylase; synthesis of malonyl CoA is increased Increased availability of malonyl CoA increases fatty acid synthesis
- 51. If palmitic acidis not being used, concentration of palmitoyl CoA increases Palmitoyl CoA inhibits acetyl CoA carboxylase Inhibition of acetyl CoA carboxylase decreases fatty acid synthesis Palmitic acid is the end product of de novo synthesis of fatty acids
- 52. Acetyl CoA carboxylaseis also subject to covalent modification Covalent modification involves its phosphorylation and dephosphorylation The phosphorylated form is inactive, and the dephosphorylated form is active
- 53. When availability ofenergy is low, glucagon secretion rises It activates adenylate cyclase in liver; the concentration of cAMP increases Increase in cAMP concentration activates protein kinase A
- 54. Active protein kinaseA phosphorylates acetyl CoA carboxylase As a result, acetyl CoA carboxylase becomes inactive Fatty acid synthesis decreases
- 55. In times ofenergy abundance, insulin secretion is high When insulin concentration is high, cAMP level decreases Protein kinase A remains inactive
- 56. Inactive protein kinaseA cannot phosphorylate acetyl CoA carboxylase As the dephosphorylated enzyme is active, fatty acid synthesis increases
- 59. Acetyl CoA carboxylaseis regulated by induction also Insulin induces the synthesis of the enzyme Increased quantity of the enzyme increases fatty acid synthesis
- 60. Unsaturated fatty acidsinclude mono- and poly-unsaturated fatty acids Linoleic acid, linolenic acid and arachi- donic acid are polyunsaturated fatty acids (PUFA) PUFA cannot be synthesized by human beings Synthesis of unsaturated fatty acids
- 61. Therefore, PUFA areknown as essential fatty acids, and must be supplied in diet Their deficiency can impair lipid transport and cause hypercholesterolaemia and dermatitis Presence of PUFA in membrane lipids increases the fluidity of membranes
- 62. Several vegetable oilsare good sources of PUFA such as: • Safflower oil • Sunflower oil • Cottonseed oil • Wheat germ oil • Soya bean oil • Rice bran oil etc
- 63. Monounsaturated fatty acidscan be synthesized by human beings They are synthesized from saturated fatty acids The synthesis occurs in endoplasmic reticulum (microsomes) of liver cells
- 64. Microsomal hydroxylase systemis required to introduce a hydroxyl group in the fatty acid NADPH is required as a source of hydrogen atoms The complete system is known as the desaturase system
- 65. The desaturase system cansynthesize: Oleic acid from stearic acid Palmitoleic acid from palmitic acid
- 67. The desaturase systemcannot introduce a double bond beyond carbon 9 Hence, linoleic acid and a-linolenic acid cannot be synthesized by this system
- 68. Arachidonic acid (20:4;5,8,11,14)is an important PUFA Several eicosanoids are synthesized from arachidonic acid Human beings can synthesize arachi- donic acid from linoleic acid Synthesis of arachidonic acid
- 69. Linoleic acid isactivated to linoleyl CoA D6-Desaturase introduces a double bond between carbon atoms 6 and 7 Two carbon atoms are added at the carboxyl end by microsomal elongation
- 70. The fatty acidformed is 20: 3; 8, 11, 14 D5-Desaturase introduces a double bond between carbon atoms 5 and 6 The fatty acid formed is 20:4; 5, 8, 11, 14 (arachidonic acid)
- 72. g-Linolenic acid isan intermediate in the synthesis of arachidonic acid Thus, both of these fatty acids can be synthesized from linoleic acid Linoleic acid and a-linolenic acid cannot be synthesized by human beings These two have to be provided in the diet
- 73. Arachidonic acid, g-linolenicacid and linoleic acid are w-6 PUFA a-Linolenic acid is an w-3 PUFA The dietary requirements of w-6 and w-3 PUFA are roughly in the ratio of 10:1