Fatty Acid Anabolism

• Fatty acid metabolism


  • Why metabolise fatty acids?
  • They contain a lot of energy
  • They form a dense energy store
• Glucose → 17kJ/g and 38 ATP/molecule
• Fatty acid (palmitic) → 38kJ/g and 129 ATP/molecule
• Glucose → Glycogen + 2x mass of water
• Fatty acids → Triglycerides + no water
• Fatty acid anabolism

  • Almost a reverse of β oxidation
  • Use of NADPH/NADP+ rather than NAD+/NADH
  • Use of Malonyl CoA as basic unit – not Acetyl CoA
• Fatty acid anabolism

  1. Acetyl CoA + ATP + HCO3- → Malonyl CoA + ADP + Pi + H+

  2. Chain extension by 2 carbons at a time

  3. Fatty acid synthase
• Fatty acid synthase (FAS)

  • 272kDa multidomain enzyme – six active sites
  • SH ACP = Acyl carrier protein
  • KS = β Ketoacyl-ACP Synthase
  • MAT = Malonyl/Acetyl CoA-ACP Transacylase
• Fatty acid anabolism

  1. Step 1: Acetyl group transferred to KS via ACP and MAT

  2. Step 2: Malonyl transferred onto ACP by MAT

  3. Step 3: KS joins the Acetyl and Malonyl (loss of CO2)

  4. Steps 2-4: C=O to CHOH, C-C to C=C, CH to CH2
• Fatty acid anabolism

  Cycle repeated 6x until enough 2C have been added to make palmitic acid (16C), which is then released (thioesterase)
• Mammary tissue expresses a different thioesterase (enzyme), which cleaves off shorter fatty acids to go into milk Triglyceride. This process is crucial during lactation as it helps produce milk fat, which is essential for the nutritional needs of infants. The presence of this particular thioesterase ensures that the fatty acids incorporated into milk are appropriate for easy digestion and absorption by the infant.
• Lipid storage and transport

  • In anabolic state, new Fatty Acid will be converted to Triglyceride and stored
  • If synthesized in the liver, lipoproteins used to export Triglyceride to adipose and other tissues
• Lipoprotein types

  • Chylomicrons
  • VLDL - Very Low Density Lipoprotein
  • IDL - Intermediate Density Lipoprotein
  • HDL - High Density Lipoprotein
  • LDL - Low Density Lipoprotein
• Lipoproteins


  • Apolipoproteins
  • Cholesteryl ester (CE)
  • Triglyceride (TG)
  • Cholesterol (Chol)
  • Phospholipid (PL)
• Lipoprotein composition


  • Triglycerides
  • Phospholipids
  • Cholesterol/Chol esters
  • Apolipoproteins
• Lipoprotein lifespan

  • Chylomicrons - 5 min
  • VLDL - Minutes to hours
  • IDL - 3 days
  • HDL - 3 - 6 days
  • LDL - Minutes to hours
• Familial Hypercholesterolaemia (FH)

  • Defect in LDL-R gene
  • Heterozygous - 50% reduction in LDL-R, Double normal plasma LDL (2500 - 5000mg/L), Coronary Atherosclerosis; 1 in 2 chance of myocardial infarction by age 50
  • Homozygous - No LDL-R at all, Plasma LDL >6000mg/L, Coronary Atherosclerosis; high chance of death before age of 20
• The enzyme fatty acid synthase is composed of two multifunctional proteins, alpha and beta.
• Fatty acids are synthesized by the addition of carbon atoms to an existing chain through condensation reactions catalyzed by different active sites on these polypeptides.
• What is the main reason for metabolising fatty acids?

  Fatty acids are metabolised because they contain a lot of energy, significantly more than glucose. For example, palmitic acid yields 38 kJ/g and 129 ATP per molecule
• What are triglycerides (TG) and why are they important in fatty acid metabolism?

  Triglycerides form a dense energy store for fatty acids. Unlike storing glucose as glycogen which requires about twice its mass in water, storing fatty acids as triglycerides requires no additional water, making it a very efficient way to store energy
• What is the role of Acetyl CoA in fatty acid anabolism?

  Acetyl CoA is the starting point in fatty acid anabolism, where it combines with ATP and bicarbonate (HCO3-) to form Malonyl CoA, which is used to extend fatty acid chains
• How does fatty acid chain extension occur during fatty acid anabolism?

  The chain extension involves a cyclical process where the fatty acid chain grows two carbons at a time. This process involves the enzymes Acetyl CoA carboxylase and fatty acid synthase in the cytoplasm
• Describe the process of transferring an acetyl group during fatty acid anabolism

  The acetyl group is transferred to β-ketoacyl-ACP synthase (KS) via Acyl Carrier Protein (ACP) and Malonyl/Acetyl CoA-ACP Transacylase (MAT)
• What occurs during the first step of fatty acid chain elongation in anabolism?

  The first step involves the condensation of an acetyl group and a malonyl group, catalyzed by β-ketoacyl-ACP synthase (KS), resulting in the formation of acetoacetyl-ACP and the release of CO2. This step extends the fatty acid chain by two carbons
• What is the role of citrate in the export of Acetyl CoA from mitochondria to cytoplasm?


  Citrate plays a crucial role in transporting Acetyl CoA from the mitochondria, where it is produced, to the cytoplasm, where fatty acid synthesis occurs. In the cytoplasm, citrate is then converted back to Acetyl CoA and oxaloacetate (OAA)
• How is Malonyl CoA formed in fatty acid anabolism?

  Malonyl CoA is formed from Acetyl CoA in a reaction catalyzed by Acetyl CoA carboxylase. This reaction requires ATP and bicarbonate (HCO3-) and results in the formation of Malonyl CoA, ADP, inorganic phosphate (Pi), and a hydrogen ion (H+)
• What are the steps involved in the elongation cycle of fatty acid anabolism?

  The elongation cycle in fatty acid anabolism includes repeated addition of two-carbon units to the growing fatty acid chain. This involves the key steps of condensation (joining of acetyl and malonyl groups), reduction (reducing carbonyl to hydroxyl), dehydration (removing water to form a double bond), and another reduction (reducing the double bond to a single bond)
• Describe the function of fatty acid synthase in fatty acid anabolism

  Fatty acid synthase is a multi-enzyme complex that plays a critical role in fatty acid synthesis. It sequentially adds two-carbon units to the growing fatty acid chain, performing a series of reactions that include condensation, reduction, dehydration, and reduction again
• What triggers the release of palmitic acid at the end of its synthesis?

  Palmitic acid, a 16-carbon fatty acid, is released at the end of its synthesis by the action of an enzyme called thioesterase. This enzyme cleaves the thioester bond linking the fatty acid to the Acyl Carrier Protein (ACP), releasing the free fatty acid
• What impact does insulin have on fatty acid anabolism?

  Insulin promotes fatty acid synthesis. It activates Acetyl CoA carboxylase through dephosphorylation, which is a key step in converting Acetyl CoA to Malonyl CoA, thus facilitating the initiation and continuation of fatty acid synthesis
• How are newly synthesized fatty acids transported from the liver to other tissues?

  Newly synthesized fatty acids in the liver are converted to triglycerides and packaged into very low-density lipoproteins (VLDL). These lipoproteins are then exported from the liver and transported to adipose tissue and other parts of the body for storage or use
• What are the different types of lipoproteins involved in lipid transport, and what are their primary functions?

  Lipoproteins involved in lipid transport include Chylomicrons (transport dietary lipids), VLDL (transport endogenous triglycerides), LDL (transport cholesterol to cells), HDL (collects excess cholesterol for return to the liver), and IDL (intermediate form converting VLDL to LDL)
• What is the role of Acyl Carrier Protein (ACP) in fatty acid synthesis?

  Acyl Carrier Protein (ACP) is crucial in fatty acid synthesis, serving as a scaffold that holds the growing fatty acid chain as it undergoes various enzymatic reactions. It helps in transferring the acyl group to enzymes for elongation
• What process is involved in the reduction steps of fatty acid synthesis?

  The reduction steps in fatty acid synthesis typically involve the conversion of carbonyl groups (C=O) to methylene groups (CH2) using NADPH as a reducing agent. This process helps in the elongation of the fatty acid chain by adding two carbons in each cycle
• How do hormones like insulin and glucagon affect fatty acid metabolism?

  Insulin promotes fatty acid synthesis by activating key enzymes such as Acetyl CoA carboxylase, which helps convert Acetyl CoA to Malonyl CoA. Glucagon, on the other hand, inhibits these processes, slowing down fatty acid synthesis and promoting fatty acid breakdown through β-oxidation