biochem 3.14

Fatty Acid Synthesis Overview

  • Fatty acid synthesis begins with a backup in the citric acid cycle, often occurring in a high energy state (high ATP levels).

  • Insulin and high glucose levels promote this process.

  • Backup leads to buildup of citrate, which exits the mitochondria into the cytoplasm.

Key Steps in Fatty Acid Synthesis

  • Citrate Conversion:

    • Citrate is cleaved into acetyl-CoA and oxaloacetate.

    • Acetyl-CoA is carboxylated to form malonyl-CoA (catalyzed by acetyl-CoA carboxylase, requiring ATP and biotin).

  • **Fatty Acid Synthase:

    • This multi-enzyme complex facilitates the synthesis, using malonyl-CoA and acyl-CoA.

    • Binding occurs at two thiol (thioester) sites (ACP and KS).

    • Involves a series of condensation, reduction, dehydration, and reduction reactions.

  • Carbon Loss:

    • In the condensation step, one carbon atom is lost as carbon dioxide during each cycle of chain elongation.

Requirements for Fatty Acid Synthesis

  • Energy and Co-factors Needed:

    • 8 acetyl-CoA

    • 7 ATP

    • 14 NADPH (generated during the process, specifically during reductions).

Regulation of Fatty Acid Synthesis

  • Positive Regulators:

    • Insulin (indicates energy abundance)

    • Citrate (accumulates when ATP is high, stimulating fatty acid synthesis).

  • Negative Regulators:

    • Glucagon and epinephrine (promote breakdown instead).

    • Palmitoyl-CoA (product of fatty acid synthesis) inhibits the process (feedback inhibition).

Fatty Acid Chain Length and Modification

  • Fatty acid synthesis can normally only produce up to 16-carbon chains in the cytoplasm.

  • To generate longer fatty acids (18+ carbons) or those with double bonds, involvement of the smooth endoplasmic reticulum is necessary.

  • Essential fatty acids (omega-3 and omega-6) obtained through diet are needed for the synthesis of polyunsaturated fatty acids beyond what the body can synthesize.

Triacylglycerol (TAG) Synthesis

  • TAG Structure:

    • Composed of glycerol and three fatty acids.

  • Synthesis Process:

    • Formation starts with glycerol-3-phosphate, which can be derived from glycolysis or through phosphorylation of glycerol by ATP.

    • G3P, when combined with 2 acyl-CoA molecules, forms phosphatidic acid (intermediate for both TAGs and phospholipids).

    • Phosphatidic acid can then have a phosphate group removed (using phosphatase) to free an OH group, allowing the addition of a third acyl group, thus completing the TAG.

Storage and Energy Use of TAGs

  • TAGs provide a larger energy reserve compared to carbohydrates:

    • Humans can store enough energy via TAGs to last up to 12 weeks, while glycogen stores only support energy needs for about 12 hours.

Glyceroneogenesis

  • Glyceroneogenesis allows for the synthesis of G3P when glucose is scarce via gluconeogenesis, primarily from pyruvate.

  • Key Enzyme: PEP carboxykinase (PEPCK) is crucial for converting oxaloacetate to PEP in this pathway.

Hormonal Regulation

  • Cortisol (a glucocorticoid):

    • Influences fat metabolism differently in adipose tissue vs. the liver.

    • In adipose tissue: suppresses PEPCK, reducing glycerol production, thus promoting fatty acid release.

    • In liver: increases PEPCK, enhancing glycerol formation, thus promoting TAG synthesis.

  • Glitazones (anti-diabetic drugs):

    • Mimic cortisol's effect in the liver by stimulating PEPCK, thus aiding in TAG formation to lower blood free fatty acid levels and improve insulin sensitivity.

Eicosanoids Overview

  • Eicosanoids are derived from arachidonic acid (20-carbon fatty acid).

  • Three classes:

    • Prostaglandins (involved in inflammation, pain, and fever regulation).

    • Thromboxanes (involved in blood clotting).

    • Leukotrienes (associated with asthma).

  • Arachidonic acid derived from membrane phospholipids is released by phospholipase A2.

  • Enzyme Inhibition:

    • NSAIDs (e.g., aspirin, ibuprofen) inhibit cyclooxygenase (COX) enzymes to reduce inflammation by limiting prostaglandin synthesis.

    • Steroidal anti-inflammatory drugs inhibit phospholipase, preventing arachidonic acid release.

Fatty Acid Synthesis Overview

Fatty acid synthesis is a complex biochemical process that begins with a backlog in the citric acid cycle, typically occurring when there are elevated energy levels reflected by high ATP concentrations. Insulin and high glucose levels significantly stimulate this metabolic pathway, promoting the conversion of carbohydrates into fatty acids for energy storage.

During this metabolic shift, the backup leads to an accumulation of citrate in the mitochondria, which is then transported into the cytoplasm for further processing.

Key Steps in Fatty Acid Synthesis

Citrate Conversion:

  • Citrate is cleaved into acetyl-CoA and oxaloacetate by the enzyme ATP citrate lyase. This conversion is crucial as acetyl-CoA serves as the building block for fatty acid chains.

  • The acetyl-CoA undergoes carboxylation to form malonyl-CoA, a reaction catalyzed by acetyl-CoA carboxylase (ACC), which requires ATP and biotin as co-factors to proceed effectively.

Fatty Acid Synthase:

  • The fatty acid synthesis is catalyzed by the Fatty Acid Synthase (FAS) complex, a multi-enzyme assembly that orchestrates the assembly of fatty acids by utilizing malonyl-CoA and acyl-CoA substrates.

  • Binding occurs at two critical thiol (thioester) sites on the enzyme complex, specifically the Acyl Carrier Protein (ACP) and the beta-ketoacyl-ACP synthase (KS) site.

  • The process encompasses a series of enzymatic reactions, including condensation, reduction, dehydration, and a second reduction, which collectively elongate the fatty acid chain.

Carbon Loss:

  • During the condensation step of the fatty acid chain elongation, one carbon atom (in the form of carbon dioxide) is lost with each cycle, a vital aspect of ensuring the chain length is correctly established.

Requirements for Fatty Acid Synthesis

Energy and Co-factors Needed:

  • 8 acetyl-CoA molecules are necessary for the synthesis of palmitate (the most common fatty acid).

  • 7 ATP molecules are utilized during the carboxylation of acetyl-CoA to form malonyl-CoA and in other subsequent reactions within the synthesis pathway.

  • 14 NADPH molecules are required for reductive biosynthesis, specifically generated during the oxidation of substrates in glycolysis and during the pentose phosphate pathway.

Regulation of Fatty Acid Synthesis

Positive Regulators:

  • Insulin acts as a key anabolic hormone that signals energy abundance and promotes fatty acid synthesis.

  • Citrate, which accumulates when ATP levels are high, stimulates fatty acid synthesis by allosterically activating acetyl-CoA carboxylase.

Negative Regulators:

  • Glucagon and epinephrine serve as counter-regulatory hormones that promote fatty acid breakdown instead of synthesis when energy is needed.

  • Palmitoyl-CoA, the end product of fatty acid synthesis, exerts feedback inhibition on acetyl-CoA carboxylase, thus downregulating the synthesis pathway.

Fatty Acid Chain Length and Modification

Fatty acid synthesis predominantly produces chains up to 16 carbons (palmitate) in length within the cytoplasm; however, to create longer fatty acids (18+ carbons) or fatty acids with double bonds, the smooth endoplasmic reticulum is involved. Essential fatty acids such as omega-3 and omega-6, which the body cannot synthesize, must be obtained through diet and are necessary for the formation of polyunsaturated fatty acids that play vital roles in cellular function and signaling.

Triacylglycerol (TAG) Synthesis

TAG Structure:

  • TAGs consist of a glycerol backbone esterified to three fatty acids, serving as a primary form of energy storage in adipose tissue.

Synthesis Process:

  • The formation of TAG begins with glycerol-3-phosphate (G3P), which is derived from glycolysis or through the phosphorylation of glycerol via ATP.

  • G3P combines with two acyl-CoA molecules to produce phosphatidic acid, a key intermediate for both TAGs and phospholipids.

  • Phosphatidic acid can undergo dephosphorylation by phosphatases, freeing an OH group to facilitate the attachment of a third acyl group, thereby completing the TAG structure.

Storage and Energy Use of TAGs

Triacylglycerols represent a significant energy reservoir that surpasses carbohydrates. Humans can store enough energy in TAGs to last approximately 12 weeks, in stark contrast to the mere 12 hours of energy supplied by glycogen stores.

Glyceroneogenesis

Glyceroneogenesis provides a mechanism for synthesizing G3P when glucose is scarce, utilizing gluconeogenesis primarily from pyruvate. The key enzyme involved in this pathway is PEP carboxykinase (PEPCK), which converts oxaloacetate to phosphoenolpyruvate (PEP). This process is particularly important in maintaining energy balance and supporting lipid metabolism under conditions of nutrient deprivation.

Hormonal Regulation

Cortisol (a glucocorticoid):

Cortisol exerts differing effects on fat metabolism in adipose tissue and the liver.

  • In adipose tissue, cortisol suppresses PEPCK activity, resulting in decreased glycerol production, and promotes fatty acid mobilization into circulation.

  • Conversely, in the liver, cortisol enhances PEPCK activity, increasing the synthesis of glycerol, which in turn promotes TAG synthesis for energy storage.

Glitazones (anti-diabetic drugs):

These pharmacological agents mimic cortisol’s effects in the liver by stimulating PEPCK, enhancing TAG formation, which ultimately aids in lowering plasma free fatty acid levels and improving insulin sensitivity, making them beneficial in managing type 2 diabetes.

Eicosanoids Overview

Eicosanoids are bioactive lipids derived from arachidonic acid, a 20-carbon fatty acid that plays crucial roles in various physiological and pathophysiological processes. There are three main classes of eicosanoids:

  • Prostaglandins: These molecules modulate inflammation, pain, and fever responses throughout the body.

  • Thromboxanes: These compounds are involved in the regulation of blood clotting and vascular function.

  • Leukotrienes: Primarily associated with asthmatic responses, they contribute to airway inflammation and bronchoconstriction.

Arachidonic acid is released from membrane phospholipids by the action of phospholipase A2, and its subsequent metabolism leads to the production of various eicosanoids, each playing distinct roles in health and disease.

Enzyme Inhibition:

NSAIDs (e.g., aspirin, ibuprofen) inhibit cyclooxygenase (COX) enzymes, effectively reducing inflammation and pain by limiting prostaglandin synthesis. Furthermore, steroidal anti-inflammatory drugs work by inhibiting phospholipase, preventing the release of arachidonic acid, which is critical for eicosanoid synthesis.

Fatty Acid Synthesis Overview

Q: What initiates fatty acid synthesis?A: Fatty acid synthesis begins with a backlog in the citric acid cycle, often occurring in a high energy state when ATP levels are elevated.

Q: What role do insulin and high glucose levels have in fatty acid synthesis?A: Insulin and high glucose levels promote fatty acid synthesis by signaling energy abundance and stimulating the conversion of carbohydrates into fatty acids.

Q: What happens during the buildup of citrate in fatty acid synthesis?A: The buildup of citrate leads to its exit from the mitochondria into the cytoplasm, where it is cleaved into acetyl-CoA and oxaloacetate.

Key Steps in Fatty Acid Synthesis

Q: How is citrate converted in fatty acid synthesis?A: Citrate is cleaved into acetyl-CoA and oxaloacetate by ATP citrate lyase. This acetyl-CoA is then carboxylated to form malonyl-CoA via the enzyme acetyl-CoA carboxylase.

Q: What is the role of fatty acid synthase?A: Fatty acid synthase (FAS) is a multi-enzyme complex that facilitates the synthesis of fatty acids using malonyl-CoA and acyl-CoA through a series of chemical reactions.

Q: What occurs during the condensation step of fatty acid synthesis?A: One carbon atom is lost as carbon dioxide during the condensation step, which is vital for establishing the correct chain length of the fatty acid.

Requirements for Fatty Acid Synthesis

Q: What are the energy and co-factors needed for fatty acid synthesis?A: The process requires 8 acetyl-CoA, 7 ATP, and 14 NADPH for the reductive biosynthesis of fatty acids.

Regulation of Fatty Acid Synthesis

Q: What are the positive regulators of fatty acid synthesis?A: Positive regulators include insulin and citrate, which promote the activity of acetyl-CoA carboxylase.

Q: What are the negative regulators of fatty acid synthesis?A: Negative regulators include glucagon, epinephrine, and palmitoyl-CoA, which inhibit the synthesis process when energy is needed or when fatty acids have been sufficiently produced.

Fatty Acid Chain Length and Modification

Q: What is the typical chain length produced in fatty acid synthesis?A: Fatty acid synthesis typically produces chains up to 16 carbons in length.

Q: How are longer fatty acids produced?A: Longer fatty acids (18+ carbons) require the involvement of the smooth endoplasmic reticulum and essential fatty acids must be obtained through the diet.

Triacylglycerol (TAG) Synthesis

Q: What is the structure of triacylglycerols?A: Triacylglycerols (TAGs) consist of a glycerol backbone esterified to three fatty acids, serving as a primary form of energy storage.

Q: What is the process of TAG synthesis?A: TAG synthesis begins with glycerol-3-phosphate, which combines with two acyl-CoA to form phosphatidic acid, before the third acyl group is added to complete the TAG.

Storage and Energy Use of TAGs

Q: How do TAGs compare to carbohydrates in energy storage?A: TAGs serve as a more substantial energy reserve than carbohydrates, with the ability to sustain energy needs for about 12 weeks compared to 12 hours for glycogen stores.

Glyceroneogenesis

Q: What is glyceroneogenesis?A: Glyceroneogenesis is the synthesis of glycerol-3-phosphate (G3P) from pyruvate when glucose is scarce, relying on the enzyme PEP carboxykinase (PEPCK).

Hormonal Regulation

Q: How does cortisol affect fat metabolism?A: Cortisol influences fat metabolism differently; it suppresses PEPCK in adipose tissue, leading to fatty acid mobilization, while enhancing PEPCK in the liver, promoting TAG synthesis.

Q: What role do glitazones play in lipid metabolism?A: Glitazones mimic cortisol's effects in the liver by stimulating PEPCK to promote TAG formation, lowering free fatty acid levels, and improving insulin sensitivity.

Eicosanoids Overview

Q: What are eicosanoids and their origin?A: Eicosanoids are bioactive lipids derived from arachidonic acid, a 20-carbon fatty acid essential in various physiological processes.

Q: What are the main classes of eicosanoids?A: The main classes include prostaglandins (involved in inflammation), thromboxanes (regulating blood clotting), and leukotrienes (linked to asthma).

Q: What is the role of phospholipase A2 in eicosanoid production?A: Phospholipase A2 releases arachidonic acid from membrane phospholipids, which is then metabolized to form various eicosanoids.

Q: How do NSAIDs affect eicosanoid synthesis?A: NSAIDs inhibit cyclooxygenase (COX) enzymes, reducing inflammation by limiting prostaglandin production, while steroidal drugs prevent arachidonic acid release by inhibiting phospholipase.