17.2 Fatty Acid Synthesis
4 min read•august 9, 2024
Fatty acid synthesis is a crucial process in lipid metabolism. It involves the creation of long-chain fatty acids from simpler molecules, using enzymes like and . This process is tightly regulated and plays a key role in and cellular function.
The synthesis of fatty acids requires specific substrates and produces important products. , , and acetyl-CoA are key players, with being the primary product. Understanding this process helps us grasp how our bodies create and store energy in the form of fats.
Fatty Acid Synthesis Enzymes
Key Enzymes in Fatty Acid Synthesis
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- Acetyl-CoA carboxylase catalyzes the first committed step in fatty acid synthesis
- Converts acetyl-CoA to malonyl-CoA
- Rate-limiting enzyme in the pathway
- Regulated by various factors (allosteric regulation, hormones, phosphorylation)
- Fatty acid synthase functions as a multi-enzyme complex
- Consists of seven distinct enzymatic activities
- Carries out the main steps of fatty acid synthesis
- Organized as a dimer with two identical subunits
- Biotin serves as a coenzyme for carboxylation reactions
- Covalently attached to acetyl-CoA carboxylase
- Acts as a CO2 carrier during the carboxylation of acetyl-CoA
- Essential for the formation of malonyl-CoA
Regulation and Structure of Fatty Acid Synthase
- Fatty acid synthase regulation occurs at transcriptional and post-translational levels
- Insulin promotes fatty acid synthase expression
- Glucagon inhibits fatty acid synthase activity
- Structure of fatty acid synthase varies between prokaryotes and eukaryotes
- Prokaryotes have individual enzymes
- Eukaryotes have a large multi-enzyme complex
- Fatty acid synthase contains multiple active sites
- Acyl carrier protein (ACP) domain shuttles intermediates between active sites
- Ketoacyl synthase domain catalyzes condensation reactions
- Reductase domains perform NADPH-dependent reductions
Fatty Acid Synthesis Substrates and Products
Key Molecules in Fatty Acid Synthesis
- Malonyl-CoA functions as the primary carbon donor in fatty acid synthesis
- Formed from acetyl-CoA by acetyl-CoA carboxylase
- Provides two-carbon units for chain elongation
- Drives the reaction forward due to decarboxylation
- NADPH serves as the reducing agent in fatty acid synthesis
- Provides electrons for reduction steps
- Generated primarily through the pentose phosphate pathway
- Essential for converting double bonds to single bonds in the growing fatty acid chain
- Palmitate represents the primary product of fatty acid synthesis
- 16-carbon saturated fatty acid
- Synthesized in seven cycles of the fatty acid synthase complex
- Can be further modified to produce other fatty acids
- Acetyl-CoA acts as the initial substrate and primer for fatty acid synthesis
- Derived from various sources (glucose metabolism, amino acid catabolism)
- Converted to malonyl-CoA or used directly in the first condensation reaction
- Concentration affects the rate of fatty acid synthesis
Stoichiometry and Energy Requirements
- Overall reaction for palmitate synthesis requires multiple components
- 8 acetyl-CoA molecules
- 7 malonyl-CoA molecules
- 14 NADPH molecules
- 7 ATP molecules
- Energy cost of fatty acid synthesis includes
- ATP consumption in the formation of malonyl-CoA
- NADPH oxidation during reduction steps
- Approximately 7 ATP equivalents per acetyl-CoA incorporated
Fatty Acid Modification
Elongation of Fatty Acids
- Elongation extends fatty acids beyond 16 carbons
- Occurs in the endoplasmic reticulum
- Uses malonyl-CoA as the carbon donor
- Involves a set of enzymes distinct from fatty acid synthase
- Elongation process mirrors fatty acid synthesis
- Condensation of malonyl-CoA with the existing fatty acid
- Reduction, dehydration, and final reduction steps
- Results in a fatty acid extended by two carbons
- Elongation produces very long-chain fatty acids
- Important for membrane lipids (sphingolipids)
- Essential for myelin formation in nerve cells
- Precursors for some signaling molecules (eicosanoids)
Desaturation of Fatty Acids
- Desaturation introduces double bonds into fatty acids
- Catalyzed by desaturase enzymes
- Requires molecular oxygen and NADH or NADPH
- Occurs in the endoplasmic reticulum
- Specific desaturases introduce double bonds at different positions
- Δ9-desaturase forms the common monounsaturated fatty acids (oleic acid)
- Δ6-desaturase and Δ5-desaturase involved in polyunsaturated fatty acid synthesis
- Humans lack certain desaturases
- Cannot synthesize linoleic acid (omega-6) and α-linolenic acid (omega-3)
- These essential fatty acids must be obtained from the diet
- Precursors for important signaling molecules and membrane components
Acetyl-CoA Transport
The Citrate Shuttle Mechanism
- Citrate shuttle transports acetyl-CoA from mitochondria to cytosol
- Acetyl-CoA cannot directly cross the mitochondrial membrane
- Citrate acts as a carrier molecule
- Enables fatty acid synthesis in the cytosol
- Process involves multiple steps and enzymes
- Acetyl-CoA combines with oxaloacetate to form citrate in the mitochondria
- Citrate exits the mitochondria via the tricarboxylate transporter
- ATP-citrate lyase cleaves citrate back to acetyl-CoA and oxaloacetate in the cytosol
- Citrate shuttle links fatty acid synthesis to glucose metabolism
- Utilizes citrate from the citric acid cycle
- Provides a way to use excess glucose for lipid synthesis
- Regulated by energy status and hormonal signals
Regulation and Implications of Acetyl-CoA Transport
- Regulation of the citrate shuttle affects fatty acid synthesis
- Insulin promotes citrate transport and ATP-citrate lyase activity
- High energy states increase citrate export from mitochondria
- Citrate shuttle impacts other metabolic pathways
- Affects the balance between fatty acid synthesis and oxidation
- Influences the availability of oxaloacetate for gluconeogenesis
- Connects lipid metabolism with carbohydrate and protein metabolism
- Malfunction of the citrate shuttle can lead to metabolic disorders
- Impaired fatty acid synthesis
- Altered energy metabolism
- Potential implications for obesity and diabetes
Key Terms to Review (15)
Acetyl-CoA Carboxylase: Acetyl-CoA carboxylase is an enzyme that catalyzes the conversion of acetyl-CoA to malonyl-CoA, a crucial step in the biosynthesis of fatty acids. This enzyme plays a pivotal role in regulating lipid metabolism and is considered a key control point for fatty acid synthesis, influencing both energy storage and membrane formation.
Ampk regulation: AMPK regulation refers to the process by which AMP-activated protein kinase (AMPK) is activated and modulated in response to cellular energy levels. This crucial enzyme acts as an energy sensor, promoting energy-producing processes while inhibiting energy-consuming ones, particularly in the context of lipid metabolism and fatty acid synthesis. It plays a significant role in maintaining cellular homeostasis by ensuring that energy demands are met without depleting cellular resources.
Beta-oxidation: Beta-oxidation is the metabolic process by which fatty acids are broken down in the mitochondria to generate acetyl-CoA, which can then enter the citric acid cycle for energy production. This process involves the sequential removal of two-carbon units from the fatty acid chain, leading to the production of reducing equivalents in the form of NADH and FADH2, which are essential for ATP generation through oxidative phosphorylation.
Cell membrane structure: Cell membrane structure refers to the arrangement and composition of the lipid bilayer and associated proteins that form the outer boundary of a cell. This structure is critical for maintaining cellular integrity, facilitating communication, and regulating the movement of substances in and out of the cell, which is essential for various metabolic processes, including fatty acid synthesis.
De novo lipogenesis: De novo lipogenesis is the biochemical process through which fatty acids are synthesized from non-fat precursors, primarily glucose and other carbohydrates. This pathway plays a crucial role in energy storage and metabolic regulation, allowing organisms to convert excess carbohydrates into fatty acids that can be stored in adipose tissue for later use. It is particularly important during periods of excess caloric intake when the body needs to manage surplus energy efficiently.
Energy Storage: Energy storage refers to the methods and processes used to capture and retain energy for future use. This concept is crucial in biological systems, where energy is stored in various forms to meet the needs of the organism during different physiological states. Understanding how energy is stored helps in grasping the roles of carbohydrates, fats, and proteins in metabolism and how organisms adapt their energy usage based on availability and necessity.
Fatty acid elongation: Fatty acid elongation is the biochemical process that increases the length of fatty acid chains by adding two-carbon units to existing fatty acids. This process plays a crucial role in the synthesis of longer-chain fatty acids, which are important for various biological functions, including membrane structure and energy storage.
Fatty acid synthase: Fatty acid synthase is a multi-enzyme complex that catalyzes the biosynthesis of fatty acids from acetyl-CoA and malonyl-CoA through a series of reactions involving reduction, dehydration, and condensation. This enzyme plays a critical role in lipid metabolism and energy storage, facilitating the conversion of carbohydrates into fats in organisms.
Insulin signaling: Insulin signaling refers to the complex biological process initiated by the binding of insulin to its receptor, which triggers a cascade of events leading to cellular responses such as glucose uptake, lipid synthesis, and overall metabolic regulation. This signaling pathway is crucial for maintaining energy homeostasis and plays a vital role in how cells utilize carbohydrates and fatty acids, linking its importance to cellular energy management.
Lipid droplets: Lipid droplets are dynamic cellular organelles that store neutral lipids, such as triglycerides and cholesterol esters, serving as energy reserves and playing crucial roles in lipid metabolism. They are formed by the accumulation of lipids in the cytoplasm and are surrounded by a phospholipid monolayer, which allows for interactions with various metabolic pathways and cellular processes.
Lipolysis: Lipolysis is the metabolic process of breaking down lipids, primarily triglycerides, into glycerol and free fatty acids. This process is essential for energy production during periods of fasting or increased energy demand, as it provides substrates for various metabolic pathways. By converting stored fat into usable energy, lipolysis plays a crucial role in maintaining energy balance and supporting metabolic adaptations in different physiological states.
Malonyl-CoA: Malonyl-CoA is a crucial intermediate in the biosynthesis of fatty acids, formed by the carboxylation of acetyl-CoA. It serves as the building block for fatty acid chains during synthesis, and its regulation plays a vital role in controlling lipid metabolism, making it essential for energy homeostasis and metabolic pathways.
NADPH: NADPH, or nicotinamide adenine dinucleotide phosphate, is a coenzyme that plays a critical role in anabolic reactions by acting as a reducing agent, providing the necessary electrons for biosynthetic processes. It is primarily produced during the light reactions of photosynthesis and is essential for the Calvin cycle, as well as other metabolic pathways like the pentose phosphate pathway and fatty acid synthesis.
Palmitate: Palmitate is a saturated fatty acid with a 16-carbon chain, commonly represented as C16:0. It plays a vital role in lipid metabolism and is a key building block in the synthesis of various lipids, including triglycerides and phospholipids, which are essential for cellular structure and energy storage.
Transcription factors: Transcription factors are proteins that help regulate the transcription of specific genes by binding to nearby DNA. They play a crucial role in determining when and how much of a gene is expressed, influencing processes such as development, differentiation, and metabolism.