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 acetyl-CoA carboxylase and fatty acid synthase. This process is tightly regulated and plays a key role in energy storage and cellular function.
The synthesis of fatty acids requires specific substrates and produces important products. Malonyl-CoA, NADPH, and acetyl-CoA are key players, with palmitate 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