Saturated fatty acids are synthesized through a process involving acetyl-CoA, NADPH, and fatty acid synthase enzymes, primarily in the cytoplasm of cells. This process converts acetyl-CoA into fatty acids, utilizing NADPH as a reducing agent.
The Synthesis Process: A Step-by-Step Breakdown
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Acetyl-CoA Transport and Generation of Malonyl-CoA: The synthesis starts with acetyl-CoA, mainly derived from carbohydrate metabolism through glycolysis. Since fatty acid synthesis happens in the cytoplasm, but acetyl-CoA is produced in the mitochondria, it needs to be transported. This is accomplished by the citrate shuttle. Citrate, formed from acetyl-CoA and oxaloacetate in the mitochondria, crosses the mitochondrial membrane. In the cytoplasm, citrate is cleaved by ATP-citrate lyase to regenerate acetyl-CoA and oxaloacetate. Oxaloacetate is then converted to pyruvate, which can re-enter the mitochondria, conserving reducing equivalents. The acetyl-CoA is then converted to malonyl-CoA by the enzyme acetyl-CoA carboxylase (ACC). This is the committed step in fatty acid synthesis. ACC requires biotin as a cofactor and ATP.
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Fatty Acid Synthase (FAS) Complex: The synthesis proceeds on a large multi-enzyme complex called fatty acid synthase (FAS). In mammals, FAS is a single polypeptide chain with all the necessary enzymatic activities. FAS has an acyl carrier protein (ACP) domain which carries the growing fatty acid chain.
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Initiation: Acetyl-CoA and malonyl-CoA bind to FAS. Acetyl-CoA binds to the ACP, and malonyl-CoA binds to another site on the enzyme.
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Elongation: This involves a cycle of four reactions:
- Condensation: Acetyl-ACP and malonyl-CoA condense, releasing CO2 and forming acetoacetyl-ACP.
- Reduction: Acetoacetyl-ACP is reduced by NADPH to D-β-hydroxybutyryl-ACP.
- Dehydration: D-β-hydroxybutyryl-ACP is dehydrated to crotonyl-ACP.
- Reduction: Crotonyl-ACP is reduced by NADPH to butyryl-ACP.
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Repetition: The butyryl-ACP now reacts with another molecule of malonyl-CoA, and the cycle repeats, adding two carbons to the fatty acid chain with each cycle.
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Termination: The process continues until palmitoyl-ACP (a 16-carbon saturated fatty acid) is formed. Palmitoyl-ACP is then cleaved by a thioesterase, releasing free palmitate.
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Further Elongation and Desaturation: Palmitate can be further elongated in the endoplasmic reticulum. It can also be desaturated (double bonds added) in the ER, but mammals cannot introduce double bonds beyond the delta-9 carbon. This means linoleate and alpha-linolenate are essential fatty acids that must be obtained from the diet.
Key Components and Their Roles
| Component | Role |
|---|---|
| Acetyl-CoA | The primary building block for fatty acid synthesis. |
| NADPH | The reducing agent, providing the necessary electrons for the reduction steps. |
| Fatty Acid Synthase | The multi-enzyme complex that catalyzes the synthesis. |
| Malonyl-CoA | A two-carbon donor derived from acetyl-CoA. |
Regulation of Fatty Acid Synthesis
Fatty acid synthesis is tightly regulated to ensure it occurs when energy is abundant. Key regulatory mechanisms include:
- Acetyl-CoA Carboxylase (ACC) Regulation: ACC is allosterically activated by citrate and inhibited by palmitoyl-CoA. It is also regulated by phosphorylation/dephosphorylation. Insulin activates ACC, while glucagon and epinephrine inhibit it.
- Nutritional Status: A high-carbohydrate diet promotes fatty acid synthesis.
In summary, saturated fatty acid synthesis is a complex process involving acetyl-CoA, NADPH, and the enzyme fatty acid synthase, primarily occurring in the cytoplasm. It is a highly regulated pathway crucial for energy storage and cellular function.
