Fatty Acid Synthesis Part 2

Introduction

• Importance: Continuation from Part 1; essential to recap Part 1 to understand Part 2.
• Purpose: Dive deeper into fatty acid synthesis, particularly focusing on building the fatty acid chain.
• Support: Encouragement to like, comment, and subscribe.

Recap from Part 1

• Substrates Needed: Recap of substrates needed to build the fatty acid chain: glucose, pyruvate, acetyl-CoA, citrate, NADPH, oxaloacetate, and malonyl-CoA.

Detailed Steps in Fatty Acid Synthesis

Conversion Steps

1. Glucose to Pyruvate: Via glycolysis.
2. Pyruvate to Acetyl-CoA: Requires oxygen, occurs in mitochondria.
3. Acetyl-CoA + Oxaloacetate: Yields citrate, enters Krebs cycle.
4. Citrate Build-up: Due to high ATP inhibiting further conversion. Citrate is transported to the cytoplasm.
5. Citrate to Acetyl-CoA and OAA: Enzyme: Citrate lyase. OAA -> Malate -> Pyruvate (generates NADPH via malic enzyme). Acetyl-CoA forms malonyl-CoA via acetyl-CoA carboxylase.

NADPH Production

1. Malic Enzyme: Converts malate to pyruvate, generating NADPH.
2. Pentose Phosphate Pathway: Converts glucose 6-phosphate to ribose 5-phosphate, generating NADPH.

Malonyl-CoA and Acetyl-CoA

• Malonyl-CoA: Formed by carboxylation of acetyl-CoA using acetyl-CoA carboxylase (rate-limiting step, regulated by insulin, citrate, glucagon, and long-chain fatty acids).
• Acetyl-CoA Carboxylase Regulation:
  • Insulin stimulates the enzyme.
  • Citrate allosterically activates the enzyme.
  • Glucagon, norepinephrine, and epinephrine inhibit via phosphorylation.
  • Long-chain fatty acids inhibit the enzyme.
• Malonyl-CoA Function:
  • Building block for fatty acid synthesis.
  • Inhibits CPT-1 and CAT-1, preventing fatty acid breakdown in mitochondria.

Fatty Acid Synthase Type I (FAS-I)

• Components: Cysteine residue (thio group) and ACP (acyl carrier protein).
• Function: Enzyme used to make fatty acids.

Fatty Acid Synthesis Process

Key Components:

1. NADPH: Reducing power.
2. Malonyl-CoA: Building block.
3. Fatty Acid Synthase Type I (FAS-I): Enzyme for synthesis.
4. Acetyl-CoA: Additional component.

Steps in the Synthesis Cycle:

1. First Step: Add acetyl group (2-carbons) to the ACP end using acetyl transacylase. CoA is released.
2. Second Step: Transfer acetyl group from ACP to cysteine residue using acyl transacylase.
3. Third Step: Add malonyl group (3-carbons) to ACP end using malonyl transacylase. CoA is released.
4. Fourth Step: Combine acetyl and malonyl groups, removing a carbon as CO2 (decarboxylation) using acyl-malonyl-ACP condensing enzyme. Forms 4-carbon beta-ketone.
5. Fifth Step: Reduce beta-ketone to hydroxyl group using NADPH and beta-ketoacyl-ACP reductase.
6. Sixth Step: Dehydrate hydroxyl group to form a double bond using 3-hydroxyacyl-ACP dehydratase, producing enoyl group.
7. Seventh Step: Reduce enoyl group to saturated fatty acid using NADPH and enoyl-ACP reductase.
8. Cycle Continuation: Transfer growing fatty acid chain to cysteine residue and repeat steps 3-7 using new malonyl-CoA (adding 2-carbons each cycle).

Fatty Acid Chain Length

• Palmitate Formation: 16-carbon chain formed after 7 rounds of the cycle (first round adds 4-carbons, each subsequent round adds 2-carbons).
• Final Step: Liberate the 16-carbon fatty acid (palmitate) from FAS-I using thioesterase.

Regulation and Control

• Insulin: Promotes fatty acid synthesis by activating acetyl-CoA carboxylase.
• ATP Levels: High ATP inhibits citrate to isocitrate conversion, promoting citrate accumulation.
• Malonyl-CoA: Inhibits fatty acid entry into mitochondria, favoring synthesis over oxidation.

Summary

• Significance: Essential for understanding how cells convert carbohydrates into fatty acids for storage or membrane synthesis.
• Enzymes and Pathways: Key roles of NADPH, acetyl-CoA carboxylase, and FAS-I in fatty acid synthesis.

Conclusion

• Revision: Continue revisiting both parts to grasp the whole fatty acid synthesis pathway.
• Engagement: Like, comment, and subscribe for more content and support.
• Next Steps: Build on this knowledge with further biochemical pathways and their regulation mechanisms.