Fatty Acid Synthesis: Part One Recap

Fatty Acid Synthesis

Recap of Part One

• Fatty acid synthesis requires glucose, which is converted into pyruvate via the glycolytic pathway
• Pyruvate is taken up into the mitochondria, where it's converted into acetyl-CoA and oxaloacetate
• Acetyl-CoA and oxaloacetate form citrate, which then goes through the Krebs cycle, producing NADH and FADH2
• However, when there's too much ATP, citrate builds up and is transported out of the mitochondria into the cytoplasm
• Citrate lyase converts citrate back into oxaloacetate and acetyl-CoA

Converting Oxaloacetate into Pyruvate

• Oxaloacetate is converted into malate, which is then converted into pyruvate by the malic enzyme
• The malic enzyme generates NADPH, a key precursor for fatty acid synthesis
• NADPH is a strong reducing agent that will be used to reduce molecules in the fatty acid synthesis pathway

Pentose Phosphate Pathway

• An alternative way to generate NADPH is through the pentose phosphate pathway
• Glucose is converted into glucose-6-phosphate, which then enters the pentose phosphate pathway
• The pentose phosphate pathway generates NADPH and ribose-5-phosphate

Acetyl-CoA and Malonyl-CoA

• Acetyl-CoA is a two-carbon structure that needs to be carboxylated to form malonyl-CoA, a three-carbon structure
• The carboxylation reaction is catalyzed by acetyl-CoA carboxylase, a rate-limiting step in fatty acid synthesis
• Malonyl-CoA is a key building block for fatty acid synthesis and is regulated by various molecules and hormones, including insulin, glucagon, norepinephrine, and epinephrine

Regulation of Acetyl-CoA Carboxylase

• Acetyl-CoA carboxylase is regulated by:
  • Insulin, which stimulates the enzyme
  • Citrate, which allosterically regulates the enzyme
  • Glucagon, norepinephrine, and epinephrine, which phosphorylate the enzyme and inhibit it
  • Long-chain fatty acids, which inhibit the enzyme

Malonyl-CoA's Role in Regulating Fatty Acid Uptake

• Malonyl-CoA inhibits the activity of carnitine palmitoyl transferase-1 (CPT-1), preventing fatty acids from entering the mitochondria and undergoing beta-oxidation
• This helps to promote fatty acid synthesis over fatty acid breakdown

Fatty Acid Synthase Type 1 (FAS1)

• FAS1 is the enzyme that catalyzes fatty acid synthesis
• FAS1 has two components:
  • A cysteine residue with a thio group
  • An acyl carrier protein (ACP) with a phosphopantetheine group
• FAS1 will use the three precursors (NADPH, malonyl-CoA, and FAS1 itself) to build fatty acid chains### Fatty Acid Synthesis
• Fatty acid synthesis involves the combination of acetyl-CoA and malonyl-CoA molecules
• Acetyl-CoA is a 2-carbon molecule, while malonyl-CoA is a 3-carbon molecule
• The synthesis process begins with the transfer of an acetyl group from acetyl-CoA to the acyl carrier protein (ACP) end
  • This step is catalyzed by the enzyme acetyl transacylase
• The resulting 2-carbon acetyl group is then transferred from the ACP end to the cysteine residue
  • This step is catalyzed by the enzyme acyl transacylase
• Next, a malonyl group from malonyl-CoA is added to the ACP end, replacing the CoA group
  • This step is catalyzed by the enzyme malonyl transacylase
• The resulting 5-carbon molecule is then condensed with the 2-carbon acetyl group, resulting in a 4-carbon molecule
  • This step is catalyzed by the enzyme acyl-malonyl ACP condensing enzyme and involves a decarboxylation reaction, resulting in the loss of one carbon atom

Beta-Keto Reduction and Dehydration

• The resulting 4-carbon molecule is in the form of a beta-keto group
• The beta-keto group is reduced to a hydroxyl group using hydride ions from NADPH
  • This step is catalyzed by the enzyme beta-keto acyl ACP reductase
• The resulting hydroxyl group is then dehydrated to form a double bond
  • This step is catalyzed by the enzyme 3-hydroxy acyl ACP dehydratase
• The resulting double bond is then reduced to a saturated fatty acid chain using hydride ions from NADPH
  • This step is catalyzed by the enzyme enol acyl ACP reductase

Fatty Acid Chain Elongation

• The resulting saturated fatty acid chain is then transferred to the cysteine residue
• The process is repeated, with the addition of a new malonyl group to the ACP end and the condensation of the resulting molecule with the growing fatty acid chain
• This process continues, with the addition of 2-carbon units at a time, until a 16-carbon fatty acid chain is formed
  • This process requires 7 rounds of fatty acid synthesis, with the first round forming a 4-carbon chain and subsequent rounds adding 2-carbon units at a time

Fatty Acid Synthesis

Overview

• Fatty acid synthesis requires glucose, converted into pyruvate via glycolysis and then into acetyl-CoA and oxaloacetate in the mitochondria
• Citrate is formed from acetyl-CoA and oxaloacetate, but when ATP is high, citrate is transported out of the mitochondria and converted back into oxaloacetate and acetyl-CoA

Generating NADPH

• Oxaloacetate is converted into malate, then pyruvate, generating NADPH through the malic enzyme
• NADPH is a strong reducing agent used to reduce molecules in fatty acid synthesis
• The pentose phosphate pathway is an alternative way to generate NADPH and ribose-5-phosphate

Acetyl-CoA and Malonyl-CoA

• Acetyl-CoA is carboxylated to form malonyl-CoA, a key building block for fatty acid synthesis, catalyzed by acetyl-CoA carboxylase
• Malonyl-CoA is regulated by insulin, citrate, glucagon, norepinephrine, epinephrine, and long-chain fatty acids

Regulation of Acetyl-CoA Carboxylase

• Insulin stimulates acetyl-CoA carboxylase
• Citrate allosterically regulates acetyl-CoA carboxylase
• Glucagon, norepinephrine, and epinephrine phosphorylate and inhibit acetyl-CoA carboxylase
• Long-chain fatty acids inhibit acetyl-CoA carboxylase

Malonyl-CoA's Role in Regulating Fatty Acid Uptake

• Malonyl-CoA inhibits carnitine palmitoyl transferase-1 (CPT-1), preventing fatty acid uptake for beta-oxidation
• This promotes fatty acid synthesis over breakdown

Fatty Acid Synthase Type 1 (FAS1)

• FAS1 catalyzes fatty acid synthesis with two components:
  • Cysteine residue with a thio group
  • Acyl carrier protein (ACP) with a phosphopantetheine group
• FAS1 uses NADPH, malonyl-CoA, and FAS1 itself to build fatty acid chains

Fatty Acid Synthesis Process

• Fatty acid synthesis involves combining acetyl-CoA and malonyl-CoA molecules
• Acetyl-CoA is a 2-carbon molecule, while malonyl-CoA is a 3-carbon molecule
• The synthesis process begins with the transfer of an acetyl group from acetyl-CoA to ACP
• The resulting 2-carbon acetyl group is then transferred to the cysteine residue
• A malonyl group from malonyl-CoA is added to ACP, replacing the CoA group
• The resulting 5-carbon molecule is condensed with the 2-carbon acetyl group, resulting in a 4-carbon molecule
• The 4-carbon molecule undergoes beta-keto reduction and dehydration to form a saturated fatty acid chain

Recap of the first part of fatty acid synthesis, covering the process of converting glucose into pyruvate, acetyl-CoA, and citrate, and its relation to the Krebs cycle. Learn about the role of ATP in this process.