Chapter 28 - Fatty Acid Synthesis

What is the key precursor in generating fatty acids?

A two-carbon molecule acetyl CoA

• separate 2 carbon units must be linked

• carbon atoms in chain must be reduced because of the double bond to oxygen

What are the three stages fatty acid synthesis can be divided into?

1. Transfer of acetyl CoA out of mitochondria into the cytoplasm

2. Activation of acetyl CoA

3. Repetitive addition and reduction of two-carbon units

How does acetyl CoA get into the cytoplasm?

They are transferred from the mitochondrial matrix as citrate

• acetyl CoA condense w/ oxaloacetate in the matrix to form citrate

What are the requirements for FA synthesis?

• 2 carbon units from acetyl CoA

• ATP

• NADPH

  • two sources of NADPH

    • Generated via return of oxaloacetate to mitochondria

    • PPP

How is acetyl CoA activated?

Requires the carboxylation of acetyl CoA to form malonyl CoA

• catalyzed via acetyl CoA carboxylase I

Carboxylase rxn proceeds in two steps ending w/ formation of malonyl CoA

• malonyl CoA is the committed step in FA synthesis

How does the elongation stage begin?

When acetyl CoA and malonyl CoA react with ACP

• ACP → acyl carrier protein, molecule that contains the same linker as CoA

• Growing chain remains linked to ACP and all additions use malonyl ACP

What are the four core repeated steps of elongation?

1. Condensation

2. Reduction

3. Dehydration

4. Reduction

What happens after the malonyl CoA condenses with acetyl CoA?

The chain is lengthened by two carbons

• the “extra” carbon in malonyl CoA is lost as carbon dioxide

• The next three steps convert C-3 keto group into methylene group

NADPH is used as a reducing power

What long are step 1 and 3 repeated?

Until each acetyl CoA is incorporated into the FA

• additions continue until a 16-carbon acyl ACP has been formed

How to make a long FA?

FA synthase is designed to process FA to a specific length: 16

• Separate enzymes are required to make FAs with more than 16 carbons

• these enzymes are on the cytoplasmic face of the endoplasmic reticulum

  • also can use malonyl CoA as a substrate for addition, grow increments of two carbons

How to make unsaturated FA?

FA synthase produces saturated FA

• Double bonds introduced by ER enzymes

  • oxidases

• Mammals lack enzymes for making double bonds beyond C-9

What is the key enzyme in regulating synthetic activity?

Acetyl CoA Carboxylase 1

• this enzyme is then regulated by phosphorylation state

  • phosphorylation via AMP-dependent kinase inactives the the carboxylase

  • inhibition reversed bt protein phosphatase 2A

What else regulates the Acetyl CoA carboxylase 1?

Allosterically by citrate

• high citrate levels activate carboxylase by promoting polymerization

How is acetyl CoA carboxylase affected by extracellular signaling?

• Glucagon and epinephrine decrease activity

• Insulin increases activity