Chapter 25: Fatty Acid Biosynthesis

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Chapter 25 Fatty Acid Biosynthesis

• CH234
• Bruce A. Hathaway

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Acetyl Coenzyme A

• Acetyl Coenzyme A is the starting material for
  fatty acid biosynthesis.
• It is derived from metabolism of carbohydrates,
  fats and some amino acids.
• The two-carbon piece provides the carbons for the
  new fatty acid.

Acetyl Coenzyme A
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Acetyl Coenzyme A (AcCoA)
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Overview of Metabolism And Energy Production
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Step 1 Preparation of Malonyl CoA

• Acetyl CoA reacts with bicarbonate to form
  Malonyl CoA.
• This is energy-requiring, so hydrolysis of an ATP
  is used to drive the reaction.
• Malonyl CoA is more reactive than Acetyl CoA.

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Step 2 Transthioesterifaction

• Both Acetyl CoA and Malonyl CoA are connected to
  Acetyl Carrier Protein (ACP), which is another
  thiol.
• One thiol replaces another to make a different
  thioester.
• ACP shuttles the molecules to the different
  enzymes needed to do the following reactions.

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Step 3 C-C Bond Formation

• Malonyl ACP loses CO2 to make a carbon anion.
• An acetyl ACP reacts with the carbon anion to
  give a four-carbon ß-ketoester.

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Step 4 Reduction of the Ketone

• The ketone is reduced to an alcohol.
• Only one stereoisomer is produced why?
• NADPH functions similar to NaBH4 in this reaction.

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NADPH

• NADPH is similar to NADH.
• It has an extra phosphate, while NADH has an H.
• Metabolism uses NADH.
• Biosynthesis uses NADPH.

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Reduction of the Ketone with NADPH

• NADPH donates a hydride H- to reduce the ketone
  the H comes from water, ultimately.
• Only one enantiomer is formed.

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Step 5 Dehydration of the Alcohol

• The alcohol is specifically dehydrated to the
  trans alkene.
• Again, only one isomer is formed.

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Step 6 Reduction of the Alkene

• NADPH H reduces the CC to an alkane.
• We have now made a four-carbon fatty acid.

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Elongation of Fatty Acids

• The Butyroyl-ACP replaces the Acetyl-ACP in Step
  3, to make a 6-carbon ketoacid.

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Elongation of Fatty Acids

• The 6-carbon keto-acid is reduced, dehydrated,
  and reduced again (steps 4-6), to make the
  six-carbon fatty acid.
• This can react with more malonyl-ACP

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Elongation of Fatty Acids

• The cycle of steps 3-6 is repeated five more
  times until the 16-carbon fatty acid is made.
• For some reason, this enzyme complex only makes
  palmitic acid.
• Longer fatty acids and unsaturated fatty acids
  are synthesized in other locations.

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Energy Requirements

• To add two carbons to Acetyl CoA, it requires 1
  ATP (to make a malonyl CoA) and 2 NADPHs.
• Each NADPH is the equivalent to 2.5 ATPs.
• Therefore, it takes the equivalent of 6 ATPs to
  add two carbons to Acetyl CoA.
• To make a 12-carbon fatty acid, lauric acid,
  requires five cycles, or 30 ATPs.
• This compares to the 20 ATPs we get from
  metabolizing lauric acid to Acetyl CoA.