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Lipid Biosynthesis


									        Lipids Fulfill a Variety of
          Biological Functions
•   Storage of energy
•   Constituents of cellular membranes
•   Anchors for membrane proteins
•   Cofactors for enzymes
•   Signaling molecules
•   Pigments
•   Detergents
•   Transporters
•   Antioxidants
Overview of Fatty Acid Synthesis
• Fatty acids are built in several passes
  processing one acetate unit at a time
• The acetate is coming from activated malonate
  in the form of malonyl-CoA
• In each pass involves reduction of a carbonyl
  carbon to a methylene carbon
    Synthesis of Malonyl-CoA (1)
• The three-carbon precursor for fatty acid
  synthesis is made from acetyl-CoA and
• The reaction is catalyzed by acetyl-CoA
  carboxylase (ACC)
• ACC contains biotin, nature’s carrier of CO2
              Fatty Acid Synthesis
• Overall goal is to attach a two-carbon acetate unit from
  malonyl-CoA to a growing chain and then reduce it
• Reaction involves cycles of four enzyme-catalyzed steps
   – Condensation of the growing chain with activated acetate
   – Reduction of carbonyl to hydroxyl
   – Dehydration of alcohol to trans-alkene
   – Reduction of alkene to alkane
• The growing chain is initially attached to the enzyme via
  a thioester linkage
• During condensation, the growing chain is transferred to
  the acyl carrier protein
• After the second reduction step, the elongated chain is
  transferred back to fatty acid synthase
“Business ends” of CoASH
and ACP are the same:
  Charging the Acyl Carrier Protein
     and Fatty Acid Synthase
• Two thiols participate in the fatty acid synthesis
   – Thiol from 4-phosphopantethine in acyl carrier protein
   – Thiol from cysteine in fatty acid synthase
• Both thiols must be charged for the condensation
  reaction to occur
   – In the first step, acetyl from acetyl-CoA is transferred to
     acyl carrier protein
   – Acyl carrier protein passes this acetate to fatty acid
   – Acyl carrier protein is then re-charged with malonyl
     from malonyl-CoA
Fatty Acid Synthase in Animals and Fungi
  is a Large Multifunctional Polypeptide
The enzymatic activities of fatty acid
synthase are organized in modules of
independent protein domains:
   Enzymatic Activities in Fatty Acid
• Condensation with acetate
   – -ketoacyl-ACP synthase (KS)
• Reduction of carbonyl to hydroxyl
   – -ketoacyl-ACP reductase (KR)
• Dehydration of alcohol to alkene
   – -hydroxyacyl-ACP dehydratase (DH)
• Reduction of alkene to alkane
   – enoyl-ACP reductase (ER)
• Chain transfer
   – Malonyl/acetyl-CoA ACP transferase
Fig cont’d on next slide…
…from previous slide
   Synthesis of Unsaturated Fatty
• Animals can readily introduce one double bond to
  palmitate and stearate
• Vertebrates cannot introduce additional double
  bonds between C10 and methyl-terminal
• We must obtain linoleate and -linolenate with
  diet; these are essential fatty acids
• Plants, algae, and some insects synthesize
  linoleate from oleate
         Synthesis of Eicosanoids

• Cyclooxygenase activity does not require metal
• Cyclooxygenase is a target for many anti-
  inflammatory drugs
         Biosynthesis of Cholesterol

                    Labeling studies show that
                    cholesterol is made from
See LNC Fig 21-32   acetyl-CoA
Recall Fig 17-18
(ketone body
See LNC Fig on p 842:
inhibitors of HMG-CoA
             Chapter 21: Summary
• Malonyl-CoA is an important precursor for biosynthesis of
  fatty acids
• Fatty acid synthesis is carried out by a large enzyme that
  contains multiple catalytic activities needed for the
  condensation, and subsequent reduction of acetate units
• Not all organisms can synthesize polyunsaturated fatty acids;
  thus, some dietary fats are “essential”
• Cholesterol biosynthesis starts with synthesis of mevalonate
  from acetate; mevalonate yields two activated isoprenes;
  series of isoprene condensation steps gives squalene;
  oxidation and ring closure of squalene gives cholesterol

  Fatty acid

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