Chapter 21: Lipid Biosynthesis

Question 1

• the lipid biosynthetic pathways are _____ and _____.
• They use _____ as a source of metabolic energy and a reduced electron carrier (usually _____) as a reductant

Answer 1

• endergonic
• reductive
• ATP
• NADPH

Question 2

Differences between fatty acid biosynthesis and breakdown

Answer 2

• occur by different pathways
• catalyzed by different sets of enzymes
• take place in different parts of the cell.
• biosynthesis requires the participation of a three-carbon intermediate, malonyl-CoA
  
  • not involved in fatty acid breakdown
  • khan: helps regulate breakdown but is neither a breakdown substrate nor a product.

Question 3

formation of malonyl-CoA from acetyl-CoA

Answer 3

catalyzed by acetyl-CoA carboxylase

• Irreversible process
• has three functional regions:
  
  • biotin carrier protein (gray)
  • biotin carboxylase: activates CO2
  • transcarboxylase: transfers activated CO2
• contains a biotin prosthetic group covalently bound in amide linkage to the ε-amino group of a Lys residue
• prosthetic group is located in one of the three polypeptides or domains of the enzyme molecule
• two-step reaction catalyzed is similar to other biotin-dependent carboxylation reactions: pyruvate carboxylase, propionyl-CoA carboxylase

Pathway

• The active enzyme in each step is shaded in blue
• biotin carboxylase activates, transfers a carboxyl group (CO₂) from bicarbonate (HCO^-3), and attaches it to a nitrogen in the biotin ring, in an ATP-dependent reaction
• The long, flexible biotin arm carries the activated CO2 from the biotin carboxylase region to the transcarboxylase active site.
• transcarboxylase, transfers activated CO₂ (shaded green) from biotin to acetyl-CoA, producing malonyl-CoA

Question 4

fatty acid synthesis

• In all organisms, the long carbon chains of fatty acids are assembled in a repeating _____ step sequence
• It is catalyzed by _____ _____ _____
• A saturated _____ _____ produced by each four-step series of reactions becomes the substrate for subsequent condensation with an activated _____ _____
• With each passage through the cycle, the fatty acyl chain is extended by ______ _____
• the reducing agent in the synthetic sequence is _____ and the activating groups are two different enzyme-bound —SH groups

Answer 4

• four
• fatty acid synthase
• acyl group
• malonyl group
• two carbons
• NADPH

Question 5

Addition of two carbons to a growing fatty acyl chain:

a four-step sequence

Answer 5

• step 1
  
  • malonyl group and acetyl / acyl group is activated by a thioester that links it to fatty acid synthase
  • extension of acyl chain by two carbons occurs
    
    • Condensation of activated acyl group and two carbons
      
      • acetyl group derived from acetyl-CoA
      • carbon derived from malonyl-CoA
    • CO₂ is eliminated from the malonyl group
  • The β-keto product of condensation is reduced in three more steps to an alcohol
    
    • nearly identical to the reactions of β-oxidation, but in reverse
• step 3
  
  • elimination of H2O creates a double bond
• step 4
  
  • double bond is reduced to form the saturated fatty acyl group.
• PDF pg. 866

Question 6

• fatty acid synthesis leads to a single product, and no ______ are released
• When the chain length reaches _____ carbons, that product, ______ leaves the cycle
• Carbons C-16 and C-15 of the palmitate are derived from the ______ and _____ carbon atoms, respectively, of an _____ used directly to prime the system at the outset
• the rest of the carbon atoms in the chain are derived from acetyl-CoA via ______
• PDF pg. 865, 867 fig. 21.4

Answer 6

• intermediates
• 16, palmitate, 16:0
• methyl, carboxyl, acetyl-CoA
• malonyl-CoA

Question 7

structure of fatty acid synthase type I systems

Answer 7

• two major variants of fatty acid synthase
• FAS I found in vertebrates
• a single multifunctional polypeptide chain
• Seven active sites for different reactions lie in separate domains
  
  • function as distinct but linked enzymes
  • subunits appear to function independently
• Three of the seven required active sites are found on the α subunit and four on the β subunit
• intermediates remain covalently attached as thioesters to one of two thiol groups
  
  • Two points of attachment
    
    • —SH group of a Cys residue in one of the synthase domains β-ketoacyl-ACP synthase (KS)
    • —SH group of acyl carrier protein
      
      • separate domain of the same polypeptide
  • Hydrolysis of thioesters is highly exergonic
  • energy released helps to make the following two steps thermodynamically favorable
    
    • Condensation (KS)
    • Translocation of butyryl group to Cys on b-ketoacyl-ACP synthase (KS)
• enzymatic activites are:
  
  • β-ketoacyl-ACP synthase (KS)
  • malonyl/acetyl-CoA–ACP transferase (MAT)
  • β-hydroxyacyl-ACP dehydratase (DH)
  • enoyl-ACP reductase (ER)
  • β-ketoacyl-ACP reductase (KR)
• The linear arrangement of the domains in the polypeptide is shown in the lower panel.
• The TE domain is a thioesterase that releases the palmitate product from ACP when the synthesis is completed
• ACP and TE domains are disordered in the crystal and are therefore not shown in the structure

Question 8

Acyl carrier protein (ACP)

Answer 8

• part of fatty acid synthase
• shuttle that holds the system together
• contains the prosthetic group 4’-phosphopantetheine
  
  • serves as a flexible arm
  • tethers the growing fatty acyl chain to the surface of the fatty acid synthase complex while carrying the reaction intermediates from one enzyme active site to the next
  • covalently attached to the hydroxyl group of a Ser residue in ACP
  • contains the B vitamin pantothenic acid, also found in the coenzyme A molecule
  • Its —SH group is the site of entry of malonyl groups