Fatty Acid Synthesis DLA

Question 1

What are fatty acids?

Answer 1

• Amphipathic: having both a
hydrophilic and a hydrophobic region.

• Free fatty acids (Unesterified) are transported in association with albumin in circulation.
• Free fatty acids have detergent character and they are esterified in TAGs, cholesteryl ester or polar membrane lipids.
• > 90% of FAs in plasma as fatty acid esters (TAGs, cholesteryl esters, phospholipids) in circulating lipoproteins

Question 2

Describe the unsaturated fatty acids

Answer 2

• Fatty acids without double bonds are saturated fatty acids.
• Unsaturated fatty acids have double bonds.
• Natural unsaturated fatty acids are in cis-configuration,
• double bonds usually 3 C’s apart • Mono or poly unsaturated
• Cis bonds introduce kinks (bends); important as part of membranes.
• Trans-fatty acids are mostly artificially formed

Question 3

How is fatty acid synthesis linked to metabolism?

Answer 3

Site of synthesis in the cell: cytosol

✓ Precursors and
coenzymes

• acetyl CoA, CoA (pantothenic acid), ATP, NADPH, CO2

Occurs in the well-fed state in the liver

Question 4

Summarize biosynthesis of fatty acids

Answer 4

Sites
• major (liver, lactating mammary gland) and
• minor (adipose tissue)

Occurs in the well-fed state in the liver

Purpose?
• Liver: reduce high blood glucose levels, form palmitate and TAGs which
are then released into the blood for eventual storage in fat cells. • Mammary gland: to provide FA for milk

Precursors and coenzymes
• acetyl CoA, CoA (pantothenic acid), ATP, NADPH, CO2

Site of synthesis in the cell
• cytosol

Question 5

What are the sources of NADPH for fatty acid synthesis ?

Answer 5

The NADPH required to provide reducing equivalents for FA biosynthesis is produce by:

1. Pentose phosphate pathway
   • Major pathway.
2. Malic enzyme (NADP+ dependent
   malate dehydrogenase)

Question 6

Describe the production of cytosolic Acetyl CoA

Answer 6

Acetyl CoA formed in mitochondria cannot cross the mitochondrial membrane into the cytosol.
• Acetyl CoA has to be converted to
Citrate
• At very high citrate levels, citrate leaves into the cytosol.
• Citrate lyase uses citrate in cytosol to form acetyl CoA and oxaloacetate

Question 7

Explain the mechanism of de novo Synthesis of fatty acid synthesis

Answer 7

The overall synthesis of palmitate from acetyl CoA requires NADPHs, ATPs and can be broken down into the following steps:

1. Formation of Malonyl CoA by acetyl CoA carboxylase
2. Synthesis of palmitate by fatty
   acid synthase (FAS).
   • Palmitate is a 16C saturated FA
3. Elongation of palmitate by elongases
4. Desaturation by desaturases

Question 8

Describe the carboxylation of acetyl CoA to form malonyl CoA

Answer 8

The first committed step of fatty acid biosynthesis is catalyzed by Acetyl CoA carboxylase (ACC);

• ACC is the Rate-limiting enzyme for fatty acid synthesis
• The enzyme contains biotin and adds a CO2 to the methyl end of acetyl CoA, resulting in a carboxyl group of malonyl CoA.
• The reaction requires 1 ATP per malonyl- CoA formed.

Question 9

What is the significance of fatty acid synthase?

Answer 9

The enzyme complex can exist as dimer in humans.

• Each monomer has seven different enzyme activities and contains an acyl-carrier domain (ACP) and a temporary holding domain with a cysteine residue.
• The multifunctional FAS enzyme catalyzes the reactions whereby two carbon units from malonyl CoA are linked together, ultimately to form palmitoyl CoA.
• Insulin upregulates the amount of enzyme expressed.

Question 10

Discuss the first step of fatty acid synthesis

Answer 10

In the first step, the acyl-carrier protein domain (ACP-SH) binds the acetyl group of acetyl CoA.

• From then on, Malonyl CoA is used for chain elongation, but it can only react with the free ACP-SH.

• Hence the acetyl group is transferred to the SH group of the holding domain and now
malonyl ACP can be formed from malonyl CoA

Many malonyl CoAs are the “fuel” for FA synthase.
• The decarboxylation of the carboxyl-group of malonyl-ACP allows condensation with the
group bound to the holding protein.[energy]

• In general, a 3-ketoacyl-ACP is formed.
• NADPH is used to reduce to 3-hydroxy-acyl ACP

Question 11

How is the fatty acyl ACP formed?

Answer 11

• After hydrolysis (step 6), a double bond is formed and a second NADPH is used for form a fatty acyl-ACP group.
• This fatty acyl group is then transferred to the SH of the holding domain and another malonyl CoA can interact with ACP-SH and continue the process of elongation of the growing fatty acyl chain until palmitate is formed and released from the FA synthase