Lipid Metabolism (II)

Fatty acid biosynthesis

Learning objectives:
 Describe the chemical structures of fatty acids
 Explain de novo synthesis of fatty acids
Significance of fatty acid metabolism

Fatty acids have 4 major roles in the cell:

 Building blocks of phospholipids and glycolipids
 Added onto proteins to create lipoproteins, which
targets them to membrane locations
 Fuel molecules - source of ATP
 Fatty acid derivatives serve as hormones and
intracellular messengers
Constituents of lipids
 Fatty acids
Fatty acids contain acidic group (- COOH)
General formula R.COOH, where R is hydrogen or an alkyl
group (-CH3, -C2H5 and so on)
Most fatty acids have an even number of carbon atoms
between 14 and 22 (most commonly 16 or 18)
It has a long chain of carbon and hydrogen forming a
hydrocarbon tail (hydrophobic).
Properties of lipids are determined by the hydrocarbon tail.
Unsaturated: contain one or more double bonds (C=C)
 Alcohol
Most lipids are esters of the alcohol glycerol, and are therefore
called glycerides.
 Fatty acids

-consists of a long carbon skeleton, usually 16-18 carbons

long and ends in a carboxyl group.
Acidic group and hydrocarbon tail of fatty acid
 Fatty acids

saturated fatty acids only single bonds

monounsaturated fatty acids one double bond

polyunsaturated fatty two or more double bonds

acids
Saturated and unsaturated fatty acids
Saturated
f.a.

monounsaturated
f.a.

polyunsaturated
f.a.

polyunsaturated
f.a.
Formation of a lipid from fatty acids and glycerol by
condensation reactions
De Novo synthesis of fatty acids

 A larger proportion of the fatty acids used by the body

is supplied by the diet.

 Excess amounts of carbohydrate and protein obtained

from the diet can be converted to fatty acids ( stored

as TAG).

 The process incorporates carbons from acetyl CoA into

growing fatty acid chain, utilizing ATP and NADPH

 Tissue locations
Fatty acid synthesis occurs primarily in :
 liver
 lactating mammary glands
 Adipose tissue (fat)
 Acetyl CoA for fatty acid synthesis comes mostly from
glycolytic breakdown of glucose.
(1) Production of Cytosolic Acetyl CoA

 First step in fatty acid synthesis:

 Transfer of acetate units from mitochondria acetyl CoA

to the cytosol, forming cytosolic acetyl CoA

 Sources of mitochondrial acetyl CoA:

i. Degradation of fatty acids

ii. Glucose (through oxidation of pyruvate)
iii. Amino acids
iv. Ketone bodies
 The CoA portion of acetyl CoA,
however, cannot cross the
inner mitochondrial
membrane
 only the acetyl portion enters
the cytosol, in the form of
citrate

 translocation of citrate from

the mitochondrion to the
cytosol, cleaved by ATP-citrate
lyase to produce cytosolic
acetyl CoA and OAA
  Translocation occurs when

TCA  mitochondrial citrate

cycle
concentration is high

 isocitrate dehydrogenase is

inhibited by the presence of

large amounts of ATP

 citrate and isocitrate

accumulate
Regulation of the TCA cycle
TCA cycle is controlled
by the regulation of
 Citrate synthase
 Isocitrate
dehydrogenase
 α-ketoglutarate
dehydrogenase
complex
 (2) Carboxylation of Acetyl CoA

 The carboxylation of acetyl CoA to form malonyl CoA is catalyzed

by acetyl CoA carboxylase and
 requires CO2 and ATP.
 The coenzyme is the vitamin, biotin, which is covalently bound to
a lysyl residue of the carboxylase
 This carboxylation is both the rate-limiting and the regulated step
in fatty acid synthesis
(3) FATTY ACID SYNTHASE-for synthesis of
palmitate

 The reaction is complex

 Serial addition of 2-carbon fragments
 Many steps

Acetyl-CoA + 7malonyl- CoA + 14NADPH + 14H+ 

palmitate + 7CO2 + 14NADP+ + 8CoA + 6H2O
Acetyl-CoA + 7malonyl- CoA + 14NADPH + 14H+ 
palmitate + 7CO2 + 14NADP+ + 8CoA + 6H2O

The 7 malonyl-CoA are derived from acetyl-CoA as

follows:
7Acetyl-CoA + 7CO2 + 7ATP 
7 malonyl-CoA +7ADP +7Pi + 7H+

Therefore, the overall net reaction :

8Acetyl-CoA +14NADPH + 14H+ + 7ATP 
palmitate + 14NADP+ + 8CoA + 6H2O +7ADP +7Pi
Major sources of NADPH for fatty acid synthesis
 Hexose Monophosphate (HMP) pathway
 Two NADPH are produced for each molecule of glucose that
enters HMP pathway
 Cytosolic conversion of malate to pyruvate
 2 3
1

4
5 6
Interrelationship between glucose and fatty acid synthesis
 Interrelationship between glucose and fatty acid
synthesis

1. The glycolytic pathway produces pyruvate, which is the

primary source of the mitochondrial acetyl CoA to be
used for fatty acid synthesis. It also produces cytosolic
reducing equivalents of NADH. Pyruvate enters the
mitochondria.
2. Mitochondrial oxaloacetate (OAA) is produced by the
first step in the gluconeogenic pathway.
3. Acetyl CoA is produced in the mitochondria and
condenses with OAA to form citrate, the first step in
the tricarboxylic acid cycle.
4. Citrate leaves the mitochondria and is cleaved in the
cytosol to produce cytosolic acetyl CoA.

5. Cytosolic reducing equivalents (NADH) produced

during glycolysis contribute to the reduction of NADP+
to NADPH needed for palmitoyl CoA synthesis

6. The carbons of cytosolic acetyl CoA are used to

synthesize palmitate, with NADPH as the source of
reducing equivalents for the pathway.
Modification of dietary and endogenous fatty
acids
 The palmitate produced by fatty acid synthase is typically

modified to give rise to the other fatty acids.

 Fatty acids from dietary sources, too, are often modified.

 These modifications may include:

 chain elongation to give longer fatty acids

 desaturation, giving unsaturated fatty acids.

Storage of fatty acids as components of
triacylglycerols (TAG)
 Glycerol + three fatty acids
 Low solubility in water
 Stored in cytosol of adipocytes
Storage of fatty acids as components of
triacylglycerols (TAG)

 Synthesis of triacylglycerols
1- Synthesis of glycerol phosphate
2- Conversion of a free fatty acid to its activated form
3- Formation of a molecule of TAG
1- Synthesis of glycerol phosphate

glycolysis
glycolysis
1- Synthesis of glycerol phosphate

 Sites ---- liver ( primary site ) and adipose tissue

 In both liver and adipose tissue , during glycolysis ,

glucose is converted Dihydroxy acetone phosphate

(DHAP).

 DHAP is reduced to glycerol phosphate with the help

of enzyme Glycerol phosphate dehydrogenase.

 In liver ---- free glycerol coming to liver is converted to

glycerol phosphate by enzyme Glycerol kinase.

 In liver this process depends on supply of glucose.

2- Conversion of a free fatty acid to its
activated form
 Long chain fatty acids are converted to fatty acyl CoA .
Enzyme required is Fatty acyl CoA synthase.

 Fatty acyl CoA participates in TAG synthesis

3- Formation of a molecule of TAG
 This pathway involves four reactions

 These include

the sequential addition of two fatty acids from

fatty acyl CoA,

the removal of phosphate, and

the addition of the third fatty acid.

Mobilization of stored fats and oxidation of
fatty acids
Release of fatty acids from TAG
 This process is initiated by hormone-sensitive lipase,
 removes a fatty acid from carbon 1 and/or carbon 3 of
the TAG
 Hormonal regulation of
triacylglycerol
degradation in the
adipocyte

i. epinephrine or glucagon binds

receptor
ii. activates adenylyl cyclase
iii. cAMP is produced and
phosphorylate cAMP-
dependent protein kinase
iv. cAMP-dependent protein
kinase phosphorylate
Hormone-sensitive lipase
Fate of glycerol

 Adipocytes lack glycerol kinase

 glycerol released during TAG degradation cannot be
metabolized
 glycerol is transported through the blood to the liver,
where it can be phosphorylated.
 The resulting glycerol phosphate can be used to form
TAG in the liver, or can be converted to DHAP by
reversal of the glycerol phosphate dehydrogenase
reaction
 DHAP can participate in glycolysis or gluconeogenesis
Fate of fatty acids
 Breakdown of TAG releases free or unesterified fatty
acids
 Transported in plasma bound with albumin
 Enter into cells
 In cells activated and oxidised to form energy
 Plasma Free Fatty acids cannot be used by
Erythrocytes as they have no mitochondria.
 Free Fatty acids cannot cross blood brain barrier -- not
a source of energy for brain.