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.
