Biosynthesis of Fatty Acids
• The acetyl-CoA is used as primer
• The addition of all the subsequent C2 units is
via malonyl-CoA
• Propionyl- CoA acts as primer
– odd number of carbon fatty acids
• Site of fatty acid synthesis
– The main pathway occurs in the cytosol
The synthesis of long-chain fatty acids
(lipogenesis)
• Carried out by two enzyme systems:
– acetyl-CoA carboxylase
– fatty acid synthase
• The pathway converts acetyl-CoA to palmitate
and requires NADPH, ATP, Mn2+, biotin,
pantothenic acid, and HCO3− as cofactors.
Fatty acid synthase
• a multienzyme complex of one polypeptide
chain with seven separate enzymatic activities
• Catalyzes the assembly of palmitate from one
acetyl-CoA and seven malonyl-CoA molecules
• Lipogenesis is regulated at
– acetyl-CoA carboxylase step by
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allosteric modifiers,
phosphorylation/dephosphorylation,
induction and repression of enzyme synthesis
Citrate activates the enzyme,
long-chain acyl-CoA inhibits its activity
Insulin activates
glucagon and epinephrine have opposite actions
• Fatty acid fate
– Esterification
• Into Acylglycerols
• to Cholesteryl ester
– Chain elongation
– Desaturation
• The equation for the overall synthesis of
palmitate from acetyl-CoA and malonyl-CoA
Fatty acid synthase multienzyme complex
Biosynthesis of long-chain
fatty acids
The 3-ketoacyl group is reduced, dehydrated,
and reduced again (reactions 3, 4, 5) to
form the corresponding
saturated acyl-S-enzyme.
• Tissues specializing in active lipogenesis
– Liver, adipose tissue, and the lactating mammary
gland
– also possess an active pentose phosphate
pathway
• Both metabolic pathways are found in the
cytosol
• Acetyl-CoA Is the Principal Building Block of
Fatty Acids
The provision of acetyl-CoA and NADPH for lipogenesis
The provision of acetyl-CoA and
NADPH for lipogenesis
Elongation of Fatty Acid Chains
• in the Endoplasmic Reticulum
• fatty acid elongase system
• elongates saturated and unsaturated fatty
acyl-CoAs (from C10 upward) by two carbons,
using malonyl-CoA as acetyl donor and NADPH
as reductant
Microsomal elongase system
Regulation of Lipogenesis
• Excess carbohydrate is stored as fat
• Lipogenesis converts surplus glucose and
intermediates such as pyruvate, lactate,and
acetyl-CoA to fat
• The nutritional state of the organism is the
main factor regulating the rate of lipogenesis
• It is depressed under conditions of
– Restricted caloric intake
– On a fat diet
– Deficiency of insulin
• an inverse relationship has been demonstrated
between hepatic lipogenesis and the
concentration of serum-free fatty acids
• Sucrose instead of glucose
– Increase lipogenesis
Regulation of Lipogenesis
• SHORT- & LONG-TERM MECHANISMS
– Allosteric & covalent modification of enzymes
– Long term
• Changes in gene expression
• Acetyl-CoA Carboxylase is the most important
enzyme in the regulation of lipogenesis
Regulation of acetyl-CoA carboxylase
by phosphorylation/dephosphorylation
• Allosteric effectors
– Citrate
• Inactive dimer to an active polymeric form
• Inactivation
– Phosphorylation
– Long chain acyl-CoA
• Negative feedback inhibition by product
• Increased lipolysis or an influx of free fatty acids into the
tissue
• Inhibit the mitochondrial tricarboxylate transporter
– Citrate effect not occur
• Acetyl-CoA carboxylase regulated by hormones
– glucagon, epinephrine, and insulin via
• Changes in its phosphorylation state
• Pyruvate Dehydrogenase
– Acyl-CoA causes an inhibition
• Inhibiting the ATP-ADP exchange transporter of
the inner mitochondrial membrane
– Increased intramitochondrial [ATP]/[ADP] ratios
• active to inactive pyruvate dehydrogenase
– availability of acetyl-CoA
• Increased levels of free fatty acids
– Increase oxidation of acyl-CoA
• Increase the ratios of [acetyl-CoA]/ [CoA] and
[NADH]/[NAD+] in mitochondria
– Inhibiting pyruvate dehydrogenase
• Insulin Also Regulates Lipogenesis
– acetyl-CoA carboxylase activity
– transport of glucose into the cell
• increasing the availability of both pyruvate and
glycerol 3-phosphate for esterification
• Converts the inactive form of pyruvate
dehydrogenase to the active form
• depress the level of intracellular cAMP
– Inhibits lipolysis
• Reduces plasma free fatty acid
• The Fatty Acid Synthase Complex & Acetyl-CoA
Carboxylase Are Adaptive Enzymes
– Starvation, feeding of fat, and in diabetes
– Induction of enzyme biosynthesis
• Insulin
• Glucagon (via cAMP)
• Polyunsaturated fatty acids
– Inhibition of expression of key enzymes of glycolysis and
lipogenesis
• longer-term regulation take several days
• direct and immediate effect
– Free fatty acids and hormones