LIPOGENESIS

dr. Isra Thristy, M.Biomed

Bagian Biokimia
FK UMSU
TIU & TIK
• Mampu Menjelaskan proses Lipogenesis
• Mampu Menjelaskan proses Elongasi
asam lemak
• Mampu Menjelaskan proses desaturasi
asam lemak
• Mampu menjelaskan mengenai
eicosanoid
Overview of
fatty acid
metabolism
showing the
major
pathways
and end
products
Lipogenesis

• Location : cytoplasm.
• Cofactor requirements include NADPH,ATP,
Mn2+, biotin, HCO3, acetyl CoA.
• Acetyl CoA is the immediate substrate.
• Free palmitate is the end product.
• Initial reaction : carboxylation of acetyl CoA
to malonyl CoA by ATP and acetyl CoA
carboxylase .
• Acetyl CoA carboxylase has a requirement
for the vitamin biotin
 Lipogenesis = Fatty acid synthesis
occurs primarily in the cytoplasm
of these tissues:
• Liver
• Adipose (fat)
• Central Nervous System
• Lactating mammary gland
Remember:
Glucagon and epinephrine
inhibit fatty acid synthesis,
and insulin stimulates it
The fatty acid synthesis may be learnt in 3
stages
• I. Production of acetyl CoA and NADPH
• II. Conversion of acetyl CoA to malonyl
CoA
• III. Reactions of fatty acid synthase
complex.
I. Production of acetyl CoA and
NADPH
• Acetyl CoA is produced in the mitochondria by the
oxidation of pyruvate and fatty acids, degradation of
carbon skeleton of certain amino acids, and from
ketone bodies.
• Mitochondria, not permeable to acetyl CoA.
• Acetyl CoA condenses with oxaloacetate in
mitochondria to form citrate.
• The transport of acetyl CoA from mitochondria to
cytosol is coupled with the cytosomal production of
NADPH and CO2 which is highly advantageous to the
cell for optimum synthesis of fatty acids.
II. Conversion of acetyl CoA to malonyl CoA
• Malonyl-CoA is formed from acetyl-CoA by a
carboxylation reaction that requires biotin and ATP.
• The enzyme is acetyl-CoA carboxylase, a regulatory
enzyme that is inhibited by phosphorylation, activated
by dephosphorylation and by citrate, and induced by
insulin.
• The enzyme that phosphorylates acetyl-CoA
carboxylase is the AMP-activated protein kinase (not
protein kinase A).
• Enzyme acetyl CoA carboxylase  is an ATP-
dependent reaction and requires biotin for CO2
fixation.
III. Reactions of fatty acid
synthase complex
• Step 1: Carboxylation of Acetyl CoA
• Step 2: Three C and Two C Units
are Added
• Step 3: Condensation
• Step 4: Reduction
• Step 5: Dehydration
• Step 6: Second Reduction
• Cycling of Reactions (7 times)
• Step 7: Palmitic acid is Released
• 1 Acetyl CoA +7 Malonyl CoA +14
NADPH +14 H+ → 1 Palmitate + 7
CO2 +14 NADP+ + 8 CoA+ 6 H2O
Fatty Acid Synthase Complex
• The Fatty Acid Synthase
Complex Is a Homodimer of Two
Polypeptide Chains Containing
Six Enzyme Activities and the
Acyl Carrier Protein

• This system exists as a multi-

enzyme complex. The enzymes
form a dimer with identical
subunits. Each subunit of the
complex is organized into 3
domains with 7 enzymes
Co-enzymes of Fatty Acid Synthesis

An important point to remember is that the co-enzyme

utilized for de novo synthesis is NADPH. The sources of
NADPH for fatty acid synthesis are:
• Pentose Phosphate Pathway (main source)
• Malic Enzyme
 The sequence
of cycles C2
needed to
produce a
C16 fatty acid
C4
from
acetyl ACP.
C6

Malonyl ACP adds 2

carbons at each cycle.

Each loop represents Dst..

one cycle.

C16
 The acyl group is now ready to condense
with a new malonyl group to repeat the process.

When fatty acyl group becomes 16 carbons long,

a thioesterase hydrolyzes it, forming free palmitate:

thioesterase
palmitoyl-ACP + H2O  palmitate + ACP-SH

Palmitate is then released from the enzyme by a thioesterase reaction

and can then undergo

separate elongation

and/or unsaturation

to yield other fatty acid molecules.

FA Elongation and desaturation
• Palmitate can be elongated and desaturated to form a series of
fatty acids
• The elongation of long-chain fatty acids can take place either in
mitochondria or in endoplasmic reticulum (microsomes), by
separate mechanisms.
• The microsomal chain elongation is more predominant and
involves successive additions of malonyl CoA with the
participation of NADPH.
• These reactions are similar to that catalysed by fatty acid
synthase. A specific group of enzymes, namely elongases , bring
about fatty acid chain elongation.
• The mitochondrial chain elongation is almost a reversal of E-
oxidation of fatty acids. Acetyl CoA molecules are successively
added to fatty acid to lengthen the chain. The reducing
equivalents are derived from NADPH.
Desaturation
• A microsomal enzyme system called fatty acyl CoA desaturase is
responsible for the formation of unsaturated fatty acids. This reaction
also involves flavin-dependent cytochrome b5 reductase, NADH and
molecular O2.
• In humans, desaturates may add double bonds at positions 5, 6, and 9
of a fatty acyl-CoA. Mammals lack the ability to introduce double bonds
in fatty acids between carbon 10 and methyl terminal (Z) end. Plants
can introduce double bonds between carbon 9 and the ω-carbon.
Therefore, certain unsaturated fatty acids from plants are required in
the human diet.
• Linoleic acid (18 : 2; 9, 12) and linolenic acid (18 : 3; 9, 12, 15) are
essential for man in the diet.
• Arachidonic acid (20 : 4; 5, 8, 11, 14) can be synthesized from linoleic
acid by desaturation and chain elongation.
• Arachidonic acid is the precursor for eicosanoids (prostaglan-dins and
thromboxanes), a group of compounds with diversified functions,
discussed elsewhere
ESSENTIAL FATTY ACID

• linoleic and α- linolenic acid → cannot be

synthesized →must be supplied from diet →it
is called as nutritionally essential fatty acids.
• The essential fatty acids→ are found in high
concentrations in various vegetable oils.
• Arachidonic acid →essential fatty acid → can
be formed from linoleic acid in most mammals
• essential fatty acids → eicosanoic ( C20 ) fatty acid →
compounds known as eicosanoids →prostaglandins,
thromboxans, leukotrienes, and lipoxins.
• Almost all celluler arachidonic acid is stored in cell
membranes as esters at C-2 of glycerol in
phosphoglicerides.
• Release of arachidonnic acid from membrane,
considered to be the rate limiting step in eicosanoid
synthesis , results from binding an appropriate chemical
signal to its receptor on a target cell plasma membrane .
• For example, the release of arachidonic acid in platelets
is caused by binding thrombin , an enzyme that plays an
important role in blood clothing
• Release of arachidonic acid  catalyzed by
phospholipase A2.
• Certain steroids that suppresss inflammation  inhibit
phospholipase A2
Eicosanoid

• NSAIDs (Aspirin and ibuprofin) block

production of Prostaglandiins and
thromboxanes
PG1 (PGE1, PGF1) dari Asam linoleat
PG2 (PGE2, PGF2) dari Asam
arakhidonat
PG3 (PGE3, PGF3) dari Asam linolenat
Referensi
• Devlin MT, Textbook of Biochemistry with Clinical
Correlations, 5th ed, Willey Liss, 2002
• Murray RK, Granner DK, Mayes PA, Harper’s
Biochemistry, 26th ed., Lange Medical Books, Mc Graw-
Hill, 2003
• DM Vasudevan, Sreekumari S, Kannan Vaidyanathan;
Textbook of Biochemistry for Medical Students; 7th ed.;
Jitendar P Vij ;2013
• Lieberman, Michael; Biochemistry, molecular biology,
and genetics; 6th ed.; Lippincott Williams & Wilkins, a
Wolters Kluwer business; 2010