 Contents :

 Cytosolic acetyl CoA production

 Acetyl CoA carboxylation to malonyl CoA
 Synthesis of palmitate
 Reductant sources
 Further elongation and Chain desaturation
 Storage as triacylglycerol components

By: Savath Sovannak

  Carbohydrates and proteins
obtained from the diet in
excess of the body's needs
for these nutrients can be
converted to fatty acids
 Location of FA synthesis :
cytoplasm of liver (mainly),
lactating mammary glands,
and adipose tissue

 The first step in fatty acid synthesis is the transfer of acetate units from mitochondrial acetyl
CoA to the cytosol :
 Mitochondrial acetyl CoA is produced by the oxidation of pyruvate and by the
catabolism of certain amino acids​​  combine with Oxaloacetate (OAA) to form Citrate
by citrate synthase
 High [Citrate]  transport of citrate to the cytosol
o Large amount of ATP  (-) isocitrate dehydrogenase  increase [Citrate]
 In the cytosol, citrate is cleaved to OAA and acetyl CoA by ATP citrate lyase

By: Savath Sovannak

 The carboxylation of acetyl CoA to malonyl CoA is catalyzed by acetyl CoA carboxylase​ (ACC) that need ATP
and biotin as coenzyme
 Biotin bind to ACC at amino group of lysine residue of PC  form Enzyme-Biotin
 Hydrolysis ATP  form Enzyme-Biotin- CO2 (HCO3-  CO2 )
 Enzyme-Biotin- CO2  transfer CO2 to Acetyl CoA  form Malonyl CoA
 Regulation of ACC
 Short term :
o Inactive form of ACC is a protomer (complex of ≥2 polypeptides)
o Active form of ACC is polymer
o ACC is activated by citrate and inhibited by Palmitoyl CoA
o Adenosine monophosphate-activated protein kinase (AMPK) 
phosphorylate and inactivate ACC
• AMP  (+) AMPK
• PKA  phosphorylate and activate AMPK
 Epinephrine and glucagon  ↑PKA
 Insulin  (+) protein phosphatase  dephosphorylate ACC
Activate ACC
 Long term :
o Prolonged consumption of a diet containing high carbohydrate, low-fat
 increase in ACC synthesis
• ACC synthesis is upregulated by carbohydrate via the transcription
factor carbohydrate response element-binding protein (ChREBP)
• by insulin via the transcription factor sterol regulatory element-
binding protein-1c (SREBP-1c) also  increase FA synthase
o Prolonged consumption of a diet containing high-fat, low-carbohydrate
diet has the opposite effect
By: Savath Sovannak
 Palmitic acid is synthesis by enzyme fatty
acid synthase (FAS)
 FAS is an homodimeric enzyme that each
monomer contains :
 6 different enzymic domains :
o Malonyl/acetyl CoA-ACP
transacylase
o 3 (or 𝛽)-Ketoacyl-ACP synthase
(condensing enzyme)
o 3-Ketoacyl-ACP reductase
o 3-Hydroxyacyl ACP dehydratase
o Enoyl-ACP reductase
o Palmitoyl thioesterase
 4'-phosphopantetheine-containing
acyl carrier protein (ACP) domain

By: Savath Sovannak

  Synthesis of Butyryl group-ACP :
1. An acetyl group is transferred from acetyl CoA
to the -SH group of the ACP by Malonyl/acetyl
CoA-ACP transacylase
2. Acetyl is transferred to a temporary -SH group
of a cysteine residue on the condensing
enzyme domain
3. Malonyl/acetyl CoA-ACP transacylase transfer
malonyl from malonyl CoA to ACP
4. The acetyl group on the cysteine residue
condenses with the malonyl group on ACP as
the C02 originally added by ACC is released by
condensing enzyme  acetoacetyl
5. 3-Ketoacyl-ACP reductase take H from NADPH
to acetoacetyl  form 3-hydroxybutyryl
6. A molecule of water is removed from 3-
hydroxybutyryl by 3-Hydroxyacyl ACP
dehydratase  form double bond between
carbons 2 and 3 (Crotonyl)
7. The double bond of crotonyl is reduced by
Enoyl-ACP reductase  form butyryl group-
ACP (4 carbon)
 Elongation by repeat the previous step :
 Transfer of the butyryl unit from the ACP to the cysteine residue on condensing enzyme domain (2)
 Attachment of a malonyl group to the ACP (3) condensation of the two groups liberating C02 (4) 
carbonyl group at 𝛽carbon (the third carbon from the sulfur) is then reduced (5), dehydrated (6), and
reduced (7)  form hexanoyl-ACP (6 carbon)  hexanoyl-ACP transfer to cysteine residue (2)
 The cycle repeat 5 more time form palmitoyl-S-ACP  Palmitoyl thioesterase cleaves the thioester
bond  releasing a fully saturated molecule of palmitate (16:0). By: Savath Sovannak
 The synthesis of one
palmitate requires 14 NADPH,
a reductant (reducing agent)
 There two sources of NADPH :
 Major : Pentose
phosphate pathway
 Minor : cytosolic
conversion of malate to
pyruvate

By: Savath Sovannak

 Although palmitate, a 16-carbon, fully saturated LCFA (16:0), is the primary end product of FAS activity, it
can be further elongated by the addition of two-carbon units primarily in the smooth endoplasmic
reticulum (SER)
 The process nee NADPH (reducing agents) and Malonyl CoA is the two-carbon donor

 Enzymes (tatty acyl CoA desaturases) also present in the SER are responsible tor desaturating LCFA (that
is, adding cis double bonds)
 The desaturation reactions require oxygen (02), NADH, cytochrome b5, and its flavin adenine
dinucleotide (FAD)-linked reductase.
 Humans have carbon 9, 6, 5, and 4 desaturases but lack the ability to introduce double bonds from
carbon 10 to the 𝝎 end of the chain

By: Savath Sovannak

Contents :
 Introduction
 Glycerol 3-phosphate synthesis
 Fatty acid activation
 TAG synthesis

By: Savath Sovannak

 Endogenous TAG is produced in liver and adipose tissue
 Adipose tissue :
 TAG is stored as fat droplets in the cytosol of the cells
 In white adipose tissue : these cytosolic lipid droplets
are the major energy reserve of the body
 In brown adipocytes : serve as a source of heat
through nonshivering thermogenesis
 In liver :
 Little TAG is stored in healthy liver.
 Instead, most is exported, packaged with other lipids
and apolipoproteins to form lipoprotein particles
called very-low-density lipoproteins (VLDL)

By: Savath Sovannak

 Glycerol 3-phosphate is the initial acceptor of fatty
acids during TAG synthesis
 Location : liver and adipose tissue
 There are two major pathways for its production :
1. First in both liver and adipose tissue: using the
reactions of the glycolytic pathway to produce
dihydroxyacetone phosphate (DHAP)
 DHAP is reduced by glycerol 3-phosphate
dehydrogenase to glycerol 3-phosphate
2. Second pathway found in the liver, but not in
adipose tissue : uses glycerol kinase to convert
free glycerol to glycerol 3-phosphate

By: Savath Sovannak

 A free fatty acid must be converted to its activated form (bound to CoA through a thioester
link) before it can participate in metabolic processes such as TAG synthesis
 FA activation is catalyzed by a family of fatty acyl CoA synthetases (thiokinases).
 Thiokinase transfers fatty acid to coenzyme A  form activated fatty acid (acyl-CoA)

By: Savath Sovannak

 Reaction :
1. Glycerol 3P + Acyl-CoA  form Lysophosphatidic acid by
acyltransferase
2. Lysophosphatidic acid + Acyl-CoA  form Phosphatidic acid
(diacylglycerolphosphate = DAG phosphate) by acyltransferase
3. DAG phosphate is hydrolyzed by phosphatase  form
Diacylglycerol (DAG)
4. DAG + Acyl-CoA  form Triacylglycerol = TAG (Triglyceride = TG)

By: Savath Sovannak