2. •Fatty acids are synthesized mainly by a de novo synthetic
pathway operating in the cytoplasm. So it is referred to as
extramitochondrial or cytoplasmic fatty acid synthase
system.
•The major fatty acid synthesised de novo is palmitic acid, the
16C saturated fatty acid. The process occurs in the liver,
adipose tissue, kidney, brain, and mammary glands.
•The starting material for the synthesis is acetyl-CoA. Acetyl-
CoA is formed in mitochondrion but synthesis occurs in
cytosol. Acetyl-CoA is impermeable to mitochondrial
membrane.
3. Transport of Acetyl CoA to Cytoplasm:
The starting material for de novo synthesis is acetyl CoA. It is
formed inside the mitochondria from pyruvate.
The inner membrane is not freely permeable to acetyl CoA.
Hence the acetyl CoA units are delivered to the cytoplasm
as citrate
Citrate is transported from mitochondria by a tricarboxylic
acid transporter. In the cytoplasm, citrate is cleaved to
oxaloacetate and acetyl CoA by ATP citrate lyase. The
oxaloacetate can returns to the mitochondria as
malate or pyruvate
4. Fig:
Transfer of acetyl CoA
from mitochondria to
cytoplasm by malate–
oxaloacetate
shuttle.
1 = citrate synthetase;
2 = ATP–citrate lyase;
3 = malate
dehydrogenase;
4 = malic enzyme
5. Fatty Acid Synthase (FAS) Complex
Fatty acid synthesis is accomplished by a multi-enzyme
complex called Fatty Acid Synthase (FAS) Complex.
The enzyme complex forms a dimer with identical
subunits and each subunit of the complex is organized
into 3 domains with 7 enzymes
6. Step 1: Carboxylation of Acetyl CoA
The first step in the fatty acid synthesis is the
carboxylation of acetyl CoA to form malonyl CoA by acetyl
CoA carboxylase .
Acetyl CoA carboxylase is not a part of the Fatty Acid
Synthase (FAS) Complex, But it is the rate-limiting enzyme.
Biotin, a member of B complex vitamins, is necessary for
this reaction.
7. ATP-dependent carboxylation provides energy input.
The CO2 is lost later during condensation with the growing
fatty acid.
The spontaneous decarboxylation drives the condensation
reaction.
H3C C SCoA
O
CH2 C SCoA
O
OOC
acetyl-CoA
malonyl-CoA
The input to fatty acid
synthesis is acetyl-CoA,
which is carboxylated to
malonyl-CoA.
8. Steps in fatty acid synthesis
1. Acetyl-CoA Carboxylase, which converts acetyl-CoA to
malonyl-CoA, is the committed step of the fatty acid
synthesis pathway. The acetyl CoA carboxylase is not a
part of the multienzyme complex.
9. Subsequent steps:
Once malonyl-CoA is synthesised, rest of fatty acid synthesis
reactions take place with FA synthase complex.
“Cys-SH” and “Pan-SH” may be considered as two arms of the
enzyme complex. “Cys-SH” is the acceptor of Acetyl-CoA whereas
“Pan-SH” takes up malonyl-CoA.
• Initially, a molecule of acetyl-CoA combines with the “Cys-SH” of
“keto acyl-synthase” of one monomeric unit (monomer I). The
coenzyme A is removed, the reaction is catalysed by the enzyme
“transacylase”,
• In a similar manner, a molecule of malonyl-CoA combines with the
adjacent “Pan- SH” of ACP of opposite monomeric unit (Monomer
II), to form “Malonyl-ACP-enzyme”. The coenzyme A of Malonyl-CoA
is also removed in this step and the reaction is catalysed by the same
“transacylase” enzyme.
10. 1. The condensation reaction of malonyl CoA and acetyl
CoA involves decarboxylation of the malonyl moiety
catalyzed by Malonyl/acetyl CoA-ACP transacylase
(Keto-acyl synthase)
11. 2. The acetoacetyl CoA is reduced to an β-hydroxyacyl
ACP by e- transfer from NADPH catalyzed by β-ketoacy-
ACP reductase
12. 3. Dehydration of β-hydroxyacyl ACP yields crotonyl ACP (a
trans double bond molecule) catalyzed by β-hydroxyacyl ACP
dehydratase. A molecule of H2O is removed from “β-OH-
butyryl-ACP” to form “α, β-unsaturated butyryl-ACP”
13. 4. Reduction of crotonyl ACP: The third and final reduction is
catalysed by “enoyl-reductase”using NADPH + H+ to yields a
saturated chain (butaryl ACP or a molecule longer by
2carbons).
14. Continuation reaction:
Now a fresh molecule of Malonyl-CoA is taken up on to the free
“Pan-SH” group of monomer II and the sequence of events is
repeated to form a saturated six carbon fatty acid. The set of
reactions on each of the monomer is repeated till a 16 carbon
palmityl-ACP is formed on “Pan- SH” of monomer II.
16. 1. The condensation reaction of malonyl CoA and acetyl
CoA involves decarboxylation of the malonyl moiety
catalyzed by Malonyl/acetyl CoA-ACP transacylase
2. The acetoacetyl CoA is reduced to an β-hydroxyacyl ACP
by e- transfer from NADPH catalyzed by β-ketoacy-ACP
reductase
3. Dehydration of β-hydroxyacyl ACP yields crotonyl ACP
(a trans double bond molecule) catalyzed by β-
hydroxyacyl ACP dehydratase
4. Reduction of crotonyl ACP by NADPH yields a saturated
chain (butaryl ACP or a molecule longer by 2carbons).
17. Following transfer of the growing fatty acid from
phosphopantetheine to the Condensing Enzyme's
cysteine sulfhydryl, the cycle begins again, with
another malonyl-CoA.
Pant
S
Cys
SH
C
CH2
CH2
O
CH3
Pant
SH
Cys
S
C
CH2
O
CH2
CH3
Pant
S
Cys
S
C
CH2
O
CH2
CH3
C
CH2
COO
O
Malonyl-S-CoA HS-CoA
7 2
7 Condensing Enzyme
2 Malonyl/acetyl-CoA-ACP Transacylase (repeat).
18. Desaturation of Fatty Acids to form unsaturated fatty acids
uses a Mixed-Function Oxidase
Palmitate and stearate serve as precursors of the two most
common monounsaturated fatty acids of animal tissues:
palmitoleate, 16:1(9), and oleate, 18:1( 9); both of these
fatty acids have a single cis double bond between C-9 and C-
10.
The double bond is introduced into the fatty acid chain by an
oxidative reaction catalyzed by fatty acyl–CoA desaturase, a
mixed-function oxidase.
Formation of unsaturated fatty acids
19.
20. The double bond is introduced into the fatty acid chain by an
oxidative reaction catalyzed by fatty acyl–CoA desaturase, a
mixed-function oxidase. Two different substrates, the fatty
acid and NADH or NADPH, simultaneously undergo two-
electron oxidations.
Mammalian hepatocytes can readily introduce double bonds
at the 9 position of fatty acids but cannot introduce
additional double bonds between C-10 and the methyl-
terminal end. Thus mammals cannot synthesize linoleate,
18:2(9,12), or -linolenate, 18:3( 9,12,15).
21. Because they are necessary precursors for the synthesis of
other products, linoleate and linolenate are essential fatty
acids for mammals; they must be obtained from dietary
plant material.
Once ingested, linoleate may be converted to certain other
polyunsaturated acids, particularly -linolenate,
eicosatrienoate, and arachidonate (eicosatetraenoate), all of
which can be made only from linoleate (see next slide).
Arachidonate, 20:4(5,8,11,14), is an essential precursor of
regulatory lipids, the eicosanoids. The 20-carbon fatty acids
are synthesized from linoleate (and linolenate) by fatty acid
elongation reactions analogous to those of fatty acid
synthesis.
22. Routes of synthesis of other fatty
acids.
Palmitate is the precursor of
stearate and longer-chain saturated
fatty acids, as well as the
monounsaturated acids palmitoleate
and oleate.
Mammals cannot convert oleate to
linoleate or -linolenate (shaded
pink), which are therefore required
in the diet as essential fatty acids.
Conversion of linoleate to other
polyunsaturated fatty acids and
eicosanoids is outlined.
23. Regulation of Fatty Acid Synthesis
The activities of the enzymes involved in fatty acid
synthesis appear to be controlled in two ways:
(a) Short-term or acute control: Which involves allosteric
or metabolic regulation and covalent modification of
enzymes.
(b) Long-term control: Involving changes in the amounts
of the enzymes brought about by changes in the rates
of synthesis and degradation.
24. 1. Acetyl-CoA carboxylase catalyses the rate limiting step in
the de novo synthesis of fatty acids and provides the earliest
unique point at which control can be exerted.
i. Acetyl-coA carboxylase is regulated by phosphorylation
and dephosphorylation. The enzyme is inactivated by
phosphorylation by AMPactivated protein kinase (AMPK),
which in turn is phosphorylated and activated by AMP-
activated protein kinase kinase (AMPKK).
Glucagon (and epinephrine), after increasing c-AMP,
activate this latter enzyme via cAMPdependent protein
kinase. The kinase kinase enzyme is also believed to be
activated by acyl-CoA. Insulin activates acetyl-CoA
carboxylase, probably through an “activator” protein and
insulinstimulated protein kinase.
25. ii. Glucagon and dibutyryl cAMP: inhibit fatty acid synthesis by
markedly decreasing cytosolic citrate concentration. They also
inhibit glycolysis at the level of phosphofructokinase, resulting
in decreased glycolytic flux into pyruvate which in turn
decreases the mitochondrial synthesis of oxaloacetate and
citrate. Decrease in citrate conc. Decreases acetyl-CoA
carboxylase activity.
iii. Fatty acyl-CoAs regulate fatty acid synthesis by inhibiting acetyl-
CoA carboxylase as a result of its depolymerisation (product
inhibition).
iv. Fatty acid synthesis may also be regulated by altering the
activity of pyruvate dehydrogenase which oxidatively
decarboxylates pyruvate to acetyl-CoA. Thus, fatty acid
synthesis is reduced by reducing the formation of acetyl-CoA
from pyruvate. High carbohydrate diet increases fatty acid
synthesis.
26. v. Insulin increases fatty acid synthesis in several ways
such as decreasing lipolysis, bringing about activation
of protein phosphatase, stimulating synthesis of
citratelyase, enhancing formation of acetyl-CoA from
pyruvate, increasing glycolysis which leads to
increased pyruvate and thus acetyl-CoA.
vi. Long-term regulation is done by stimulation of
acetyl-CoA carboxylase, fatty acid synthase,
ATPcitrate lyase.
29. -oxidation of fatty acids
• Most naturally occurring fatty acids have an even
number of carbon atoms.
• The pathway for catabolism of fatty acids is
referred to as the -oxidation pathway, because
oxidation occurs at the -carbon (C-3).
Fatty acids are degraded in the mitochondrial
matrix via the -Oxidation Pathway.
31. Fatty acid activation:
• Fatty acids must be esterified to Coenzyme A before
they can undergo oxidative degradation, be utilized
for synthesis of complex lipids, or be attached to
proteins as lipid anchors.
• Acyl-CoA Synthases (Thiokinases) of ER & outer
mitochondrial membranes catalyze activation of long
chain fatty acids, esterifying them to coenzyme A.
• This process is ATP-dependent, & occurs in 2 steps.
• There are different Acyl-CoA Synthases for fatty acids
of different chain lengths.
32. Acyl-CoA Synthases
Exergonic PPi (P~P)
hydrolysis, catalyzed by
Pyrophosphatase, makes
the coupled reaction
spontaneous.
2 ~P bonds of ATP are
cleaved.
The acyl-CoA product
includes one "~"
thioester linkage.
33. In step 1 , the carboxylate
ion displaces the outer two
and phosphates of ATP to
form a fatty acyl–adenylate,
the mixed anhydride of a
carboxylic acid and a
phosphoric
acid.
In step 2 , the thiol group of
coenzyme A carries out
nucleophilic attack on the
enzyme-bound mixed
anhydride, displacing AMP
and forming the thioester
fatty acyl–CoA. The
overall reaction is highly
exergonic.
PPi 2Pi
34. Carnitine Palmitoyl Transferases catalyzes transfer of a
fatty acid between the thiol of Coenzyme A and the
hydroxyl on carnitine.
H3C N CH2 CH CH2
CH3
CH3
OH
COO
+
R
C
SCoA
O
+
H3C N CH2 CH CH2
CH3
CH3
O
COO
+
C
R
O
+ HSCoA
carnitine
fatty acyl carnitine
Carnitine Palmitoyl
Transferase
Transfer of the fatty
acid moiety across
the mitochondrial
inner membrane
involves carnitine.
35. Carnitine-mediated transfer of the fatty acyl moiety into the
mitochondrial matrix is a 3-step process:
1. Carnitine Palmitoyl Transferase I, an enzyme on the cytosolic
surface of the outer mitochondrial membrane, transfers a fatty
acid from CoA to the OH on carnitine.
2. An antiporter in the inner mitochondrial membrane mediates
exchange of carnitine for acylcarnitine.
cytosol mitochondrial matrix
O O
R-C-SCoA HO-carnitine HO-carnitine R-C-SCoA
HSCoA R-C-O-carnitine R-C-O-carnitine HSCoA
O O
1
2
3
37. 3. Carnitine Palmitoyl Transferase II, an enzyme
within the matrix, transfers the fatty acid from carnitine
to CoA. The fatty acid is now esterified to CoA in the
matrix.
Control of fatty acid oxidation is exerted mainly at
the step of fatty acid entry into mitochondria.
Malonyl-CoA (which is also a precursor for fatty acid
synthesis) inhibits Carnitine Palmitoyl Transferase I.
Malonyl-CoA is produced from acetyl-CoA by the
enzyme Acetyl-CoA Carboxylase.
38. FAD is the prosthetic group that functions as e
acceptor for Acyl-CoA Dehydrogenase.
H3C (CH2)n C C C SCoA
H
H
H
H O
1
2
3
H3C (CH2)n C C C SCoA
H
H O
O
H2O
FADH2
FAD
H
fatty acyl-CoA
trans-2
-enoyl-CoA
Acyl-CoA Dehydrogenase
-Oxidation Pathway: steps
Step 1. Acyl-CoA Dehydrogenase catalyzes oxidation of the
fatty acid moiety of acyl-CoA to produce a double bond
between carbon atoms 2 & 3.
39. Step 2. Enoyl-CoA Hydratase catalyzes stereospecific
hydration of the trans double bond produced in the 1st
step, yielding L-hydroxyacyl-Coenzyme A.
H3C (CH2)n C C C SCoA
H
H
H
H O
1
2
3
H3C (CH2)n C C C SCoA
H
H O
H3C (CH2)n C CH2 C SCoA
OH
O
H2O
FADH2
FAD
H
fatty acyl-CoA
trans-2
-enoyl-CoA
3-L-hydroxyacyl-CoA
Acyl-CoA Dehydrogenase
Enoyl-CoA Hydratase
40. H3C (CH2)n C C C SCoA
H
H O
H3C (CH2)n C CH2 C SCoA
OH
O
H2O
2
H
H3C (CH2)n C CH2 C SCoA
O
O
H+
+ NADH
NAD+
CH3 C SCoA
O
H3C (CH2)n C SCoA +
O
HSCoA
3-L-hydroxyacyl-CoA
-ketoacyl-CoA
fatty acyl-CoA acetyl-CoA
(2 C shorter)
Hydroxyacyl-CoA
Dehydrogenase
-Ketothiolase
Step 3. Hydroxyacyl-CoA Dehydrogenase catalyzes
oxidation of the hydroxyl in the b position (C3) to a
ketone. NAD+ is the electron acceptor.
Step 4. -
Ketothiolase
catalyzes thiolytic
cleavage of
ketoacyl-CoA
releasing Acetyl-
CoA and fatty
acyl-CoA (2 C
less).
42. Summary of one round of the -oxidation pathway:
fatty acyl-CoA + FAD + NAD+ + HS-CoA
fatty acyl-CoA (2 C less) + FADH2 + NADH + H+
+ acetyl-CoA
•The -oxidation pathway is cyclic.
•The product, 2 carbons shorter, is the input to another
round of the pathway.
•If, as is usually the case, the fatty acid contains an
even number of C atoms, in the final reaction cycle
butyryl-CoA is converted to 2 copies of acetyl-CoA.
45. • During high rates of fatty acid oxidation, primarily in
the liver, large amounts of acetyl-CoA are generated.
These exceed the capacity of the TCA cycle, and one
result is the synthesis of ketone bodies.
• The synthesis of the ketone bodies (ketogenesis)
occurs in the mitochondria allowing this process to
be intimately coupled to rate of hepatic fatty acid
oxidation.
• Conversely, the utilization of the ketones (ketolysis)
occurs in the cytosol. The ketone bodies are
acetoacetate, β-hydroxybutyrate, and acetone.
49. • The formation of acetoacetyl-CoA occurs by condensation
of two moles of acetyl-CoA catalyzed by thiolase.
• Acetoacetyl-CoA and an additional acetyl-CoA are
converted to β-hydroxy-β-methylglutaryl-CoA (HMG-CoA)
by mitochondrial HMG-CoA synthase
• HMG-CoA in the mitochondria is converted to acetoacetate
by the action of HMG-CoA lyase.
• Acetoacetate can undergo spontaneous decarboxylation to
acetone, or be enzymatically converted to β-
hydroxybutyrate through the action of β-hydroxybutyrate
dehydrogenase.
50. Ketone body oxidation
• Ketone bodies are utilized by extrahepatic tissues via a
series of cytosolic reactions that are essentially a reversal
of ketone body synthesis. The initial steps involve the
conversion of β-hydroxybutyrate to acetoacetate and of
acetoacetate to acetoacetyl-CoA.
• The first step involves the reversal of the β-
hydroxybutyrate dehydrogenase reaction
• The second reaction of ketolysis involves the action of
succinyl-CoA:3-oxoacid-CoA transferase, also called 3-
oxoacid-CoA transferase.
55. • The sphingolipids are composed of a polar head
group and two nonpolar tails.
• The core of sphingolipids is the long-chain amino
alcohol, sphingosine.
• The sphingolipids include the sphingomyelins and
glycosphingolipids (the cerebrosides, sulfatides,
globosides and gangliosides).
• Sphingomyelins are the only sphingolipid class that
are also phospholipids. Sphingolipids are
components of all membranes but are particularly
abundant in the myelin sheath.
57. • The biosynthesis of sphingolipids takes place in four stages:
1. Synthesis of the 18-carbon amine sphinganine from
palmitoyl-coa and serine;
• This reaction occurs on the cytoplasmic face of the
endoplasmic reticulum (ER) and is catalyzed by serine
palmitoyltransferase
• SPT is the rate-limiting enzyme of the sphingolipid biosynthesis
pathway.
2. Attachment of a fatty acid in amide linkage to yield N-
acylsphinganine catalyzed by ceramide synthases
3. Desaturation of the sphinganine moiety to form n-
acylsphingosine (ceramide); and
4. Attachment of a head group to produce a sphingolipid
such as a cerebroside or sphingomyelin
59. Sphingolipids are then made from
ceramide which is synthesized in
the endoplasmic reticulum from the
amino acid serine
Sphingomylin synthase
60. • Gangliosides are synthesized from ceramide
by the stepwise addition of activated sugars
(eg, UDPGlc and UDPGal) and a sialic acid,
usually N-acetylneuraminic acid
61. • Glycosphingolipids, or glycolipids, are composed of a ceramide
backbone with a wide variety of carbohydrate groups (mono- or
oligosaccharides) attached to carbon 1 of sphingosine.
• The four principal classes of glycosphingolipids are the
cerebrosides, sulfatides, globosides and gangliosides.
• Cerebrosides have a single sugar group linked to ceramide. The
most common of these is galactose (galactocerebrosides), with
a minor level of glucose (glucocerebrosides).
• Galactocerebrosides are found predominantly in neuronal cell
membranes. By contrast glucocerebrosides are not normally
found in membranes, especially neuronal membranes; instead,
they represent intermediates in the synthesis or degradation of
more complex glycosphingolipids.
63. • The synthesis pathway of phospholipids starts by reducing
dihydroxyacetone phosphate to glycerol phosphate, with
NADH as the reductant
• Alternatively, existing glycerol molecules may be
phosphorylated by glycerol kinase.
• This is followed by two successive additions of acyl ester.
Fatty acid (typically 16-18 C atoms) is first converted to the
active CoA thioester by acyl CoA synthetase:
• The last product, 1,2-diacylglycerol-3-phosphate, is also
known as phosphatidic acid, and its phospholipid
derivatives are phosphatidyl-X. Phospholipids also tend to
have a saturated fatty acid in position 1 and an unsaturated
fatty acid in position 2.
64.
65.
66.
67. • Phospholipid precursors are activated by
forming a cytidine diphosphate derivative
• CDP-diacylglycerol contains a high energy
bond between the two phosphates, so can act
as a donor of diacylglycerol (bond breaks
between glycerol and phosphate) or as a
donor of the phosphatidyl radical
68.
69. • Microorganisms use the head group hydroxyl
compound to displace CMP and then link up to
the phosphatidyl radical.
• The amino acid serine , which has a hydroxyl
group side chain provides the head group for the
negative phospholipid, phosphatidyl serine .
• Phosphatidyl serine can then be decarboxylated
to produce the important neutral phospholipid,
phosphatidyl ethanolamine.
70.
71. • In animals, phosphatidyl ethanolamine and
phosphatidyl choline are made by a different
strategy, in which ethanolamine and choline are
activated as CDP ethanolamine and CDP choline
• Diacylglycerol then displaces CMP to bond to the
phosphate attached to the headgroup, as shown
for the synthesis of phosphatidyl choline, a
major animal phospholipid.
72.
73. • The strategy used in animals is optimized for what is called
salvage synthesis, in which existing molecules of
ethanolamine, choline and diacylglyerol are reused.
Phosphatidyl ethanolamine + serine
phosphatidyl serine + ethanolamine
phosphatidyl ethanolamine
CO2 phosphatidyl serine decarboxylase
phosphatidyl ethanolamine serine
transferase
Decarboxylation of phosphatidyl serine produces new
molecules of ethanolamine.
74. The “salvage” pathway from
phosphatidylserine to
phosphatidylethanolamine and
phosphatidylcholine
New molecules of choline are made on
the phospholipid structure of
phophatidyl ethanolamine.
The methyl donor is a compound is S-
adenosyl methionine or SAM
for short, leaving behind S-
adenosylhomocysteine, SAHC
80. • The sphingolipids are composed of a polar head
group and two nonpolar tails.
• The core of sphingolipids is the long-chain amino
alcohol, sphingosine.
• The sphingolipids include the sphingomyelins and
glycosphingolipids (the cerebrosides, sulfatides,
globosides and gangliosides).
• Sphingomyelins are the only sphingolipid class that
are also phospholipids. Sphingolipids are
components of all membranes but are particularly
abundant in the myelin sheath.
82. • The biosynthesis of sphingolipids takes place in four
stages:
1. Synthesis of the 18-carbon amine sphinganine from
palmitoyl-coa and serine;
• This reaction occurs on the cytoplasmic face of the endoplasmic
reticulum (ER) and is catalyzed by serine palmitoyltransferase
• SPT is the rate-limiting enzyme of the sphingolipid biosynthesis
pathway.
2. Attachment of a fatty acid in amide linkage to yield N-
acylsphinganine catalyzed by ceramide synthases
3. Desaturation of the sphinganine moiety to form n-
acylsphingosine (ceramide); and
4. Attachment of a head group to produce a sphingolipid such
as a cerebroside or sphingomyelin
84. Sphingolipids are then made from
ceramide which is synthesized in
the endoplasmic reticulum from
the amino acid serine
Sphingomylin
synthase
85. • Gangliosides are synthesized from ceramide
by the stepwise addition of activated sugars
(eg, UDPGlc and UDPGal) and a sialic acid,
usually N-acetylneuraminic acid
86. • Glycosphingolipids, or glycolipids, are composed of a ceramide
backbone with a wide variety of carbohydrate groups (mono-
or oligosaccharides) attached to carbon 1 of sphingosine.
• The four principal classes of glycosphingolipids are the
cerebrosides, sulfatides, globosides and gangliosides.
• Cerebrosides have a single sugar group linked to ceramide.
The most common of these is galactose (galactocerebrosides),
with a minor level of glucose (glucocerebrosides).
• Galactocerebrosides are found predominantly in neuronal cell
membranes. By contrast glucocerebrosides are not normally
found in membranes, especially neuronal membranes;
instead, they represent intermediates in the synthesis or
degradation of more complex glycosphingolipids.
88. • The synthesis pathway of phospholipids starts by reducing
dihydroxyacetone phosphate to glycerol phosphate, with
NADH as the reductant
• Alternatively, existing glycerol molecules may be
phosphorylated by glycerol kinase.
• This is followed by two successive additions of acyl ester.
Fatty acid (typically 16-18 C atoms) is first converted to
the active CoA thioester by acyl CoA synthetase:
• The last product, 1,2-diacylglycerol-3-phosphate, is also
known as phosphatidic acid, and its phospholipid
derivatives are phosphatidyl-X. Phospholipids also tend to
have a saturated fatty acid in position 1 and an
unsaturated fatty acid in position 2.
89.
90.
91.
92. • Phospholipid precursors are
activated by forming a cytidine
diphosphate derivative
• CDP-diacylglycerol contains a high
energy bond between the two
phosphates, so can act as a donor
of diacylglycerol (bond breaks
between glycerol and phosphate)
or as a donor of the phosphatidyl
radical
93.
94. • Microorganisms use the head group hydroxyl
compound to displace CMP and then link up to
the phosphatidyl radical.
• The amino acid serine , which has a hydroxyl
group side chain provides the head group for the
negative phospholipid, phosphatidyl serine .
• Phosphatidyl serine can then be decarboxylated
to produce the important neutral phospholipid,
phosphatidyl ethanolamine.
95.
96. • In animals, phosphatidyl ethanolamine and
phosphatidyl choline are made by a different
strategy, in which ethanolamine and choline are
activated as CDP ethanolamine and CDP choline
• Diacylglycerol then displaces CMP to bond to the
phosphate attached to the headgroup, as shown
for the synthesis of phosphatidyl choline, a
major animal phospholipid.
97.
98. • The strategy used in animals is optimized for what is called
salvage synthesis, in which existing molecules of
ethanolamine, choline and diacylglyerol are reused.
Phosphatidyl ethanolamine + serine
phosphatidyl serine + ethanolamine
phosphatidyl ethanolamine
CO2 phosphatidyl serine decarboxylase
phosphatidyl ethanolamine serine
transferase
Decarboxylation of phosphatidyl serine produces new
molecules of ethanolamine.
99. The “salvage” pathway from
phosphatidylserine to
phosphatidylethanolamine and
phosphatidylcholine
New molecules of choline are made on
the phospholipid structure of
phophatidyl ethanolamine.
The methyl donor is a compound is S-
adenosyl methionine or SAM
for short, leaving behind S-
adenosylhomocysteine, SAHC
