Biochemie-8-2-lipidy 1
Can the body form new
triglycerides?
Biochemie-8-2-lipidy 2
In the organism:
• Synthesis of FA (excluding essential)
• Synthesis of triglycerides
Biochemie-8-2-lipidy 3
Synthesis of fatty acids from acetyl-CoA
Where does it takes place?
especially in the liver, adipocytes, lactating mammary gland
(not in the intestinal mucosa)
When does it takes place?
if enough of acetyl-CoA,
which is not necessary
to metabolize energy
after a meal, when enough glucose,
which is catabolized to acetyl-CoA
?
Biochemie-8-2-lipidy 4
1. Transport of acetyl-CoA from the matrix into the
cytoplasm
2. Formation of malonyl-CoA
3. A series of reactions of fatty acid synthase
Synthesis of fatty acids from acetyl-CoA
(cytoplasm of cells)
cellular localization : cytoplasm
That synthesis of FA occurs in the cytoplasm may cause trouble. Most Ac-CoA in
the body forms in mitochondria (oxidative decarboxylation of pyruvate formed
from starch, glucose, amino acids,...).
It is therefore necessary to provide transport of Ac-CoA from the mitochondria
into the cytoplasm.
(+ formation of NADPH+H+)
Biochemie-8-2-lipidy 5
Transport of acetyl-CoA from
matrix to the cytoplasm
in matrix acetyl-CoA is formed by an oxidative
decarboxylation of pyruvate (from glucose and
amino acids)
when does it
occur?
• acetyl-CoA does not pass freely through mitochondrial
membrane
• transport as citrate
unless citrate is required in the citrate cycle
Biochemie-8-2-lipidy 6
When is citrate not required
for CC?
If enough ATP
Synthesis of fatty acids takes place if the cell
has enough energy and enough acetyl-CoA
Citrate needed in the TCA cycle if the cell has enough energy (glucose), and
can thus build up a stock for a rainy day. The cell is in this state especially
after a meal.
Biochemie-8-2-lipidy 7
Transport of citrate to the cytoplasm
8
Transport of citrate into the
cytoplasm
CYTOPLASM MATRIX
oxalacetate + acetyl-CoA
ADP + Pi
ATP
oxalacetate acetyl-CoA
CoA
citratecitrate
pyruvate, FA
Takes place when high concentrations of
ATP – inhibition of isocitratedehydrogenase
CoA
isocitrate
Biochemie-8-2-lipidy 9
Formation of malonyl-CoA
Acetyl-CoA does not have sufficient
energy to enter into synthetic reactions
Carboxylation (cofactor = biotin) catalyzed by
acetyl-CoA-carboxylase
Biochemie-8-2lipidy 10
Synthesis of malonyl-CoA
http://jb.asm.org/content/194
/1/72/F1.large.jpg
Biochemie-8-2-lipidy 11
Fatty acid synthase
• multienzyme complex with seven enzymatic activities
• contains ACP (acyl carrier protein) to which it
binds phosphopantetheine
• mammalian dimeric form comprising two
identical complexes
• in parallel two molecules of fatty acids are
formed
Biochemie-8-2-lipidy 1212
enoylreductase
hydratase
oxoacylreductase
ACP
thioesterase
3-oxoacylsynthase
acetyltransacylase
malonyltransacylase
oxoacylsynthase
acetyltransacylase
malonyltransacylase
thioesterase
ACP
oxoacylreductase
hydratase
enoylreductase
ACP
ACP
functional
division of
subunits
Pan
Pan
Biochemie-8-2-lipidy 13
Pantothenic acid
Phosphopantetheine is half of the
structure of CoA
-alanine cysteaminepantoic acidACP
http://upload.wikimedia.org/wikipedia/co
mmons/thumb/d/d8/Phosphopantetheine.
svg/799px-Phosphopantetheine.svg.png
Biochemie-8-2-lipidy 14
General FA synthesis reaction
• acyl (acetyl in the first step) is
bound to –SH of enzyme
• malonyl bound to the Pan-SH
CO-CH2-CH2-CH3
1 2 3
S
Pan-S-CO-CH2-COOH
NOVÁK, Jan. Biochemie I. Brno:
Muni, 2009, Metabolismus lipidů s.
19
Biochemie-8-2-lipidy 15
Acyl (acetyl in the
first step) is
transmitted to the
malonyl-CoA, then
beta-oxoacyl is
formed, releasing
CO2
CO-CH2-CH2-CH3CO-CH2
CO2
-oxoacyl
CO-CH2-CH2-CH3
1 2 3
1 2 3
-CO-CH2-COOHPan-S
Pan-S
Cys-S
NOVÁK, Jan. Biochemie I.
Brno: Muni, 2009,
Metabolismus lipidů s. 19
Biochemie-8-2-lipidy 16
+ 2 H
-hydroxyacyl
hydrogenation
(NADPH)
CO-CH2-CH2-CH3CO-CH2
CO-CH2 CH-CH2-CH2-CH3
OH
Other reactions take
place in relation to
fosfopantetein
Pan-S
Pan-S
NOVÁK, Jan. Biochemie I.
Brno: Muni, 2009,
Metabolismus lipidů s. 20
Biochemie-8-2-lipidy 1717
- H2O dehydratation
,-unsaturated acyl
CO-CH2 CH-CH2-CH2-CH3
OH
CO-CH CH-CH2-CH2-CH3
Pan-S
Pan-S
NOVÁK, Jan.
Biochemie I. Brno:
Muni, 2009,
Metabolismus lipidů s.
20
Biochemie-8-2-lipidy 18
saturated acyl longer by 2C
another reaction with malonyl-CoA
CO-CH2 CH2-CH2-CH2-CH3Pan-S
+ 2H hydrogenation (NADPH)
CO-CH CH-CH2-CH2-CH3Pan-S
NOVÁK, Jan. Biochemie
I. Brno: Muni, 2009,
Metabolismus lipidů s. 20
Biochemie-8-2-lipidy 1919
Reactions at FA synthase complex
collectively
acetyl transacylase
malonyl transacylase
1CH3C-SCoA
O
1
CysSH CysS -C-CH3
O
+ + CoASH
PanSH +
-OOC-CH2C-SCoA
Pan-S-C-CH2COO-
O
O
2
2
+ CoASH
Biochemie-8-2-lipidy 20
CO2
3-oxoacyl synthase
3-oxoacyl reductase
hydratase
•1
•2
•3
Pan-S-C-CH2COO- + Cys
O
12
Pan-S-C-CH2-C-CH3
OO
2S-C-CH3
O
OOO
Pan-S-C-CH2-
C-CH3
Pan-S-C-CH2-
CH-CH3
OH
+ NADPH+H+ NADP+
2 2
O
Pan-S-C-CH2-CH-CH3
OH
Pan-S-C-CH=CH-CH3
O
+ H2O
22
Biochemie-8-2-lipidy 21
enoylreductase
malonyl transacylase
•4
+ NADPH+H+
NADP+Pan-S-C-CH=CH-CH3
O
Pan-S-C-CH2CH2-CH3
O
22
CysSH CysS-C-CH2CH2CH3
O
Pan-S-C-CH2CH2-CH3
O
+ + PanSH
11 2 2
Biochemie-8-2-lipidy 22
+
1
O
CysS-C-CH2CH2CH3
2
O
Pan-S-C-CH2COO- Pan-S-C-CH2-C-CH2-CH2-CH3
O O
CO2
PanSH + -OOC-CH2C-SCoA Pan-S-C-CH2COOO
O
2
2
+ CoASH
Biochemie-8-2-lipidy 23
Pan-S-palmitoyl Palmitát
Pan-SH
After passing through steps 1-4
sevenfold …
Biochemie-8-2-lipidy 24
Balance of synthesis of palmitate (16 C)
CH3CO-S-CoA + 7 HOOC-CH2CO-S-CoA + 14 NADPH + 14 H+
CH3 -(CH2)14 -COOH + 7 CO2 + 6 H2O + 8 CoASH + 14 NADP+
7 CH3CO-S-CoA + 7 ATP + 7 CO2
Biochemie-8-2-lipidy 25
Product of FA synthase in mammals
16:0 (palmitate) (main)
18:0 (stearate) (minor)
NOVÁK, Jan. Biochemie I. Brno:
Muni, 2009, Metabolismus lipidů s. 22
Biochemie-8-2-lipidy 26
acetyl-CoA-carboxylase (formation of malonyl-CoA)
Activation
acetyl-CoA
insulin
Inhibition
acyl-CoA
glucagon
adrenaline
Regulation of the FA synthesis
Hormonal regulation provided by insulin (increases the synthesis of FA in the cell if enough glucose - a
lot of energy, we can create reserves) and glucagon (reduces the synthesis of FA - the cell has little
glucose, can not synthesize FA, it is necessary to carry out their β-oxidation).
Biochemie-8-2-lipidy 27
NADPH is required for the synthesis of FA
Sources of NADPH
Pentose cycle
malate dehydrogenase
malate  pyruvate + CO2
NADP+ NADPH
Biochemie-8-2-lipidy 28
Summary: synthesis and degradation of fatty
acids is carried out by two separate tracks
I – insulin, G - glucagon
-oxidation synthesis
Localization mitochondria cytoplasm
Acyl transporter CoA ACP
Primary unit C2 C2
Redox cofactors NAD+, FAD NADPH
Enzymes separately complex
Hormonal regulation ratio I/G low ratio I/G high
Biochemie-8-2-lipidy 29
Elongation and desaturation of FA
• On FA synthase complex can be synthesized fatty acids with a maximum
length of 18 C, all of which are saturated FA.
• Our body needs for various processes more than 18 C FA and unsaturated
FA.
• To receive all via food would be very disadvantageous, therefore in our body
are enzymes used for lengthening (elongation) and double bond formation
(desaturation) of FA.
Biochemie-8-2-lipidy 30
Elongation of FA
endoplazmatic reticulum – elongation by malonylCoA,
cofactor NADPH
mitochondria – reverse of -oxidation
Elongation of FA is carried out on –COOH end
Biochemie-8-2-lipidy 31
• Desaturation of fatty acids is a process which leads to the formation of
double bonds. Human (and other animals) are equipped with only a
limited number of enzymes (desaturases) that catalyze these reactions,
namely Δ9, Δ6 and Δ5 desaturases.
• Desaturation process begins by creating a double bond between the
9th and 10th carbon. We expect to desaturate (ie. dehydrogenation)
uses a cofactor FAD and the double bond formed directly, but it is not,
desaturation is somewhat more complicated.
Desaturation
9, 6, 5 desaturases, plants also 12, 15 desaturases
complexes of membrane-bound proteins in the endoplasmic
reticulum of the liver cells
Biochemie-8-2-lipidy 3232
Mechanism of desaturation of fatty acids
O O
1
9
10
S
CoA
O
S
CoA
OH
H
O
H
NADH + H+
H
H2O NAD
+
+ +
S CoA
O
HH
H2O+
Hydroxylation. Oxygen participates
the hydroxylation, but only one atom
gives rise to the the -OH group on
10th carbon. The second oxygen
atom must be reduced to water, which
is assisted by NADH + H+.
Following dehydration,
double bond is
created. The resulting
unsaturated FA has cis
configuration.
Biochemie-8-2-lipidy 33
FAD
FADH2 Fe 2+
Fe 3+NADH+H+
NAD+
Fe 2+
Fe 3+
CH2-CH2-
O2
2H2O
Cyt b5
1. hydroxylation: RCH2CH2R + O2 + AH2  RCH(OH)CH2R + H2O + A
2. dehydration: RCH(OH)CH2R  RCH=CHR + H2O
-CH=CHMechanism
of desaturation of fatty acids
Fatty acids participate in all reactions in the form of acyl-CoA
The double bond is thus formed by hydroxylation and dehydration. Hydroxylation
is performed by oxygen. Its reduction again is somewhat more complicated than
that illustrated in the scheme. The electrons needed for the reduction are
transferred from NADH + H+ to FADH2 and then to the iron atoms.
Biochemie-8-2-lipidy 34
Desaturation of fatty acids
The first step in the desaturation to form a double bond at the ninth
carbon of stearic or palmitic acid. Most organisms have 9 desaturase.
• Animals form a further double bond only in a region between an
existing double bond and the carboxyl terminus (6, 5 desaturase)
• Plants also have 12 and 15 desaturase (found in vegetable oils n-6
and a smaller amount of n-3 unsaturated FA)
• 15 desaturase is located in particular in plants vegetating in cold
water (algae, plankton)
• The high content of n-3 unsaturated fatty acids in fat of fish (fish feed
on plankton, which has the ability to synthesise n-3 fatty acids to a
greater extent)
Biochemie-8-2-lipidy 35
Desaturation of fatty acids
18 : 0 18 : 1 (9) 18 : 2 (9,12) 18 : 3 (9,12,15)
n-3n-9 n-6
all organisms plants
plants, mainly
plankton
linoleic acid linolenic acid
Animals can synthesize more of the FA by combination of
elongation and desaturation. They have, however, only
available 6 and 5 desaturases.
oleic acid
Biochemie-8-2-lipidy 36
18 : 0 18 : 1 (9) 18 : 2 (9,12) 18 : 3 (9,12,15)
n-3n-9 n-6
20:1
22:1
24:1
18:2 (6,9)
20:2
20:3
22:3
22:4
18:3 (6,9,12) 18:4 (6,9,12,15)
20:3 (8,11,14)
20:4(5,8,11,14)
22:4 (7,10,13,16)
22:5 (4,7,10,13,16)
20:4 (8,11,14,17)
20:5(5,8,11,14,17)
22:5 (7,10,13,16,19)
plants plankton
6 desaturase
elongase
5 desaturase
elongase
6 desaturase
elongase
5 desaturase
elongase
Biochemie-8-2-lipidy 37
Polyunsaturated FA n-3 and n-6 are necessary for the
construction of membranes.
Arachidonic acid and eicosapentaenoic acid are
necessary for the synthesis of prostanoids.
Linoleic and linolenic acids are essential for humans.
Their food intake is required.
The sources are vegetable oils and fish oil.
Deficiency of polyunsaturated FA n-3 and n-6 in
experimental animals induces disturbances in
permeability of the skin, weight loss, accumulation of
cholesterol.
Biochemie-8-2-lipidy 38
Triglycerides as energy reserves
Triglycerides are the most effective means of saving
energy
They are stored without ties of water, while a gram of
glycogen binds two grams of water
15 kg of fat is equivalent to 100 kg of hydrated glycogen
compound Combustion heat (kJ/g)
Glycogen
TG
17
38
Biochemie-8-2-lipidy
39
Synthesis of triglycerides
glycerol-3P lysophosphatidate
P
CO
CH2O
CH2OCOR
HSCoA
A P ATP
CHOH
CH2OH
PCH2O
CHOH
CH2OH
CH2OH
RCOSCoA HSCoA
glycerol
RCOSCoA
1. Synthesis of
lysophosphatidate
NAD
+
P
CH2OH
CO
CH2O
CH2O P
CH2OCOR
CHOH
ER - liver, fat cells,
intestinal mucosa
NADH + H+ NADPH + H+
NADP
*
Does not take
place in adipocytes
dihydroxyacetone
phosphate
Biochemie-8-2-lipidy 40
RCOSCoA
CH2O P
CH2OCOR
CHOH
HSCoA
P
CH2OCOR
CHOCOR
CH2O
2. Synthesis of phosphatidate
lysophosphatidate phosphatidate
usually unsaturated
esterification to carbon 2
usually unsaturated
Biochemie-8-2-lipidy 4141
P
CH2OCOR
CHOCOR
CH2O
Pi
R
RCOSCoA HSCoA
CH2OCOR
CHOCOR
CH2OCOR
PC (phosphatidylcholine),
PE
(phosphatidylethanolamine),
PS (Phosphatidylserine
)
PI
(phosphatidylinositol),
cardiolipin
triglyceride
3. Synthesis of triglycerides
Small intestine  CM
Liver  VLDL
adipose tissue  storage
hydrolase
CH2OCO
CHOCOR
CH2OH
ER
phosphatidate
Biochemie-8-2-lipidy 42
Metabolism of phospholipids and
glycolipids
Among the main phospholipids belong :
• phosphatidylcholine – PC
• phosphatidylethanolamine – PE
• phosphatidylserine – PS
• phosphatidylinositol – PI
• cardiolipin – CL
Biochemie-8-2-lipidy 43
Biosynthesis of
glycerophospholipids
• Occurs in all cells except erythrocytes
• Part of cell membranes
• Some initial reactions are the same as in
the synthesis of triglycerides
Biochemie-8-2-lipidy 44
Localization of synthesis of
phospholipids in cell
Synthesis takes place on the phospholipid membranes of
the smooth and rough ER
Enzymes catalyzing the synthesis are integral membrane
proteins with active centers facing the cytoplasm
Newly synthesized phospholipids are built into the outer
layer membranes
By flippases they are transmitted to the inner layer
ER membrane
cytoplasm
flippase
Biochemie-8-2-lipidy 45
In the other membranes PLs are transmitted either by
continuous diffusion between membranes or
membrane vesicles
In the cytoplasm PLs are transmitted using
phospholipid transfer proteins
The synthesis of phospholipids is based either on
phosphatidate or 1,2-diacylglycerol
Biochemie-8-2-lipidy 46
Synthesis of triglycerides and
glycerophospholipids - following a joint reaction
Pi
PI, cardiolipin
P
CH2OCOR
CHOCOR
CH2O
R
RCOSCoA HSCoA
CH2OCOR
CHOCOR
CH2OCOR
PC,PE,PS
triglyceride
hydrolase
CH2OCO
CHOCOR
CH2OH
diglyceridephosphatiate
Biochemie-8-2-lipidy 47
Glycerophospholipids
Phosphatidylcholine – PC
Phosphatidylethanolamine – PE
Phosphatidylserin – PS
Phosphatidylinositol – PI
Cardiolipin - CL http://medcell.med.yale.edu/lect
ures/images/phospholipid.jpg
Biochemie-8-2-lipidy 48
1) Choline + ATP  Choline-P + ADP
Activation of choline takes place in two steps
CH2
N
CH3
CH3
+
CH3
P
O
O
O CH2O-
cholinephosphate
Choline must be activated prior to the synthesis
A) Synthesis of phosphatidylcholine
Biochemie-8-2-lipidy 49
2) choline-P + CTP  CDP-choline + PPi
PO
O(CH3)3N-CH2-CH2-O
P
O-
N
NO
NH2
CH2
OH OH
O
O
OO
+ CDP-choline
Compare with the activation of
glucose in glycogen synthesis
Biochemie-8-2-lipidy 50
3) Synthesis of activated choline of
phosphatidylcholine and 1,2-diacylglycerol
CDP-choline + 1,2-DG  phosphatidylcholine + CMP
CH2-O-CO-R
CH-O-CO-R
O
O-
CH2-O-P-O-CH2-CH2-N(CH3)3
+
Besides that we synthesize
phosphatidylcholine, we accept it in food
and store large part in the intestines
Note the activation of choline by CTP,
in carbohydrate metabolism glucose is
activated by UDP.
Biochemie-8-2-lipidy 51
Functions
A) Phosphatidylcholine
(pulmonary surfactant)
• Pulmonary surfactant generally is a mixture of phospholipids (90%)
and protein (10%), the main phospholipid is
dipalmitoylphosphatidylcholine.
• The task of pulmonary surfactant is to decrease surface tension at
the surface of the alveoli. This makes them easier to open during
aspiration (inhaling) and prevent "sticking" their walls (alveolar
collapse) during expiratory (exhalation). Deprivation of human lung
surfactant means experiencing respiratory distress.
Biochemie-8-2-lipidy 52
pulmonary surfactant
main component is dipalmitoylphosphatidylcholine
reduces the surface tension on the surface of alveoli,
facilitates opening of the alveoli during aspiration
lack of surfactant - respiratory distress
The walls of the alveoli are
covered with water molecules,
during exhalation the walls go
close to each other and bind due
to attractive forces, then the
expansion may prevent reuse
Pulmonary surfactant eliminates
these attractive forces
Biochemie-8-2-lipidy 53
activation of ethanolamine
ethanolamine + ATP  ethanolamine-P + ADP
ethanolamine-P + CTP  CDP-ethanolamine + PPi
B) Synthesis of
phosphatidylethanolamine
Synthesis
CDP-ethanolamine + 1,2-DG 
phosphatidylethanolamine + CMP
Biochemie-8-2-lipidy 54
N-methylation using S-adenosylmethionine
 phosphatidylcholine (in the liver)
C) Conversion of phosphatidylethanolamine
to phosphatidylcholine
- alternative route of synthesis of
phosphatidylcholine
CH2O-CO-R
R-CO-OCH
CH2O-P-O-CH2 -CH2-NH2
O
O-
Biochemie-8-2-lipidy 55
Choline in the diet
No disorder has yet been defined related to lack of choline
Choline deficiency in rats induced disorders structures ER
membranes and fatty liver
Choline is sometimes classified among the group B vitamins
In the US, the recommended daily dose of choline is 500 mg
Foods rich in choline:
liver, meat, nuts, eggs
Biochemie-8-2-lipidy 56
phosphatidylethanolamine + serine  phosphatidylserine +
ethanolamine
D) Biosynthesis of phosphatidylserine
proceeds differently
phosphatydylethanolamine may be
produced by decarboxylation
CH2O-CO-R
R-CO-OCH
CH2OPOCH2CHNH2
O COO
OH
-
Biochemie-8-2-lipidy 57
E) biosynthesis of phosphatidylinositol
1) Activation of phosphatidic acid
phosphatidic acid + CTP  CDP-diacylglycerol + PPi
P
O
N
NO
NH2
CH2
OH OH
O
O
O-O-
CH2-O-CO-R
CH-O-CO-R
CH2-O
O
P O
CDP-diacylglycerol
NOVÁK, Jan. Biochemie I. Brno:
Muni, 2009, Metabolismus lipidů s. 29
Biochemie-8-2-lipidy 58
CH2O-CO-R
R-CO-OCH
OH
O
CH2OPO
OH
OH
OH
OH
OH
2) synthesis
CDP-diacylglycerol + inositol  phosphatidylinositol
Biochemie-8-2-lipidy 59
Synthesis of phosphatidylinositol phosphate
PI + ATP PIP + ADP
PIP + ATP PIP2 + ADP
PIP2 + ATP PIP3 + ADP
CH2O-CO-R
R-CO-OCH
OH
O
CH2OPO
OH
OH
OH
OH
OH
4
5
3
Biochemie-8-2-lipidy 60
CH2O-CO-R
R-CO-OCH
OH
O
CH2OPO
OH
OH
OH
OH
OH
CH2O-CO-R
R-CO-OCH
OH
O
CH2OPO OH
OH
OH
OP
OP
PIP
PIP2
PI
ATP
ADP
ATP
ADP
Synthesis of phosphatidylinositol phosphate
CH2O-CO-R
R-CO-OCH
OH
O
CH2OPO
OH
OH
OH
OH OP
PIP3
Biochemie-8-2-lipidy 61
• binding of certain
mediators in the
cytoplasmic membrane
receptor activates
phospholipase C
• that catalyzes the
cleavage of PIP (PIP2
and PIP3) to DG and IP2
(IP3 and IP4)
• these products act as
second messengers in
the cell
CH2O-CO-R
R-CO-OCH
OH
O
CH2OPO OH
OH
OH
OP
OP
The role of PIPs in the transmission of signals across
the cytoplasmic membrane
Biochemie-8-2-lipidy 62
second messenger
substance that is produced in the cell as a
result of binding of the hormone or the
neurotransmitter to a membrane receptor
•mediates the effect of the hormone or
mediator in cell
• transmits information in a cell on other
intracellular systems
Biochemie-8-2-lipidy 63
In addition to the functions of the second messenger
PI performs the function of phosphatidylinositol anchor
• Phosphatidylinositol anchored in the membrane with bound polysaccharide chain.
On this chain can then be bound proteins that need to communicate with the
environment (e.g. alkaline phosphatase, acetylcholinesterase, antigens ...). That
they are connected to the "PI anchor“ puts them above the surface of the membrane
and thus can perform its functions (they are accessible to other enzymes, hormones)
Biochemie-8-2-lipidy 64
Phosphatidylinositol anchor
glycosylphosphatidylinositol
structure on the cell surface
polysaccharide chain is
connected on
phosphatidylinositol in
membrane
- binding of proteins
(alkaline phosphatase,
acetylcholinesterase,
antigens ...)
Biochemie-8-2-lipidy 65
Biosynthesis of cardiolipinu
CDP-diacylglycerol + glycerol-3-P
phosphatidylglycerol-3-P
Pi
phosphatidylglycerol
CDP-diacylglycerol
cardiolipin + CMP
Biochemie-8-2-lipidy 66
O-
CH2-O-CO-R
CH-O-CO-R
CH2-O
O
P O CH2 CH
OH
CH2OH
phosphatidylglycerol
O-
CH2-O-CO-R
CH-O-CO-R
CH2-O
O
P O CH2 CH CH2
OH O-
O
O
P
CH2-O-CO-R
CH-O-CO-R
CH2O
cardiolipin
CDP-DAG
CMP
Biosynthesis of cardiolipinu (in detail)
Biochemie-8-2-lipidy 67
With the biggest amount of
cardiolipin?
the inner mitochondrial
membrane
Biochemie-8-2-lipidy 68
Replacement of acyl groups at C-2 of phospholipids:
diacylglycerols: on C-2 of oleic acid
phospholipids: on C-2 of polyunsaturated acid
(usually arachidic)
The exchange takes place through transacylation
reactions
Biochemie-8-2-lipidy 69
meaning of glycerophospholipids
• structural component of membranes
• component of lipoproteins
• special features
source of polyunsaturated FA for synthesis and
exchange
"Anchoring proteins in membranes"
Biochemie-8-2-lipidy 70
Modified phospholipids
• plasmalogens
• Platelet activating factor (PAF)
glycerolphosphoether lipids
NOVÁK, Jan. Biochemie I. Brno:
Muni, 2009, Metabolismus lipidů s. 32
Biochemie-8-2-lipidy 71
Plasmalogens
nerve and muscle tissue (myocardium - 50% of
phospholipids)
mitochondrial lipids
choline (heart)
ethanolamine (myelin)
serine
CH2-O
C
CH2-O P
OH
O
O X
HOC
O
R
CH=CH-R
Alkenyl
acyl
Replacing acyl
for alkyl (of
alcohol) and
desaturation
Biochemie-8-2-lipidy 72
PAF (platelet activating factor)
The main mediator of
hypersensitivity, anaphylactic
shock, acute inflammation.
It is produced in leukocytes.
alkyl
acetyl
aggregates platelets, acting as
vasodilator and has a number
of other physiological effects
CH3
CH2-O
C
CH2-O P
OH
O
O
HOC
O
cholin
CH2-R
Acyl exchange
for alkyl
Replacing
acyl for acetyl
Increased solubility
Biochemie-8-2-lipidy
7373
Cleavage of phospholipids - phospholipase
Phospholipases are also
used in remodeling of
phospholipids
A1
A2
several types
D (in plants)
C
PI-system
CH2 O C
O
CH
CH2
O C
OOP
O
O
O...........
A1
cleaves acyl at first carbon
A2 cleaves acyl at second carbon, is used e.g. in remodeling of phospholipids
(e.g. substitution of oleic acid for PUFA) and cleavage of PUFAs, which are then
involved in the metabolism of eicosanoids
C cleaves the bond between the phosphate and glycerol on third carbon; the
phospholipase is used in phosphatidylinositol system (when an "IPs" of „PIPs")
D cleaves phosphoester bond between the phosphate and the other structure
attached to the phosphate (e.g. ethanolamine, choline, ...); phospholipase is
featured only in plants
Biochemie-8-2-lipidy 74
Sphingolipids
- general structure
binding of phosphate
binding of choline
1
2
3
4
HO
NH2
OH
binding of fatty acid
sphingosin Sphinx of Thebes
Meaning: intercellular
communication,
antigenic determinants
Biochemie-8-2-lipidy 75
Sphingomyelin
Biochemie-8-2-lipidy 76
Sphingolipid biosynthesis
• Biosynthesis of sphingosine (sphinganine)
- summarily
16 C 1C3 C 18 C
oxosphinganinepalmitate serine CO2
++
oxosphinganine sphinganine
NADPH+H+
NADP FAD FADH2
sphingosine
Biochemie-8-2-lipidy 77
CH3 (CH2 )14 COS-CoA + CHCH2 OH
COON
H3
+
CH3 (CH2 )1 4 COCHCH2 OH
N H3
+
2CO + CoA-SH
oxosphinganine
Biosynthesis of sphingosine (sphingenine)
1.
Biochemie-8-2-lipidy 78
CH3 (CH2)12 CH2 CH2
+
C CH CH2 OH
O
NH3
CH3 (CH2)12 CH2 CH2
+
CH CH CH2 OH
OH
NH3
CH3 (CH2)12 CH CH CH CH CH2 OH
OH
NH3
+
NADPH + H+
NADP
FAD
FADH2
oxosphinganine
sphinganine
sphingosine
2.
3.
4.
Biochemie-8-2-lipidy 79
1. Connecting of FA activated by amide bond
= ceramide
18
1
2
3
4
HO
NH2
OH
2. Reaction with CDP-choline:
CH2OH binds with
phosphocholine
= sphingomyelin
Biosynthesis of
sphingomyelin
Biochemie-8-2-lipidy 80
N
O
OH
H
O O
OH
OH
OH
HO
ceramid
galaktosa
O-glykosidová vazba
glycosphingolipids
- oligosaccharide component attached by O-glycosidic
linkage to ceramide (via CH2OH of sphingosine)
Galactosylceramide
Cerebrosides: more molecules of monosaccharides attached
via glycosidic linkage
Biochemie-8-2-lipidy 81
N
O
OHO
H
O
OH
HO
O
CH2OH
O
OH
O
OH
CH2OH
O
COO
HN
COCH3
OH
HOCH2 CH
OH
CH
OH
Structure of ganglioside
sialic acid is bound to the oligosaccharide
Occurrence: mainly ganglion
cell membranes
Biochemie-8-2-lipidy 82
Synthesis of cerebrosides:
ceramide + UDP-gal  ceramide-gal + UDP
……… + Binding of other UDP-monosaccharides
Synthesis of sulphatides:
sulfation of cerebrosides using PAPS
Synthesis of gangliosides:
ceramide + UDP-hexose + CMP-NeuAc (CMPN-acetylneuraminic
acid)
Biochemie-8-2-lipidy 83
Degradation of sphingoglycolipids
and sphingosine
• Takes place in lysosomes
• Enzyme catalyzed hydrolytic reactions (galactosidase
enzymes, hexosaminidase, gangliosidneuraminidase,
glucocerebrosidase)
• Each of the enzymes is specific for one monosaccharide
which it eliminates a type of glycoside bond that is cleaved.
• Lack of any of these enzymes leads to the accumulation
of substrates in lysosomes - disease called
sphigolipidosis
• Sphingomyelin cleaved by sphigomyelinase to ceramide
and fatty acid
Biochemie-8-2-lipidy 84
Sphigolipidosis
Lipid accumulation in the tissues due to congenital deficiency of
degradative enzymes
Mainly affected by CNS
Examples:
Tay-Sachs disease: hexoaminidase A deficiency, accumulation of
GM2 ganglioside, mental retardation, blindness,
hepatosplenomegaly, baby dying within 3 years of life
Gaucher disease: reduction in activity beta-glucosidase at 10-
20%, the onset of adulthood, thrombocytopenia, splenomegaly,
psychomotor disturbances, rigidity and half of the cases develop
epilepsy
Biochemie-8-2-lipidy 85
Lipid peroxidation is similar to the radical substitution
of alkanes - we can distinguish three phases called
initiation, propagation and termination.
• At initiation (yellow-colored) molecule is a fatty acid
radical is attacked, most often a hydroxyl radical. The
radical attacks the most sensitive point of the fatty
acid, which is -CH2- between two double bonds (see
chart). Radical torn away from hydrogen, whereby the
fatty acids creates radical, which is referred to as L •.
In the thus formed radical reshuffle will double bonds
(from isolated become conjugated, because we are
talking about the creation of a conjugated diene).
Conjugated diene is highly reactive and reacts with
oxygen molecules to form lipoperoxylového radical
LOO •. Lipoperoxylo radical is extremely reactive and
can react with another molecule of the fatty acid to
form the radical of the L • and of themselves create
hydroperoxide LOOH.
• This (the emergence of radical L •) to begin the
process of propagation (orange-colored).
• In propagation - producing free radicals until:
two different radicals meet
radical and antioxidant meet, which is most
commonly tocopherol
• If one of the above cases, we are talking about
termination.
NOVÁK, Jan. Biochemie I. Brno: Muni,
2009, Metabolismus lipidů s. 38
Biochemie-8-2-lipidy 86
• The primary products of lipid peroxidation are hydroperoxides LOOH.
Greater danger for the organism present the secondary products. They
can attack other biomolecules (not only fatty acids), or are directly toxic
to the organism (the most dangerous are dialdehydes, e.g.
malondialdehyde, 4-hydroxynonenal).
Biochemie-8-2-lipidy 87
Antioxidants
• These are substances which prevent lipid peroxidation. We distinguish
between:
• preventive antioxidants (prevent the formation of free radicals and so do
not even start lipid peroxidation)
• catalase / peroxidases (decompose hydrogen peroxide and prevent its
conversion to hydroxyl radicals)
• superoxide dismutase (scavenges superoxide anion radical)
• transferrin, ferritin, ceruloplasmin (substances which sequester ions of
copper and iron, and do not allow them to enter the Fenton reaction)
• antioxidants stopping promotion (these are substances that have the
ability to react with radicals to form stable products, thereby preventing a
chain reaction and must have a lipophilic character)
• tocopherol (vitamin E)
• carotenoids
• ubiquinol (located on the mitochondrial membrane)
• flavonoids