Biochemistry: Ihrevale LIPID META Bolism 1

BIOCHEMISTRY
COMPLEX LIPID METABOLISM
ihrevale LIPID META 1

BOLISM
BOLISM
BOLISM
Ketone Bodies are synthesized in the Liver
BOLISM
BOLISM
BOLISM
BOLISM
Ketone Body Metabolism
Occurs in mitochondria
of extrahepatic cells
Succinyl-CoA
Acetoacetate
CoA transferase

BOLISM
Ketone Body Metabolism
-oxidation

BOLISM
Lipids—Classification by structure
ALL
ALL LIPIDS
LIPIDS
Hydrophobic-soluble
Hydrophobic-soluble in in organic
organic
solvents
solvents && HH2200 insoluble
insoluble biochemicals
biochemicals
Fatty Lipids
Lipids That
That DoDo NOT
NOT have
have
Fatty Acids
Acids && Lipids
Lipids
containing Esterified
Esterified Fatty
Fatty Acids
Acids
containing esterified
esterified
Fatty
Fatty Acids
Acids
Eicosanoids
Eicosanoids
Fatty
Fatty Acids
Acids && Cholesterol
Cholesterol
Triglycerides Membrane
Membrane Lipids
Lipids Bile
Triglycerides Bile salts
salts
(Polar)
(Polar) Steroids
Steroids
Phospholipids Glycolipids
Glycolipids
Phospholipids
Some
Some
Some
Some
Glycerophospholipids
Glycerophospholipids Sphingolipids
Sphingolipids
ihrevale LIPID META Sphingolipids
Sphingolipids 10
BOLISM
BIOSYNTHESIS OF COMPLEX LIPIDS
1.
1. LIPOPROTEINS-proteins
LIPOPROTEINS-proteins that that bind,
bind, transport
transport and
and
regulate
regulate lipids.
lipids.
2.
2. PLASMALOGENS-phosphoglycerolipids
PLASMALOGENS-phosphoglycerolipids found found in
in
membranes
membranes
3.
3. PLATELET
PLATELET ACTIVATING
ACTIVATING FACTOR
FACTOR aa lipid
lipid mediator
mediator
that
that modulates
modulates cellular
cellular response.
response.

BOLISM
Glycerophospholipid
Glycerophospholipid

BOLISM
Glycerophospholipid
Glycerophospholipid
X=H, Phosphatidic Acid
•Phosphatidic acid is a key precursor in the biosynthesis

of glycerolipids.
•CDP-diglyceride is the activated form of phosphatidic

acid.
•CDP-diglyceride is an intermediate in the biosynthesis

of ihrevale
phosphatidylinositol,
LIPID META phosphatidylglycerol and 13
BOLISM
cardiolipin.
How is CDP-diglyceride formed?

BOLISM
Two General Strategies for the formation of Phosphodiester
Bonds in Glycerophospholipids
Phosphatidylinositol Phosphatidylcholine &

& cardiolipin phosphatidylethanolamine
useihrevale LIPID 1META
Strategy
BOLISM
use strategy 2 15
BOLISM
• Phosphatidylinositol
derivatives play an important
role in metabolic regulation and
signal transduction (when
extracellular substances
influence intracellular
processes). 4
5
• Phosphatidylinositol 4,5-
bisphosphate (PIP2) is a key
metabolite in signal
transduction.
• It is converted into 2 other

second messengers,
diacylglycerol and inositol 1,4,5-
4 1
trisphosphate, through the 5
action of phospholipase C.
BOLISM
Phospholipase C
•Metabolism
In the lipid cycle,
of
• The synthesis
diglyceride is
Phosphatidylinositol
•converted
In the inositol
pathway is
todivided
CDP-
Bisphosphate (PIP2):
phosphate
diglyceride portion
into a lipidincycle of the
two and
cycle,
reactions.
an inositolCDP-
phosphate
• Synthesis of PIP2 is
phosphatidylinositol
diglyceride
cycle. reacts
IP3 phosphatase PIP kinase cyclic.
undergoes
with inositoltwoto form
Diglyceride
Kinase successive
phosphatidylinositol
phosphorylation
and CMP.
reactions with ATP as the
phosphoryl donor to
IP2 phosphatase regenerate PIP2.
PI kinase Cytidyl
transferase
IP phosphatase CDP-diglyceride
Phosphatidylinositol
Inositol PIP synthase

BOLISM
Synthesis of Phosphatidylcholine
and Phosphatidylethanolamine
Phosphatidylcholine &
phosphatidylethanolamine
use strategy 2

BOLISM
When ethanolamine and
choline are the starting
compounds of the
metabolic pathways, the
pathways are called
salvage pathways.

BOLISM
SALVAGE
Exergonic
ethanolamine transphosphorylation
ethanolamine phosphate
CTP-ethanolamine
Isoexergonic
transferase
ethanolamine
CDP-ethanolamine
Exergonic
Phospho-
ethanolami transferase
ne
transferase

BOLISM ethanolamine
When phosphatidyl-choline is made from
phosphatidylethanolamine
OR phosphatidyl-ethanolamine is made from

phosphatidyl-serine
phophatidylserine
decarboxylase
exchange enzyme
the Synthesis pathways are said to

be de novo pathways.
single enzyme

BOLISM
Phosphatidylserine Synthesis
1. Phosphatidylserine is made in an exchange reaction involving
phosphatidylethanolamine.
2. Phosphatidylserine can undergo a decarboxylation reaction to

produce phosphatidylethanolamine. This decarboxylation reaction
is exergonic and unidirectional.
Fig. 12-5
Page 179

BOLISM
END of Glycerophospholipids
Fig. 12-4
Page 179
Metabolism of
ethanolamine, choline
& serine derivatives
Phosphatidylethanolamine can be
converted to phosphatidylcholine (in
liver) by three successive methylation
reactions. The activated methyl donor is
S-adenosylmethionine (AdoMet). AdoMet
is synthesized from methionine and ATP.
The amino group of
phosphatidylethanolamine reacts
successively with three molecules of
AdoMet to form the mono-, di- and tri-
methyl (choline) ethanolamine
derivatives.

BOLISM
Sphingolipids
Sphingolipids
••Sphingolipids
Sphingolipids are
are in
in the
the plasma
plasma membrane
membrane of of virtually
virtually
all
all cells.
cells. They
They are
are abundant
abundant in in brain
brain &
& nerve
nerve tissue.
tissue.

BOLISM
Ceramide is an important
precursor or intermediate in
the formation of the 3 classes
of sphingolipids.
There are three general

classes of sphingolipids:
1. shingomyelin
2. cerebrosides
3. gangliosides
These three classes have

different substituents
attached to the C1-hydroxyl
group of sphingosine.
Sphingomyelin contains
phosphocholine.
Cerebrosides contain a
monosaccharide
gangliosides contain an
oligosaccharide.
BOLISM
Ceramide Synthesis • 4 step synthesis

BOLISM
1
• The 1st step is catalyzed by 3-ketosphinganine

synthase (PLP). This is a unidirectional exergonic
reaction forming 3-ketosphinganine from serine and
palmitoyl-CoA.
BOLISM
2
•In the 2nd step, 3-ketosphinganine reductase

catalyzes the reduction of 3-ketosphinganine to
sphinganine. This rxn is bidirectional
BOLISM
3
•In the 3rd step, a transferase adds a fatty acid to the

amino group of sphinganine to form N-acylshinganine.
BOLISM
•The 4th step, catalyzed by a
dehydrogenase, produces ceramide
from N-acylshinganine.

BOLISM
Cerebrosides are synthesized from ceramide
• Cerebrosides and gangliosides

contain carbohydrate linked to the
terminal alcohol group of ceramide
via a glycosidic bond. The donors
of the carbohydrates are UDP-
sugars. This reaction is exergonic
and unidirectional.
BOLISM
Sphingomyelin is synthesized from ceramide
•Choline from
phosphatidylcholine
is transferred to the
C1-hydroyl group of
ceramide.
•Conversion of
ceramide to
sphingomyelin is
isoergonic.

BOLISM
Sulfate esters occur in
some sphingolipids
•The sulfate esters are transferred to

the cerebroside saccharides from a
sulfur donor called: 3’-
phosphoadenosine-5’-phosphosulfate
(PAPS).
• PAPS has an extraordinarily high

energy bond between the sulfate and
phosphate groups.

BOLISM
Galactocerebroside
Galactocerebroside 3-sulfate
3-sulfate Synthesis
Synthesis from
from Galactocerebroside
Galactocerebroside

BOLISM
Cerebroside &
Ganglioside
Synthesis Summary
Cerebrosides
contain 1
saccharide.
Gangliosides
contain more than
one saccharide (2+).

BOLISM
Page 188
Fig. 12-16
Genetic defects inlysosomal enzymes

degrading gangliosides lead to lipid storage
disease

BOLISM
CHOLESTEROL
CHOLESTEROL SYNTHESIS
SYNTHESIS
••Cholesterol
Cholesterol hashas aa crucial
crucial role
role in
in
the
the structure
structure of of many
many membranes
membranes
and
and as
as aa precursor
precursor of of steroid
steroid
hormones
hormones and and bile
bile acids.
acids.
••Cholesterol
Cholesterol is is made
made from
from acetyl-
acetyl-
CoA.
CoA. The
The first
first step
step isis the
the
condensation
condensation of of 33 acetate
acetate units
units toto
form
form mevalonate.
mevalonate.
••The
The synthesis
synthesis of of mevalonate
mevalonate is is
catalyzed
catalyzed byby 33 enzymes:
enzymes:
1.
1. Thiolase
Thiolase
2.
2. HMG-CoA
HMG-CoA synthase
synthase
3.
3. HMG-CoA
HMG-CoA reductase
reductase
The rate-limiting reaction in cholesterol
biosynthesis
ihrevale LIPID is catalyzed by HMG-CoA
META 38
reductase
BOLISM
•• Mevalonate
Mevalonate undergoes
undergoes 33
successive
successive phosphorylation
phosphorylation
reactions
reactions involving
involving ATP.
ATP.
•• The
The products
products include
include 5-
5-
phosphomevalonate
phosphomevalonate thenthen 5-
5-
pyrophosphomevalonate,
pyrophosphomevalonate,
then
then 3-phospho-5-
3-phospho-5-
pyrophosphomevalonate
pyrophosphomevalonate and and
33 ADP
ADP molecules.
molecules.
•• Subsequent
Subsequent
decarboxylation
decarboxylation andand yields
yields
isopentenyl
isopentenyl pyrophosphate
pyrophosphate
and
and further
further isomerization,
isomerization,
dimethlyallyl
dimethlyallyl pyrophosphate.
pyrophosphate.
BOLISM
Condensation
Condensation of
of 22 dimethylallyl
dimethylallyl pyrophosphate
pyrophosphate
molecules
molecules (isoprenoid
(isoprenoid units)
units) yields
yields geranyl
geranyl
pyrophosphate
pyrophosphate which
which condenses
condenses withwith isopentenyl
isopentenyl
pyrophosphate
pyrophosphate to
to yield
yield farnesyl
farnesyl pyrophosphate.
pyrophosphate.

BOLISM
Geranyl
Geranyl pyrophosphate
pyrophosphate condenses
condenses withwith
isopentenyl
isopentenyl pyrophosphate
pyrophosphate to
to yield
yield farnesyl
farnesyl
pyrophosphate.
pyrophosphate.

BOLISM
Two
Two molecules
molecules of
of fanesyl
fanesyl pyrophosphate
pyrophosphate condense
condense to
to
form
form squalene.
squalene.

BOLISM
Squalene
Squalene reacts
reacts with
with
molecular
molecular oxygen
oxygen andand
undergoes
undergoes an an epoxidation
epoxidation
and
and ring
ring closures
closures to to form
form
lanosterol.
lanosterol. Lanosterol
Lanosterol is is
converted
converted to to cholesterol
cholesterol by by
removal
removal of of three
three methyl
methyl
groups,
groups, reduction
reduction of of aa double
double
bond
bond andand isomerization.
isomerization.
Three
Three molecules
molecules of of ATP
ATP are are
required
required toto make
make each
each
isoprenoid
isoprenoid unit.
unit. Six
Six
isoprenoid
isoprenoid units
units are
are used
used to to
synthesize
synthesize cholesterol,
cholesterol, so so 66 xx
33 == 18
18 ATP/cholesterol
ATP/cholesterol
molecule.
molecule.
BOLISM
Inhibitors of HMG-CoA reductase
Familial Hypercholesterolemia
(Zocor)

BOLISM
Conversion of Cholesterol to Neutral Sterols and Bile Salts
Cholesteryl esters are formed in the

liver through the action of acyl-CoA-
cholesterol acyl transferase. This
enzyme catalyzes the transfer of a fatty
acid from coenzyme A to the hydroxyl
group of cholesterol. Cholesteryl ester
is more hydrophobic than cholesterol &
is transported in lipoprotein particles
to other tissues that use cholesterol or
stored in the liver.

Bile, ihrevale
cholesterol
LIPID & cholesteryl ester
META 45
emulsify dietary fat
BOLISM
Bile Synthesis in Liver
Hydroxylation,
Acyltransfer
& hydrolysis.
Note that the
reactions are
irreversible.

BOLISM
BOLISM
••Lipoprotein
Lipoprotein particles
particles form
form 55 major
major classes
classes defined
defined by
by particle
particle
Lipoprotein
Lipoprotein
••Because
Because particles
particles
lipid
lipid
density: is
is not
not perform
perform
soluble
soluble
chylomicrons,
three
three
in
HDL,in major
major
aqueous
aqueous
LDL, IDL,
functions:
functions:
solution,
solution,
VLDL
density: chylomicrons, HDL, LDL, IDL, VLDL
itit must be transported through the bloodstream &
1. Transport dietary fat from the intestinal mucosa to other &
1. must be
Transport transported
dietary fat from through
the the
intestinal bloodstream
mucosa to other
an
an elaborate
elaborate
tissues
tissues (exogenousprotein
(exogenousproteinlipidtransport
lipid transport) system
transport
transport) system has has evolved
evolved
to
to complete
complete this
this important
important function.
function.
2.
2. Transfer
Transfer triglyceride
triglyceride and
and cholesterol
cholesterol from
from liver
liver to
to other
other
tissues
tissues (endogenous
(endogenous lipidlipid transport)
transport)
3.
3. Transfer
Transfer cholesterol
cholesterol from
from extrahepatic
extrahepatic tissues
tissues to
to the
the liver
liver
(reverse
(reverse cholesterol
cholesterol transport).
transport).

BOLISM
Structure
Structure of
of LDL
LDL

BOLISM
VARIABLE
Structural
Structural
Chylomicron formation
Structural
Inhibits VLDL uptake by liver

Structural

BOLISM Recognition by
LDL & chylomicron remnant
•Main function is to transport dietary fat
(mostly triglyceride, some cholesterol
and cholesteryl ester).
•The triglyceride is hydrolyzed by

lipoprotein lipase and fatty acids enter
cells.
•Glycerol liberated in the extracellular

space is metabolized in cells that
contain glycerol kinase (liver & kidney).
•As triglyceride is hydrolyzed, chylomicrons grow smaller, becoming

remnants that contain cholesterol, cholesteryl ester, apo-B-48 and apo-E.
•The remnants are removed from blood by the liver in an apoE-receptor

driven process.
•In the liver the remnants are digested to yield cholesterol and fatty
acids.
BOLISM
•The major function of VLDL is to
transport large amounts of triglyceride
and small amounts of cholesterol from
the liver to other tissues.
•When the diet contains more fatty

acids than are needed immediately as
fuel, they are sometimes converted
into triacylglycerols in the liver and
packaged into VLDL particles.
•Excess dietary carbohydrate can also be converted into triacylglycerols

in the liver and exported as VLDLs.
•VLDLs contains some cholesterol, cholesteryl esters, apoB-100, apoC-I,

apoC-II, ApoC-III, and apo-E.
•They are transported from the liver to muscle and adipose tissue where
lipoprotein lipase causes the release of free fatty acids from triglycerols.
•Most VLDL remnants are removed from blood by hepatocytes in an

apoE-receptor driven process.
BOLISM
IDL & LDL--The major function of IDL & LDL
is to transport large amounts of triglyceride
and small amounts of cholesterol from the
liver to other tissues.
•The loss of triglycerides from VLDL

particles converts the particles into
remnants of intermediate density called IDL.
•The amount of triglyceride and cholesterol

in IDL is intermediate between VLDL & LDL.
•Removal of triglyceride converts the IDL particles to LDL.
•~1/2 of LDL is taken up by the liver and the remainder by extrahepatic tissues.
•LDL contains most of the cholesterol in the plasma after an overnight fast and
75% is in the form of cholesteryl ester.
•LDL particles typically lack apoE.
•LDL particles are

ihrevale LIPID taken up by apoB-100 receptors or by apoE receptors.
META 53
BOLISM
HDL is a reverse cholesterol transport
lipoprotein. It takes up cholesterol and
transfers it to hepatocytes.
HDL is synthesized in the liver and

small intestine as protein-rich particles
that initially contain relatively little
cholesterol and no cholesteryl esters.
HDLs contain apoA-1, apoC-1, apoC-II,

LCAT, and more.
LCAT on the surface of HDL particles converts cholesterol and

phosphatidyl choline of chylomicron and VLDL remnants to cholesteryl
esters which are taken up by the HDL particle.
The cholesterol esters are hydrophobic & migrate to the core of the HDL
particle where they are taken up by the liver & the cholesterol is
unloaded.

BOLISM
Lipid Enzymes Learn

BOLISM
Lipoprotein
Lipoprotein lipase
lipase (capillaries)
(capillaries) & & Hepatic
Hepatic lipase
lipase (liver
(liver
sinusoids):
sinusoids): catalyze
catalyze the
the hydrolysis
hydrolysis of
of triglyceride
triglyceride from
from
lipoprotein
lipoprotein particles.
particles. This
This enzyme
enzyme is is on
on the
the surface
surface of
of the
the
capillary
capillary lumen.
lumen. ItIt generates
generates fatty
fatty acids
acids and
and glycerol.
glycerol.

BOLISM
Lipid Enzymes
LCAT
LCAT catalyzes
catalyzes the the transfer
transfer of
of the
the C-2
C-2 fatty
fatty acyl
acyl group
group of
of
phophatidylcholine
phophatidylcholine (lecithin
(lecithin is
is aa common
common name
name for
for
phophatidylcholine)
phophatidylcholine) to to cholesterol
cholesterol toto produce
produce cholesteryl
cholesteryl ester
ester and
and
lysolecithin.
ihrevale LIPIDThis
lysolecithin. META reaction
This reaction converts
converts cholesterol
cholesterol from
from aa polar
polar 57
BOLISM
molecule
molecule to to aa non-polar,
non-polar, very
very hydrophobic
hydrophobic ester.
ester.
LDL
LDL Receptor-Mediated
Receptor-Mediated Endocytosis
Endocytosis
1.
1. Binding
Binding
2.
2. Coated
Coated pitpit && vessicle
vessicle form
form 1
3.
3. Endocytosis
Endocytosis
4.
4. Vesicle
Vesicle fuses
fuses to to become
become
endosome.
endosome.
5.
5. Endosome
Endosome fuses fuses with
with
lysosome. 2
lysosome.
6.
6. Fatty
Fatty acids
acids andand cholesterol
cholesterol 7 3
are
are released
released into
into thethe
cytoplasm.
cytoplasm.
7.
7. The
The receptor
receptor protein
protein isis
recycled
recycled (endosome)
(endosome) or or 4
degraded
degraded (lysosome).
(lysosome).
8.
8. Intracellular
Intracellular cholesterol
cholesterol
causes
causes lower
lower levels
levels of
of LDL
LDL 5
receptor
receptor and and reduced
reduced
synthesis
synthesis of of HMG-CoA
HMG-CoA 6
reductase.
reductase. TheseThese leadlead to
to
reduced 8
reduced uptake
uptake and and synthesis
synthesis
of
of cholesterol.
cholesterol.
BOLISM
BOLISM
BOLISM
This is a normal coronary artery
with no atherosclerosis and a
widely patent lumen that can
carry as much blood as the
myocardium requires.
Here is occlusive coronary

atherosclerosis. The coronary
at the left is narrowed by 60 to
70%. The coronary at the right
is even worse with evidence
for previous thrombosis with
organization of the thrombus
and recanalization such that
there are three small lumens
ihrevale LIPID META remaining. 61
BOLISM
Steroid Biosynthesis
All steroid hormones are
synthesized from pregnenolone.
Pregnenolone is subsequently
converted to progesterone and
then cortisol, corticosterone &
testosterone. A second synthesis
pathway can make testosterone
without a progesterone
intermediate.

BOLISM
Pregnenolone Synthesis
The
The conversion
conversion of
of cholesterol
cholesterol toto
pregnenolone
pregnenolone is
is rate-limiting
rate-limiting in
in steroid
steroid
hormone
hormone biosynthesis.
biosynthesis.
Hydroxylation
Hydroxylation reactions
reactions play
play aa very
very
important
important role
role in
in the
the synthesis
synthesis of of
cholesterol
cholesterol from
from squalene
squalene and and in in the
the similar to fatty acid
conversion
conversion of of cholesterol
cholesterol intointo steroid
steroid desaturation
hormones
hormones and and bile
bile salts.
salts. All
All these
these
hydroxylations
hydroxylations require
require NADPH
NADPH and and O O22..
One
One oxygen
oxygen atom
atom from
from O O22 goes
goes to to the
the
substrate
substrate and
and the
the second
second is is reduced
reduced to to
HH220.
0. The
The enzymes
enzymes catalyzing
catalyzing these
these
reactions
reactions are
are monoxygenases.
monoxygenases. All All
hydroxylation
hydroxylation reactions
reactions during
during steroid
steroid
biosynthesis
biosynthesis areare catalyzed
catalyzed byby mixed-
mixed-
function
function oxidases
oxidases thatthat use
use NADPH,
NADPH, O O22,,
and
and mitochondrial
mitochondrial cytochrome
cytochrome P-450.P-450.
The
The second
ihrevale enzyme
second enzyme
LIPID step
METAstep is
is catalyzed
catalyzed by
by 63
aa different
BOLISM
different enzyme,
enzyme, desmolase.
desmolase.
Pregnenolone
Estradiol: 18 carbon atoms
and aromatic A ring.
Testosterone: 19 carbon
atoms
Progesterone, aldosterone,
and cortisol contain 21 carbon
atoms. Aldosterone contains
an aldehyde group on C18.
Glucocoricoids contain a
hydroxyl group on C11.

Synthesis of progesterone,
aldosterone and cortisol:
Progesterone- 2 steps: 1. a
3-alcohol dehydrogenase
catalyzed the NAD+-dependent
oxidation of alcohol to a
ketone& 2. double bond
migration (Fig. 12-31).
Aldosterone- 4 steps:
catalyzed by ER enzyme 21-
hydoxylase and mitochondrial
enzymes: 11-hydroxylase,
18-hydroxylase, and 18-
hydroxysteroid oxidase. All 4
reactions require NADPH, O 2,
and cytochrome P-450.
Cortisol- 3 steps: Catalyzed
by 17- and 21-hydoxylases
and a mitochondrial 11-
hydroxylase. All 3 reactions
require NADPH, O2, LIPID
ihrevale and META 64
cytochrome P-450.
BOLISM
Eicosanoid Synthesis
The Cyclooxygenase Pathway
The first step in the synthesis of 1
9 5 3
prostaglandins is the generation of 7
arachidonate from phospholipids. This is
13
catalyzed by phopholipase A2 and is the rate- 11 15 17 19
limiting reaction in the pathway of eicosanoid
biosynthesis. This hydrolysis is unidirectional
and exergonic.
9 7 1
3
Prostaglandin biosynthesis: In a reaction 5
catalyzed by cyclooxygenase, arachidonate

reacts with 2 molecules of oxygen to form 11
13 15 17 19
PGH2. PGH2 is a precursor that can be used
to synthesize the other protaglandins,
protacyclins, and thromboxanes.
NSAIDS inhibit synthesis of

prostaglandins, protacyclins, &
thromboxanes by inhibiting the enzyme,
cyclooxygenase. Cyclooxygenase is
bound to the membranes of the
endoplasmic reticulum.
BOLISM
NSAIDS inhibit
synthesis of
prostaglandins,
protacyclins, &
thromboxanes by
inhibiting the
enzyme,
cyclooxygenase.

BOLISM
The Linear Lipoxygenase Pathway
Synthesis of leukotrienes--
• Lipoxygenases catalyze the
insertion of oxygen in the 5, 12,
or 15 position of the various
eicosanoids.
•The products are

hydroperoxyeicosatetraenoates
or HPETEs. 5-HPETE is the
precursor of leukotrienes.
•Dehydration of 5-HPETE yields

leukotriene C4.
•Leukotriene C4 undergoes
hydrolysis to form D4.
•The hydrolysis reactions are

exergonic
BOLISMand unidirectional.
Plasmalogens are
phosphoglycerolipids
that contain an ether
bond at sn-1 and
phosphoethanolamine
or phosphocholine at
sn-3. Plasmalogens are
in the membranes of
brain, heart,
erythrocytes, and other
tissues. Plasmalogens
make up about 20% of
the phospholipid in
human nervous tissue.

BOLISM
Plasmalogen Biosynthesis
The pathway for

biosynthesis begins
with the exergonic
acylation of
dihydroxyacetone
phosphate to form 1-
1
acyl-dihydroxy-acetone
3-phosphate.
In the 2nd step, a

saturated fatty alcohol 2
replaces the acyl group
to form 1-
alkyldihydroxyacetone
3-phosphate. This is
catalyzed by a
synthase.
BOLISM
In the 3rd step, sn2 is
reduced by NADPH
to form an alcohol
from a ketone. This
reaction is catalyzed
by a reductase. 3
In the 4th step, a fatty

acid is added to the 4
hydroxyl group at
sn2 by FA acyl-CoA

BOLISM
In the 5th step, an
ethanolamine is
attached by ester 5
bond to the
phosphoryl group on
sn-3. (text is
different)
In the 6th step, the C- 6

C bond adjacent to
the ether is oxidized
by a mixed-function
oxidase to yield
plasmalogen.

BOLISM
Platelet Activating Factor (PAF)
PAF is an ether-containing
phospholipid that causes
platelet degranulation. It also
acts on muscle, liver, kidney
and brain. PAF is released
during inflammatory and allergic
responses.
PAF is unusual in that it has an

acetyl ester at sn-2 rather than a
FA. It is synthesized from a
plasmalogen intermediate, 1-
alkyl-2-acylglycerol-3-
phosphocholine.
Phospholipase A2 catalyzes
the hydrolysis of this
compound to form 1-alkyl-2-
acylglycerol-3-
phosphocholine.
Subsequent acylation forms
PAF. BOLISM
O
Example derivatives H3C

OH O
of cholesterol CH3
CH3
H H
HO OH Cholic acid
O CH3
C OH
CH3 CH3
CH3
H H H H
O HO
Progesterone Estradiol
BOLISM
More cholesterol derivatives
OH Testosterone
CH3
CH3
H H
Aldosterone CH2OH Cortisol CH2OH
C O
O
O CH3
HO OH
HO
CH3 CH3
H H
H H
O
O
BOLISM
And even more
7-dehydrocholesterol
H3C CH3
CH3
CH3
CH3 H3C CH3
h* CH3 OH
CH3
HO
cholecalciferol
(vitamin D3)
CH2
1,25-Dihydroxy-
2 successive hydroxylations
HO OH cholecalciferol
BOLISM
Overview of
cholesterol synthesis
Acetyl-CoA
(1)
HMG-CoA-
reductase
Ketone bodies HMG-CoA Mevalonate (C6)
3 ATP
3 ADP CO2
Activated C15 Activated C10 Activated C5
Squalene (linear C )
Lanosterol (C30) Cholesterol
76
BOLISM
Overview of cholesterol synthesis
(2) 3-P-5-PP-
mevalonate
O CH3
Acetyl-CoA O C C C C O P P
H2 H2 H2
O
P
Acetoacetyl-CoA
3 ADP
3 ATP
O CH3 O O CH3
CoA S C C C C O CoA-SH O C C C C OH
H2 H2 H2 H2 H2
OH OH
HMG-CoA
Mevalonate
2 NADPH+H+ 2 NADP+
ihrevale LIPID META HMG-CoA-reductase 77
BOLISM
(3)
3-Phospho-5-pyrophospho-mevalonate
O CH3
O C C C C O P P
H2 H2 H2
Geranyl-PP O
P
CH3 CH3
H3C C C C C C O P P
H H2 H2 H H2 CO2 P
CH3
H2C C C O P P
H2 H2
P-P
CH3 Isopentenyl-PP
H3C C C O P P
H H2
ihrevale LIPID META Dimethylallyl-PP 78

BOLISM
CH3 CH3 CH3
H3C C C C C C O P P H2C C C O P P
H H2 H2 H H2 H2 H2
Overview of cholesterol
synthesis (4)
P P
CH3 CH3 CH3
H3C C C C C C C C C O P P
H H2 H2 H H2 H2 H H2
NADPH P P O C
H2
C
H
C
H2
C
H2
C
H
C
H2
C
H2
C
H
CH3
CH3 CH3 CH3
NADP+
+
2 P P
CH3 CH3 CH3

H2 H2 H2 H H2 H H2 H
C C C C C C C C CH3
H3C C C C C C C C C
H H2 H H2 H H2 H2 H2
CH3 CH3 CH3
BOLISM
(5)
CH3 CH3 CH3
H2 H2 H2 H H2 H H2 H
C C C C C C C C CH3
H3C C C C C C C C C
H H2 H H2 H H2 H2 H2
CH3 CH3 CH3

BOLISM
(6)
NADPH+H+
NADP+
O
O2 H2 O H
+
+
C
HO
HO

BOLISM
The ‘smooth’ endoplasmic reticulum is the
site of sterol metabolism

BOLISM
Cholesterol Transport
1. Synthesis occurs mostly in the liver

(cytosol / ER)
2. Transport to peripheral organs in
lipoproteins (LDL)
• free cholesterol
• cholesterol ester
3. Cellular uptake in peripheral organs by receptor
mediated endocytosis (LDL receptor)
4. Transport of excess cholesterol from periphery to
liver by HDL
5. Elimination of excess cholesterol occurs in the bile
BOLISM
Lecithin:cholestero CH3
CH3
H3 C
l acyltransferase
+
H3C N CH3
CH3
(LCAT)
CH3
O H CH3
H H
O O O
O O O
LCAT

BOLISM
Regulation of cholesterol biosynthesis (1)
1. At the enzyme level: major regulatory target is HMG-CoA

reductase, which catalyzes the committed step and is
inhibited by cholesterol
2. At the genetic level: transcription of HMG-CoA-reductase
is activated by transcription factors binding to SRE (sterol
regulatory elements)
• low cholesterol causes SCAP to bind SREBP
• SCAP drags SREBP along from the ER to the Golgi
• In the Golgi, S1P awaits SREBP and cleaves it. After
an additional cleavage (S2P),
• SREBP is released from the Golgi membrane and
translocates to the nucleus
• SREBP binds SRE and switches on transcription
BOLISM
Transcriptional regulation of cholesterol
biosynthesis (1)
SREBP
(sterol regulatory element binding protein)
ER membrane
Exposed loop SCAP

(proteolytic cleavage site) (SREBP cleavage activating protein)

BOLISM
biosynthesis (2)
S1P
High cholesterol Golgi
ER ER
Low cholesterol:
Golgi
SCAP binds SREBP
S1P (and S2P) cleave SREBP

ER
BOLISM
biosynthesis (2)
membrane of nucleus
SRE
HMG-CoA reductase mRNA

RNA polymerase
BOLISM
Medical aspects of cholesterol metabolism (1)
Main risk: Atherosclerosis
• Deposition of LDL in
vessel wall
• Release of cholesterol
• Inflammatory and
degenerative reaction
Risk factors:
1. High blood pressure – provides initial ‘micro’-
damage to endothelium
2. High LDL – yields cholesterol deposits
BOLISM
Medical aspects of cholesterol metabolism (2)
Causes of Hypercholesterinemia:
1. Diet (not as important as you would think)
2. Genetic factors – e.g., LDL receptor defect
• homozygous: life expectancy ~30-40 yr, next to
intractable
• heterozygous: still serious, but tractable to some extent
Other, multigenic constellations do occur
(various degrees of severity)
Therapeutic approaches:
1. Limiting intake (diet)
2. Suppressing synthesis (HMG-CoA reductase
inhibitors)
3. Promotion of excretion (Cholestyramine)
BOLISM
Lovastatin – a competitive antagonist
of HMG-CoA reductase
HO HO
COOH COOH
OH OH
O
Lovastatin Mevalonate
BOLISM
O
Cholestyramine disrupts the OH

H3C
O
‘enterohepatic cycle’
CH3
CH3
of bile acids H H
HO OH
+
+ + -+
+
+
-+ + -+
+

BOLISM

Biochemistry: Ihrevale LIPID META Bolism 1

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Biochemistry: Ihrevale LIPID META Bolism 1

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BIOCHEMISTRY

COMPLEX LIPID METABOLISM

ihrevale LIPID META 1

ihrevale LIPID META 8

ihrevale LIPID META 9

ihrevale LIPID META 11

ihrevale LIPID META 12

X=H, Phosphatidic Acid

•Phosphatidic acid is a key precursor in the biosynthesis

•CDP-diglyceride is the activated form of phosphatidic

•CDP-diglyceride is an intermediate in the biosynthesis

ihrevale LIPID META 14

Phosphatidylinositol Phosphatidylcholine &

• It is converted into 2 other

Inositol PIP synthase

ihrevale LIPID META 19

ihrevale LIPID META 20

ihrevale LIPID META 21

OR phosphatidyl-ethanolamine is made from

the Synthesis pathways are said to

ihrevale LIPID META 22

2. Phosphatidylserine can undergo a decarboxylation reaction to

ihrevale LIPID META 23

ihrevale LIPID META 24

ihrevale LIPID META 25

There are three general

These three classes have

ihrevale LIPID META 27

• The 1st step is catalyzed by 3-ketosphinganine

•In the 2nd step, 3-ketosphinganine reductase

•In the 3rd step, a transferase adds a fatty acid to the

ihrevale LIPID META 31

• Cerebrosides and gangliosides

ihrevale LIPID META 33

•The sulfate esters are transferred to

• PAPS has an extraordinarily high

ihrevale LIPID META 34

ihrevale LIPID META 35

ihrevale LIPID META 36

Genetic defects inlysosomal enzymes

ihrevale LIPID META 37

ihrevale LIPID META 40

ihrevale LIPID META 41

ihrevale LIPID META 42

ihrevale LIPID META 44

Cholesteryl esters are formed in the

ihrevale LIPID META 46

ihrevale LIPID META 48

ihrevale LIPID META 49

Inhibits VLDL uptake by liver

ihrevale LIPID META 50

•The triglyceride is hydrolyzed by

•Glycerol liberated in the extracellular

•As triglyceride is hydrolyzed, chylomicrons grow smaller, becoming

•The remnants are removed from blood by the liver in an apoE-receptor

•When the diet contains more fatty

•Excess dietary carbohydrate can also be converted into triacylglycerols

•VLDLs contains some cholesterol, cholesteryl esters, apoB-100, apoC-I,

•Most VLDL remnants are removed from blood by hepatocytes in an

•The loss of triglycerides from VLDL

•The amount of triglyceride and cholesterol

•Removal of triglyceride converts the IDL particles to LDL.

•LDL particles typically lack apoE.