Transcript Fatty Acid Synthesis

Chapter 24
Lipid Biosynthesis
Biochemistry
by
Reginald Garrett and Charles Grisham
Outline
1. How Are Fatty Acids Synthesized?
2. How Are Complex Lipids Synthesized?
3. How Are Eicosanoids Synthesized, and What
Are Their Functions?
4. How Is Cholesterol Synthesized?
5. How Are Lipids Transported Throughout the
Body?
6. How Are Bile Acids Biosynthesized?
7. How Are Steroid Hormones Synthesized and
Utilized?
24.1 – How Are Fatty Acids
Synthesized?
The Biosynthesis and Degradation Pathways
are Different
• As in cases of glycolysis/gluconeogenesis
and glycogen synthesis/breakdown, fatty
acid synthesis and degradation go by
different routes
• There are five major differences between
fatty acid breakdown and biosynthesis
The Differences Between fatty acid biosynthesis
1.
2.
3.
4.
5.
and breakdown
Intermediates in synthesis are linked to
-SH groups of acyl carrier proteins (as
compared to -SH groups of CoA)
Synthesis in cytosol;
breakdown in mitochondria
Enzymes of synthesis are one polypeptide
(fatty acid synthase) in animals
Biosynthesis uses NADPH/NADP+;
breakdown uses NADH/NAD+ & FAD
Stereochemistry (D-b-hydroxyacyl)
Activation by Malonyl-CoA
•
•
•
•
•
Acetate Units are Activated for Transfer in Fatty
Acid Synthesis by Malonyl-CoA
Fatty acids are built from 2-C units -- acetyl-CoA
Acetate units are activated for transfer by
conversion to malonyl-CoA
Decarboxylation of malonyl-CoA and reducing
power of NADPH drive chain growth
Chain grows to 16-carbons (palmitate)
Other enzymes add double bonds and more Cs
The sources of Acetyl-CoA
• Amino acid degradation produces cytosolic
acetyl-CoA
• Fatty acid oxidation produces mitochondrial
acetyl-CoA
• Glycolysis yields cytosolic pyruvate which is
converted to acetyl-CoA in mitochondria
• Citrate-malate-pyruvate shuttle provides
cytosolic acetate units and reducing
equivalents for fatty acid synthesis
The reducing power: NAPDH
• Produced by malic enzyme
• Produced in pentose phosphate pathway
(chapter 22)
The "ACC enzyme" commits acetate
to fatty acid synthesis
Acetyl-CoA Carboxylase
• Carboxylation of acetyl-CoA to form malonylCoA is the irreversible, committed step in fatty
acid biosynthesis
• ACC uses bicarbonate and ATP (& biotin)
– E.coli enzyme has three subunits
– Animal enzyme is one polypeptide with all three
functions - biotin carboxyl carrier, biotin
carboxylase and transcarboxylase
Figure 24.2
(a) The acetyl-CoA
carboxylase reaction
produces malonyl-CoA for
fatty acid synthesis. (b) A
mechanism for the acetylCoA carboxylase reaction.
Bicarbonate is activated for
carboxylation reactions by
formation of Ncarboxybiotin. ATP drives
the reaction forward, with
transient formation of a
carbonylphosphate
intermediate (Step 1). In a
typical biotin-dependent
reaction, nucleophilic
attack by the acetyl-CoA
carbanion on the carboxyl
carbon of N-carboxybiotin a transcarboxylation yields the carboxylated
product (Step 2).
Malonyl-CoA
Figure 24.3
In the acetyl-CoA carboxylase reaction, the biotin ring, on its flexible tether, acquires
carboxyl groups from carbonylphosphate on the carboxylase subunit and transfers them to
acyl-CoA molecules on the transcarboxylase subunits.
Acetyl-CoA Carboxylase
ACC forms long, active filamentous polymers
from inactive protomers
• As a committed step, ACC is carefully
regulated
• Palmitoyl-CoA (product) favors monomers
• Citrate favors the active polymeric form
Citrate
Inactive protomers
active polymer
Acyl-CoA
Figure 24.4
Models of the acetyl-CoA
carboxylase polypeptide, with
phosphorylation sites
indicated, along with the
protein kinases responsible.
Phosphorylation at Ser1200 is
primarily responsible for
decreasing the affinity for
citrate.
Phosphorylation of ACC modulates
activation by citrate and inhibition by
palmitoyl-CoA
• Unphosphorylated E has high affinity for
citrate and is active at low [citrate]
• Unphosphorylated E has low affinity for palmCoA and needs high [palm-CoA] to inhibit
• Phosphorylated E has low affinity for citrate
and needs high [citrate] to activate
• Phosphorylated E has high affinity for palmCoA and is inhibited at low [palm-CoA]
Figure 24.5
The activity of acetylCoA carboxylase is
modulated by
phosphorylation and
dephosphorylation.
The dephospho form
of the enzyme is
activated by low
[citrate] and inhibited
only by high levels of
fatty acyl-CoA. In
contrast, the
phosphorylated form
of the enzyme is
activated only by
high levels of citrate,
but is very sensitive
to inhibition by fatty
acyl-CoA.
The acyl carrier protein carry the
intermediates in fatty acid synthesis
• ACP is a 77 residue protein in E. coli - with
a phosphopantetheine
• The same functional group of CoA
Fatty Acid Synthesis
•
•
•
•
•
•
•
Acetyl-CoA-ACP transacylases (ATase)
Malonyl-CoA-ACP transacylases (MTase)
b-ketoacyl-ACP synthase (KSase)
b-ketoacyl-ACP reductase (KRase)
b-hydroxyacyl-ACP dehydratase (DH)
Enoyl-ACP reductase (ERase)
Thioesterase (TEase) in animals
Figure 24.7
The pathway of palmitate
synthesis from acetyl-CoA
and malonyl-CoA. Acetyl
and malonyl building blocks
are introduced as acyl
carrier protein conjugates.
Decarboxylation drives the
b-ketoacyl-ACP synthase
and results in the addition
of two-carbon units to the
growing chain.
Concentrations of free fatty
acids are extremely low in
most cells, and newly
synthesized fatty acids
exist primarily as acyl-CoA
esters.
Fatty Acid Synthesis in Bacteria and
Plants
• The separate enzymes in bacteria and plants
• Pathway initiated by formation of acetyl-ACP
and malonyl-ACP by transacylases
• Decarboxylation drives the condensation of
acetyl-CoA and malonyl-CoA by KSase
• Next three steps look very similar to the fatty
acid oxidation in reverse
• Only differences: D configuration and NADPH
Fatty Acid Synthesis
Acetyl-CoA + 7 malonyl-CoA + 14 NAPDH + 14 H+
Palmitoyl-CoA + 7 HCO3- + 14 NAPD+ + 7 CoA-SH
The formation of malonyl-CoA:
7 Acetyl-CoA + 7 HCO3- + 7 ATP47 malonyl-CoA + 7 ADP3- + 7Pi2- +7H+
The overall reaction:
8 Acetyl-CoA + 7 ATP4- + 14 NAPDH + 14 H+
Palmitoyl-CoA + 14 NAPD+ + 7 CoA-SH + 7 ADP3- + 7Pi2-
(213 KD)
In yeast: a6b6
(203 KD)
Figure 24.8
In yeast, the functional groups
and enzyme activities required
for fatty acid synthesis are
distributed between a- and bsubunits.
Fatty Acid Synthase in Animals
Fatty Acid Synthase - a multienzyme complex
• Dimer of 250 kD multifunctional polypeptides
– Domain 1: AT, MT & KSase
– Domain 2: ACP, KRase, DH, ERase
– Domain 3: Thioesterase
Figure 24.9
Fatty acid
synthase in
animals contains
all the functional
groups and
enzyme activities
on a single
multifunctional
subunit. The active
enzyme is a headto-tail dimer of
identical subunits.
(Adapted from Wakil,
S. J., Stoops, J. K.,
and Joshi, V. C.,
1983.Fatty acid
synthesis and its
regulation. Annual
Review of
Biochemistry 52:537579.)
Figure 24.10
Acetyl units are covalently linked to a serine residue at the
active site of the acetyl transferase in eukaryotes. A similar
reaction links malonyl units to the malonyl transferase.
Further Processing of FAs
Additional elongation & desaturation
• Additional elongation occurs in
mitochondria and the surface of ER
• The reducing coenzyme for the second step
is NADH, whereas the reductant for the
fourth step is NADPH.
• In ER, involving malonyl-CoA
Figure 24.12
Elongation of fatty acids
in mitochondria is
initiated by the thiolase
reaction. The b-ketoacyl
intermediate thus
formed undergoes the
same three reactions
(in reverse order) that
are the basis of boxidation of fatty acids.
Reduction of the b-keto
group is followed by
dehydration to form a
double bond. Reduction
of the double bond
yields a fatty acyl-CoA
that is elongated by two
carbons. Note that the
reducing coenzyme for
the second step is
NADH, whereas the
reductant for the fourth
step is NADPH.
( in mitochondria)
Further Processing of FAs
Introduction of cis double bonds
• E.coli add double bonds during the fatty acid
synthesis
• After four normal cycles, b-hydroxydecanoyl
thioester dehydrase forms a double bond b, g
to the thioester
• O2-independent
Figure 24.13
Double bonds are
introduced into the
growing fatty acid
chain in E. coli by
specific dehydrases.
Palmitoleoyl-ACP is
synthesized by a
sequence of
reactions involving
four rounds of chain
elongation, followed
by double bond
insertion by bhydroxydecanoyl
thioester dehydrase
and three additional
elongation steps.
Another elongation
cycle produces cisvaccenic acid.
Further Processing of FAs
•
•
•
•
•
Introduction of cis double bonds
Eukaryotes add double bond until the fatty
acyl chain has reached its full length
(usually 16 to 18 carbons)
Desaturase
Cytochrome b5 reductase & Cytochrome b5
All three proteins are ssociated with the ER
membrane
NADH & O2 are required; O2-dependent
Figure 24.14
The conversion of stearoyl-CoA to oleoyl-CoA in eukaryotes is catalyzed by stearoyl-CoA
desaturase in a reaction sequence that also involves cytochrome b5 and cytochrome b5
reductase. Two electrons are passed from NADH through the chain of reactions as shown,
and two electrons are also derived from the fatty acyl substrate. linoleic acid in eukaryotes.
This is the only means by which animals can synthesize fatty acids with double bonds at
positions beyond C-9.
• Mammals cannot synthesize most
polyunsaturated fatty acids
– Essential fatty acids
– Introduce double bonds between the double bond at
the 8- or 9- position and the carboxyl group
– form a double bond at 5-position (6) if one already
exists at the 8-position (9)
Arachidonic acid
• mammals can also add double bonds to
unsaturated fatty acids
• synthesized from linoleic acid in eukaryotes
• The precursor for prostaglandins and other
biologically active derivatives
Figure 24.15
Arachidonic acid is
synthesized from linoleic
acid in eukaryotes. This is
the only means by which
animals can synthesize fatty
acids with double bonds at
positions beyond C-9.
Regulation of Fatty Acid Synthesis
Allosteric modifiers, phosphorylation and
hormones
• Allosteric regulation
– Malonyl-CoA blocks the carnitine acyltransferase
and thus inhibits b-oxidation
– Citrate activates acetyl-CoA carboxylase
– Fatty acyl-CoAs inhibit acetyl-CoA carboxylase
Figure 24.16
Regulation of fatty
acid synthesis and
fatty acid oxidation
are coupled as
shown. Malonyl-CoA,
produced during fatty
acid synthesis,
inhibits the uptake of
fatty acylcarnitine
(and thus fatty acid
oxidation) by
mitochondria. When
fatty acyl-CoA levels
rise, fatty acid
synthesis is inhibited
and fatty acid
oxidation activity
increases. Rising
citrate levels (which
reflect an abundance
of acetyl-CoA)
similarly signal the
initiation of fatty acid
synthesis.
Regulation of FA Synthesis
• Phosphorylation and hormones
– Citrate activation and acyl-CoA inhibition of ACC
are dependent on the phosphorylation state
– Phosphorylation causes inhibition of fatty acid
biosynthesis
• Hormone signals regulate ACC and fatty acid
biosynthesis
– Glucagon activates lipases/inhibits ACC
– Insulin inhibits lipases/activates ACC
Figure 24.17
Hormonal signals regulate
fatty acid synthesis,
primarily through actions
on acetyl-CoA
carboxylase. Availability
of fatty acids also depends
upon hormonal activation
of triacylglycerol lipase.
24.2 – How Are Complex Lipids
Synthesized?
Complexed lipids:
1. Glycerolipid
–
–
Triacylglycerols
Glycerophospholipids
2. Sphingolipids
Phospholipids (membrane components)
1. Glycerophospholipids
2. Sphingolipids
Synthetic pathways depend on different
organism
• Sphingolipids and triacylglycerols only
made in eukaryotes
• Phosphatidylethanolamine (PE) accounts
for 75% of phospholipids in E.coli
– No PC, PI, sphingolipids, cholesterol in E.coli
– But some bacteria do produce PC
Glycerolipid Biosynthesis
Glycerolipids are synthesized by phosphorylation
& acylation of glycerol
• Phosphatidic acid (PA) is the precursor for all
other glycerolipids in eukaryotes
• Eukaryotic systems can also utilize DHAP as a
starting point
Unsatuated
Fatty Acid
Figure 24.18
Synthesis of
glycerolipids in
eukaryotes begins with
the formation of
phosphatidic acid,
which may be formed
from dihydroxyacetone
phosphate or glycerol
as shown.
Satuated
Fatty Acid
Glycerolipid Biosynthesis
• PA is converted either to DAG or CDP-DAG
• DAG is a precursor for synthesis of TAG,
phosphatidylethanolamine (PE) and
phosphatidylcholine (PC)
• TAG is synthesized mainly in adipose tissue,
liver, and intestines
Figure 24.19
Diacylglycerol and CDPdiacylglycerol are the
principal precursors of
glycerolipids in eukaryotes.
Phosphatidylethanolamine
and phosphatidylcholine
are formed by reaction of
diacylglycerol with CDPethanolamine or CDPcholine, respectively.
Glycerolipid Biosynthesis
• PE synthesis
– begins with phosphorylation of ethanolamine to
form phosphoethanolamine
– Transfer of a cytidylyl group from CTP to from
CDP-ethanolamine
– Phosphoethanolamine transferase link
phosphoethanolamine to the DAG
• Synthesis of PC is entirely analogous
• PC can also be converted from PE by
methylation reactions
• Exchange of ethanolamine for serine converts
PE to PS (phosphatidylserine)
Figure 24.21
The interconversion of
phosphatidylethanolamine
and phosphatidylserine in
mammals.
Other PLs from CDP-DAG
Figure 24.22
• CDP-diacylglycerol is used in eukaryotes to
produce:
– Phosphatiylinositol (PI) in one step
• 2-8% in animal membrane
• Breakdown to form inositol-1,4,5-triphosphate &
DAG (second messengers)
– Phosphatiylglycerol (PG) in two steps
– Cardiolipin in three steps
Figure 24.22
CDP-diacylglycerol is a
precursor of
phosphatidylinositol,
phosphatidylglycerol, and
cardiolipin in eukaryotes.
Plasmalogen Biosynthesis
Dihydroxyacetone phosphate (DHAP) is the
precursor to the plasmalogens
• Acylation of DHAP
• Exchange reaction produces the ether
linkage by long-chain alcohol (acyl-CoA
reductase)
• Ketone reduction
• Acylation again
• CDP-ethanolamine delivers the head group
• A desaturase produces the double bond in
the alkyl chain
Figure 24.23
Biosynthesis of
plasmalogens in
animals. (1) Acylation at
C-1 is followed by (2)
exchange of the acyl
group for a long-chain
alcohol.(3) Reduction of
the keto group at C-2 is
followed by (4 and 5)
transferase reactions,
which add an acyl
group at C-2 and a
polar head-group
moiety, and a (6)
desaturase reaction
that forms a double
bond in the alkyl chain.
The first two enzymes
are of cytoplasmic
origin, and the last
transferase is located at
the endoplasmic
reticulum.
Acyl-CoA
Acyl-CoA
reductase
Figure 24.24
Platelet-activating factor,
formed from 1-alkyl-2lysophosphatidylcholine
by acetylation at C-2, is
degraded by the action of
acetylhydrolase.
Sphingolipid Biosynthesis
High levels made in neural tissue
1. Initial reaction is a condensation of serine and
palmitoyl-CoA (by 3-ketosphinganine
synthase)
–
2.
3.
4.
•
3-ketosphinganine synthase is PLP-dependent
Ketone is reduced with help of NADPH
Acylation to form N-acyl-sphinganine
Desaturated to form ceramide
Ceramide is precursor for other sphingolipids
Figure 24.25
Biosynthesis of
sphingolipids in animals
begins with the 3ketosphinganine synthase
reaction, a PLP-dependent
condensation of palmitoylCoA and serine.
Subsequent reduction of the
keto group, acylation, and
desaturation (via reduction
of an electron acceptor, X)
form ceramide, the
precursor of other
sphingolipids.
Sphingolipid Biosynthesis
Ceramide is precursor for other sphingolipids
• Sphingomyelin
–
–
–
•
Cerebrosides
–
–
•
Rich in myelin sheath
Insulates nerve axons
By transfer of phosphocholine from PC
Glycosylation of ceramide
Galactosylceramide makes up ~15% of the lipid of
myelin sheath
Gangliosides
–
Cerebrosides contain one or more sialic acid
Figure 24.26
Glycosylceramides (such as
galactosylceramide),
gangliosides, and
sphingomyelins are
synthesized from ceramide
in animals.
Gangliosides
1.
UDP-glucose
2.
UDP-galactose
3.
UDP-N-acetylgalactosamine
4.
CMP-sialic acid
(N-acetylneuraminidate)
24.3 – How Are Eicosanoid Synthesized
and What Are Their Functions?
•
•
Eicosanoid are all derived from 20-carbon
fatty acid (arachidonic acid)
Eicosanoids are local hormones
1. Exert their effect at very low concentration
2. Usually act near their sites of synthesis
•
•
PLA2 releases arachidonic acid from
phospholipids (PC)
Can be released by PLC & DAG lipase
Figure 24.27
Arachidonic acid, derived
from breakdown of
phospholipids (PL), is the
precursor of prostaglandins,
thromboxanes, and
leukotrienes. The letters
used to name the
prostaglandins are
assigned on the basis of
similarities in structure and
physical properties. The
class denoted PGE, for
example, consists of bhydroxyketones that are
soluble in ether, whereas
PGF denotes 1,3-diols that
are soluble in phosphate
buffer. PGA denotes
prostaglandins possessing
a,b-unsaturated ketones.
The number following the
letters refers to the number
of carbon - carbon double
bonds. Thus, PGE2
contains two double bonds.
Specificities of phospholipases A1, A2, C, and D.
Eicosanoids are local hormones
• Eicosanoids include
–
–
–
–
Prostaglandins (PG)
Thromboxanes (Tx)
Leukotrienes
Other hydroxyeicosanoic acid
• Tissue injury and inflammation triggers
arachidonate release and eicosanoid
synthesis
• All PGs are cyclopentanoic acids
• Initiated by PGH synthase associated with
the ER
• PGH synthase
• Prostaglandin
endoperoxide synthase
• Cyclooxygenase
• Catalyzes simultineous
oxidation and cyclization of
arachidonic acid
Two isoforms in animals
(a) COX-1: normal, physiological production of PG
(b) COX-2: induced by cytokines, mitogens, and
endotoxins in inflammatory cells
(a)
COX-1
(b) COX-2
Aspirin & NSAIDs
• Aspirin and other nonsteroid anti-inflammatory
drugs (NSAIDs) inhibit the cyclooxygenase
– Aspirin covalently
– Others noncovalently
Specifically
inhibition of COX2
24.4 – How Is Cholesterol
Synthesized?
Occurs primarily in the liver
• The most prevalent steroid in animal cells is
cholesterol
• Serve as cell membranes, precursor of bile
acids and steroid hormones, and vitamin D3
•
1.
2.
3.
Occurs primarily in the liver
Biosynthesis begins in the cytosol
with the synthesis of mevalonate
from acetyl-CoA
First step is a thiolase reaction
Second step makes HMG-CoA
Third step produces 3R-mevalonate
• HMG-CoA reductase
• The rate-limiting step in cholesterol
biosynthesis
• HMG-CoA reductase is site of action
of cholesterol-lowering drugs
Figure 24.32
A reaction mechanism for
HMG-CoA reductase. Two
successive NADPHdependent reductions
convert the thioester,
HMG-CoA, to a primary
alcohol.
Regulation of HMG-CoA Reductase
As rate-limiting step, it is the principal site of
regulation in cholesterol synthesis
1. Phosphorylation by cAMP-dependent
kinases inactivates the reductase
2. Degradation of HMG-CoA reductase half-life is 3 hrs and depends on
cholesterol level: High [cholesterol]
means a short half-time
3. Gene expression (mRNA production) is
controlled by cholesterol levels: If
[cholesterol] is low, more mRNA is made
Figure 24.33
HMG-CoA reductase activity
is modulated by a cycle of
phosphorylation and
dephosphorylation.
Squalene is synthesized from
Mevalonate
• Six-carbon mevalonate makes 5-carbon
isopentenyl pyrophosphate and dimethylallyl
pyrophosphate
• Condensation of these two 5-carbon
intermediates produces geranyl pyrophosphate
(10-carbon)
• Addition of another isopentenyl pyrophosphate
yields farnesyl pyrophosphate
• Two farnesyl pyrophosphates link to form
squalene
• Bloch and Langdon
were first to show
that squalene is
derived from acetate
units and that
cholesterol is derived
from squalene
geranyl pyrophosphate
Figure 24.34
The conversion of
mevalonate to squalene.
Cholesterol from Squalene
•
•
•
•
At the endoplasmic reticulum membrane
Squalene monooxygenase converts squalene
to squalene-2,3-epoxide
2,3-oxidosqualene:lanosterol cyclase
converts the epoxide to lanosterol
Though lanosterol looks like cholesterol, 20
more steps are required to form cholesterol
All at/in the endoplasmic reticulum
membrane
Figure 24.35
Cholesterol is
synthesized from
squalene via
lanosterol. The primary
route from lanosterol
involves 20 steps, the
last of which converts
7-dehydrocholesterol
to cholesterol. An
alternative route
produces desmosterol
as the penultimate
intermediate.
Inhibiting Cholesterol Synthesis
•
•
•
•
Merck and the Lovastatin story...
HMG-CoA reductase is the key - the ratelimiting step in cholesterol biosynthesis
Lovastatin (mevinolin) blocks HMG-CoA
reductase and prevents synthesis of
cholesterol
Lovastatin is an (inactive) lactone
In the body, the lactone is hydrolyzed to
mevinolinic acid, a competitive inhibitor of
the reductase, Ki = 0.6 nM
HB page 797
The structures of (inactive ) lovastatin, (active)
mevinolinic acid, mevalonate, and synvinolin.
24.5 – How Are Lipids Transported
Throughout the Body?
Lipoproteins are the carriers of most lipids in
the body
• Lipoprotein - a cluster of lipids, often with a
monolayer membrane (phospholipids), together
with an apolipoprotein
Lipoproteins
• HDL & VLDL are assembled primarily in the
ER of liver cells (some in intestines)
• Chylomicrons form in the intestines
• LDL not made directly, but is made from VLDL
• LDL appears to be the major circulatory
complex for cholesterol & cholesterol esters
Lipoproteins
• Chylomicrons carry TAG & cholesterol esters
from intestine to other tissues
• VLDLs carry lipid from liver
• Mostly in the capillaries of muscle and
adipose cells, lipoprotein lipases hydrolyze
triglycerides from lipoproteins, making the
lipoproteins smaller and raising their density
• Thus chylomicrons and VLDLs are
progressively converted to IDL and then
LDL, which either return to the liver for
reprocessing or are redirected to adipose
tissues and adrenal glands
Figure 24.38
Lipoprotein
components are
synthesized
predominantly in the
ER of liver cells.
Following assembly
of lipoprotein
particles (red dots) in
the ER and
processing in the
Golgi, lipoproteins
are packaged in
secretory vesicles for
export from the cell
(via exocytosis) and
released into the
circulatory system.
Lipoproteins
• LDLs are main carriers of cholesterol and
cholesterol esters
• Newly formed HDL contains virtually no
cholesterol esters
– Cholesterol esters are accumulated through the
action lecithin:cholesterol acyltransferase
(LCAT)
• HDLs function to return cholesterol and
cholesterol esters to the liver
Figure 24.39
Endocytosis and degradation of
lipoprotein particles. (ACAT is
acyl-CoA cholesterol
acyltransferase.)
The LDL Receptor
•
•
•
•
•
A complex plasma membrane protein
LDL binding domain on N-terminus
N-linked and O-linked oligosaccharide domains
A single TMS
A cytosolic domain essential to aggregation of
receptors in the membrane during endocytosis
Dysfunctions in or absence of LDL receptors
lead to familial hypercholesterolemia
Figure 24.40
The structure of the LDL
receptor. The aminoterminal binding domain is
responsible for recognition
and binding of LDL
apoprotein. The O-linked
oligosaccharide-rich
domain may act as a
molecular spacer, raising
the binding domain above
the glycocalyx. The
cytosolic domain is
required for aggregation of
LDL receptors during
endocytosis.
24.6 – How Are Bile Acids
Biosynthesized?
•
•
•
•
Carboxylic acid derivatives of cholesterol
Essential for the digestion of food, especially for
solubilization of ingested fats
Synthesized from cholesterol in the liver, stored in
the gallbladder, and secreted as need into the
intestine
Cholic acid conjugates with taurine and glycine to
form taurocholic and glycocholic acids
First step is oxidation of cholesterol by a mixedfunction oxidase (7a-hydroxylase)
24.7 – How Are Steroid Hormones
Synthesized and Utilized?
Desmolase (in mitochondria) converts cholesterol
to pregnenolone, precursor to all others
• Pregnenolone migrates from mitochondria to
ER where progesterone is formed
• Progesterone is a branch point - it produces sex
steroids (testosterone and estradiol), and
corticosteroids (cortisol and aldosterone)
Figure 24.43
The steroid
hormones are
synthesized from
cholesterol, with
intermediate
formation of
pregnenolone and
progesterone.
Testosterone, the
principal male sex
hormone steroid,
is a precursor to
b-estradiol.
Cortisol, a
glucocorticoid, and
aldosterone, a
mineralocorticoid,
are also derived
from progesterone.
(27C)
(19C)
aromatase
(18C)
(21C)
• Anabolic steroids are illegal and dangerous
Figure 24.44
The structure of
stanozolol, an anabolic
steriod.