Lecture 30
– Quiz on Wednesday: fatty acid synthesis
(You will have 15 min to take the quiz; we
will still have a lecture on WED.)
– Membranes
– Final is from 8AM-10AM on Dec. 12
Page 933
Fatty acid biosynthesis
1.
Acetyl-CoA is converted by MAT to
Acetyl ACP
2.
Acetyl-ACP is attached to KS
(condensation reaction).
3.
Malonyl ACP is formed by MAT.
4.
Acetyl-group is coupled to beta
carbon of malonyl-ACP with release
of CO2 to form acetoacetyl-ACP(2b)
by KS.
5.
Reduction of acetoacetyl-ACP with
NADPH to form D--hydroxybutyrlACP by DH
6.
Dehydration of D--hydroxybutyrlACP by ER to form a,b-transbutenoyl-ACP
7.
Reduction of the double bond to
form butyryl-ACP
8.
Repeat until Palmitoyl-ACP (C16) is
formed.
9.
ACP is cleaved by TE releasing free
fatty acid.
Polar Lipids
• Differ from triglycerides since they have one or
more polar head groups.
• 2 main types: glycerol or sphingosine based
• Main class are phospholipids
• involved in membrane structure
• Amphipathic
Fat molecules are hydrophobic, whereas phospholipids are
amphipathic.
(A) Triacylglycerol, a fat
molecule, is entirely
hydrophobic.
(B) Phospholipids such as
phosphatidyl-ethanolamine are
amphipathic, containing both
hydrophobic and hydrophilic
portions.
The hydrophobic parts are
shaded red, and the hydrophilic
parts are shaded blue and
green.
(The third hydrophobic tail of the
triacylglycerol molecule is drawn
here facing upward for
comparison with the
phospholipid, although normally
it is depicted facing down.)
Examples of polar lipids - Glycerophospholipids and
Sphingolipids
•
The membrane lipids are composed of the
glycerophospholipids and sphingolipids, which have
polar and nonpolar regions.
Figure 9.7
Glycerophospholipids
Phosphatidic acid
4 major
glycerophospholipids
are polar/charged:
Other examples of phosphoglycerol derivatives
• Can be in sugars (glycolipids)
• Diphosphatidyl glycerol
O
O
RCO-CH2
O
CH2-OCR
O
RCO-CH
CH-OCR
O
OH
O
CH2-O-P-O-CH2-CH-CH2-O-P-O-CH2
O-
glycerol
O-
Figure 9.8
Sphingolipid
Structure
sphingosine
Fatty acid
Polar head
4 major sphingolipids
are:
Found in nerve cell
membranes
brain, nervous system.
Tay-Sachs disease:
accumulation of
ganglioside in brain
and spleen causes
death by age 4.
Sphingolipids
• Sphingomyelin (also considered a
phospholipid)
• Important in myelin sheath of nerve cell
membrane.
• Cerebrosides are glycolipids - found in brain
and other tissues.
• Sugar attached at P.
• Ganglosides are sphingolipids with several
sugars as head groups. Terminal sugar is sialic
acid.
Lipid/membrane consitutents that cannot be
saponified.
• Triacylglycerides, phospholipids, and
sphingolipids can be saponified (hydrolyzed
with OH-)
• Some cannot be saponified: steroids
(cholesterol-based) and terpenes.
The molecular structure common to all steroids
Steroid structures have four fused rings, A, B, C, and D.
Figure 9-10b Cholesterol molecular structure - a steroid
•
Cholesterol has a polar head group (OH) and a
nonpolar tail.
•
Cholesterol and ester derivatives are abundant in
(blood) plasma proteins called lipoproteins.
•
Lipoproteins transport cholesterol to tissues for use
in cell membranes and hormone precursors.
Figure 9-10 The molecular structure common to all steroids
•
C30 Cholesterol molecule
is derived from 5-carbon
isoprene subunit.
Cholesterol is traditionally only associated with animal
cells, but derivatives are also identified in plants.
Figure 9-10 (c) A cholesterol fatty acid ester
•
Cholesterol ester formed between the cholesterol
hydroxyl group and a fatty acid with a long
aliphatic side chain.
•
This is a common modification of cholesterol
under physiological conditions.
Figure 7-6 Structure of the Cholesterol, a Component of
Mammalian Cell Membranes
(c) The most common
membrane sterols are
cholesterol in animals
and several related
phytosterols in plants.
Cholesterol and Eggs in the diet
From Jennifer Moll,Your Guide to Cholesterol.
About fifteen years ago, egg consumption was discouraged by many health care
practitioners because of their high cholesterol content. The average intact egg contains
about 210 mg of cholesterol, whereas the recommended intake of cholesterol is 300
mg. However, a study published in the Journal of the American Medical Association, in
addition to several other studies, refute this. This study looked at the effects of egg
consumption in 100,000 men and women, and concluded that eggs alone do not contribute
to high cholesterol. In fact, when cholesterol was omitted from the diet of these subjects,
their total cholesterol levels decreased only by 1%. What researchers did discover was
that individuals who consumed eggs also consumed bacon, ham, butter, and other
food products that could contribute to high cholesterol levels. Not only do these
foods have high cholesterol, they also contain high amounts of saturated fats and
trans-fats--both of which contribute to high cholesterol levels and atherosclerosis.
Given these studies and the fact that eggs are an excellent source of nutrition, the
American Heart Association now recommends that you can eat one egg a day, as opposed
to three or four per week it previously allowed. Eggs are a rich source of protein, containing
the essential amino acids required by your body. In addition to protein, eggs also contain
many vitamins, minerals, and a fatty molecule called lecithin, which aids in transporting and
metabolizing fats in the body .It is cautioned that if you do consume one egg a day, you
might need to watch your total cholesterol levels since too much cholesterol could raise
your LDL levels.
Figure 7-8 The Structure of Hopanoids
Abundant in petroleum (crude
oil) deposits, suggesting a
prokaryotic (bacterial) role in
formation of oil deposits
(a) A hopanoid, one of a class of
sterol-like molecules that
appear to function in the
plasma membranes of at least
some prokaryotes as sterols
do in the membranes of
eukaryotic cells.
(b) The structure of cholesterol,
for comparison. A weakly
hydrophilic side chain (CH2OH or -OH) protrudes from
each molecule.
Figure 9-11(b-d) Structures of bioactive products produced
from cholesterol.
b) Estradiol - a female sex hormone.
c) Testosterone - a male sex
hormone.
d) Cortisol - a regulator of glucose
metabolism.
Figure 9-11 (e,f) Structures of bile salts produced from
cholesterol.
e) Cholate - a bile salt derived
from cholic acid.
f) Glycholate - a bile salt
derived from glycholic
acid.
•
Bile salts are stored in the gallbladder, secreted into
intestines to solubilize, adsorb dietary fats.
•
Bile salts have carboxylic acid groups that ionize at
physiological pH (>pH 5.0)
Terpenes
•
Terpene class of lipids includes all molecules
biosynthesized from isoprenes (including cholesterol).
•
Important terpenes include beta-carotene, lycopene,
squalene.
•
Terpenes often have strong odors.
Eicosanoids
•
•
Three classes of the Eicosanoid class of lipids:
1.
Prostaglandins - isolated from prostrate gland, found
in nearly all tissues.
2.
Thromboxanes - 6-membered rings with oxygen - may
help in blood clotting.
3.
Leukotrienes - isolated from leukocytes, cause
contraction of smooth muscle.
All are derived from polyunsaturated 20-carbon
fatty acid, arachidonate (20:4 D5,8,11,14).
Three classes of the Eicosanoid lipids are all derived from
polyunsaturated 20-carbon fatty acid, arachidonate (20:4 D5,8,11,14).
•PGE2
induces wakefulness
•PGD2
promotes sleep
Table 9.4 Common fat-soluble vitamins (terpenes)
Figure 9.14 Two insect pheromones
Housefly
attractant
Honeybee queen
attractant
Key Functions of Cell Membranes
• Cell membranes have at least five distinct
functional roles:
1. Define the boundaries of the cell and its
organelles.
2. Serve as locations for specific functions.
3. Provide for and regulate transport
processes.
4. Contain the receptors needed to detect
external signals.
5. Provide mechanisms for cell-to-cell
contact, communication, and adhesion.
Figure 11–5 A typical membrane lipid molecule has a hydrophilic
head and hydrophobic tails.
Figure 9.9 Assembly of polar lipids into lipid bilayer
structures (sheets)
Hydrophobic interactions provide stabilizing energy to
hold the bilayer together.
Lipid aggregates
•
In aqueous solutions, amphiphilic molecules form micelles.
• Have a hydrophobic interior to eliminate contacts
between water and the hydrophobic tails.
•
Micelles form only after a critical micelle concentration is
reached (dependent on the amphiphile). For short tails
(dodecyl sulfate) need higher conc. (1 mM) whereas for
longer hydrophobic tails in biological lipids need a lower
concentration (<10-6)
Lipid bilayers
•
•
•
Glycerolipids and sphingolipids form bilayers
Structural basis for biological membranes
Impermeable to most polar substances
•
A suspension of phospholipids can be disrupted using
sonciation to form liposomes-closed self-sealing lipid
vesicles bounded by a single-bilayer.
Biological membranes are lipid bilayers with which proteins
are associated.
•
Figure 11–11 Amphipathic phospholipids form a bilayer in water.
(A) Schematic drawing of a
phospholipid bilayer in water.
(B) Computer simulation showing the
phospholipid molecules (red heads and
orange tails) and the surrounding water
molecules (blue) in a cross section of a
lipid bilayer.
Figure 11–12 Phospholipid bilayers spontaneously close in on
themselves to form sealed compartments.
The closed structure is stable
because it avoids the exposure
of the hydrophobic
hydrocarbon tails to water,
which would be energetically
unfavorable.
Important Features of Lipid Distribution in Cell
Membranes
•
Lipid bilayer membranes are fluid structures.
•
Rate of lipid diffusion within a lipid monolayer (lateral
diffusion) is very rapid.
•
Rate of lipid exchange between layers (transverse diffusion)
is very slow.
•
Specific proteins (e.g., in smooth ER) will move specific lipids
from one membrane to the other, termed “flippases” or
phospholipid translocators.
Consequence:
•
Most membranes have unequal distribution of lipids in each
monolayer of the bilayer structure: “membrane asymmetry”
Figure 7-11 Demonstration of Lipid Mobility Within
Membranes by Fluorescence Recovery After
Photobleaching
Lipid Fluidity in Cell Membranes
•
Lipid bilayer membranes are fluid structures.
•
Bilayer fluidity will vary with temperature.
•
Each lipid bilayer has a (Phase) Transition temperature
Tm (melting temperature).
•
Tm increases with increasing chain length (butter vs.
cooking oil).
•
Tm decreases with increasing degree of unsaturation
(poor packing of bent tails).
•
Tm modulated by cholesterol: broadens effective Tm:
Lowers Tm at high temp., increases Tm at low temp.
Figure 11–6 Phosphatidylcholine is the most common phospholipid
in cell membranes
This particular phospholipid is built from five parts: the hydrophilic head, choline, is linked via a phosphate
to glycerol, which in turn is linked to two hydrocarbon chains, forming the hydrophobic tail.
The two hydrocarbon chains originate as fatty acids— that is, hydrocarbon chains with a –COOH group at
one end—which become attached to glycerol via their –COOH groups.
A kink in one of the hydrocarbon chains occurs where there is a double bond between two carbon
atoms; it is exaggerated in these drawings for emphasis.
The “phosphatidyl-” part of the name of phospholipids refers to the phosphate–glycerol–fatty acid portion of
the molecule.
Figure 7-14 The Effect of Unsaturated Fatty Acids on the Packing of
Membrane Lipids
(a) Membrane phospholipids with no unsaturated fatty acids fit together tightly because the
fatty acid chains are parallel to each other. (b) Membrane lipids with one or more unsaturated
fatty acids do not fit together as tightly because the cis double bonds cause bends in the
chains, which interfere with packing. Each of the structures shown is a phosphatidylcholine
molecule, with either two 18-carbon saturated fatty acids (stearate) (part a) or two 18-carbon
fatty acids, one saturated (stearate) and the other with one double bond (oleate) (part b).
Figure 7-13 The Effect of Chain Length and the Number of Double Bonds on
the Melting Point of Fatty Acids
•
The melting point of fatty acids:
1. increases with chain length
for saturated fatty acids.
2. decreases dramatically with
the number of double
bonds for fatty acids with a
fixed chain length.
•
The 18-carbon fatty acids in
part b are stearate, oleate,
linoleate, and linolenate, with
0, 1, 2, and 3 double bonds,
respectively.
Figure 11–16 Cholesterol stiffens cell membranes
11_16_Cholesterol.jpg
(A) The structure of cholesterol.
(B) How cholesterol fits into the gaps
between phospholipid molecules in a
lipid bilayer. The chemical formula of
cholesterol is shown in Figure 11–7.
Orientation of Cholesterol Molecules in a Lipid Bilayer
(a) Cholesterol molecules are present in both lipid
layers in the plasma membranes of most animal
cells, but a specific molecule is localized to one of
the two layers. (b) Each molecule orients itself in the
lipid layer so that its single hydroxyl group is close to
the polar head group of a neighboring phospholipid
molecule, where it forms a hydrogen bond with the
oxygen of the ester bond between the glycerol
backbone and a fatty acid.
Regulation of Cell Membrane Fluidity
•
Most organisms can regulate membrane
fluidity.
“homoviscous adaptation” in coldblooded poikilothermic organisms occurs
by regulating lipid composition:
•
•
•
•
Change ratio of 16-carbon to 18-carbon lipids
via hydrolase enzyme (smaller lipids have
lower Tm).
Change degree of unsaturation (via desaturase
enzyme).
Important for bacteria, plants, reptiles,
amphibians, hibernating mammals.
Figure 9.16 Distribution of lipids in two monolayers of the human
erythrocyte
Figure 7-7 Phospholipid Composition of Several Kinds of Membranes
The relative abundance of different kinds of
phospholipids in biological membranes varies greatly
with the source of the membrane.
Table 9.5
Figure 11–1 Cell membranes act as selective barriers.
11_01_Cell.membranes.jpg
Membranes serve as barriers between two compartments—
either between the inside and the outside of the cell (A) or
between two intracellular compartments (B).
In either case the membrane prevents molecules on one
side from mixing with those on the other.
Figure 7-3 Timeline for the Development of the Fluid Mosaic Model
•The fluid mosaic model of
membrane structure that Singer and
Nicholson proposed in 1972 was the
culmination of studies that date back
to the 1890s.
•Future developments and revisions?
Figure 11–15 Phospholipids can move within the plane of the
membrane
(Fast)
(Very Slow)
11_15_Phospho,move.jpg
(Fast)
(Fast)
The drawing shows the types of movement possible for phospholipid
molecules in a lipid bilayer.
Figure 7-10 Movements of Phospholipid Molecules Within Membranes
A phospholipid molecule is capable of three kinds of movement in a membrane: rotation about
its long axis; lateral diffusion by exchanging places with neighboring molecules in the same
monolayer; and transverse diffusion, or "flip-flop," from one monolayer to the other.
In a pure phospholipid bilayer at 37 degrees C, a typical lipid molecule exchanges places with
neighboring molecules about 10 million times per second and can move laterally at a rate of
about several micrometers per second. Flip-flops are rare, occur < 1 week-1 - Hr-1
Figure 9.18 The fluid mosaic model for biological
membranes
Figure 10–33 Freeze-fracture electron microscopy.
This drawing shows how the
technique provides images
of both the hydrophobic
interior of the cytosolic half
of the bilayer (the P face)
and the hydrophobic interior
of the external half of the
bilayer (the E face).
After the fracturing process,
the exposed fracture faces
are shadowed with platinum
and carbon, the organic
material is digested away,
and the resulting platinum
replica is examined in an
electron microscope.
Figure 10–34 Freeze-fracture electron micrograph of human red blood
cells.
Note that the density of intramembrane particles on the cytosolic (P)
face is higher than on the external (E) face.
Figure 9–33 The thylakoid membranes from the chloroplast of a plant
cell.
In this freeze-fracture electron micrograph, the thylakoid membranes, which perform
photosynthesis, are stacked up in multiple layers. The plane of the fracture has moved from
layer to layer, passing through the middle of each lipid bilayer and exposing transmembrane
proteins that have sufficient bulk in the interior of the bilayer to cast a shadow and show up as
intramembrane particles in this platinum replica. The largest particles seen in the membrane
are the complete photosystem II—a complex of multiple proteins.
Figure 11–21 Membrane proteins can associate with the lipid bilayer in
several different ways
11_21_proteins.associ.jpg
(A) Transmembrane proteins can extend across the bilayer as a single a helix, as
multiple a helices, or as a rolled-up  sheet (called a  barrel).
(B) Some membrane proteins are anchored to the cytosolic surface by an amphipathic a
helix.
(C) Others are attached to either side of the bilayer solely by a covalent attachment to a
lipid molecule (red zigzag lines).
(D) Finally, many proteins are attached to the membrane only by relatively weak,
noncovalent interactions with other membrane proteins.
Figure 7-19 The Main Classes of Membrane Proteins
Membrane proteins are classified according to their mode of attachment to the membrane.
Integral membrane proteins contain one or more hydrophobic regions that are embedded
within the lipid bilayer. Peripheral membrane proteins are too hydrophilic to penetrate into the
membrane but are attached to the membrane by electrostatic and hydrogen bonds that link
them to adjacent membrane proteins or to phospholipid head groups. Lipid-anchored
proteins are hydrophilic and do not penetrate into the membrane; they are covalently bound
to lipid molecules that are embedded in the lipid bilayer. (f) Proteins on the inner surface of
the membrane are usually anchored by either a fatty acid or a prenyl group. (g) On the outer
membrane surface, the most common lipid anchor is glycosylphosphatidylinositol (GPI).
Page 403
Figure 12-29 Prenylated proteins. (a) A farnesylated
protein and (b) a geranylgeranylated protein.
Prenylated proteins
•
•
Derived from isoprenoid groups
Proteins associated with intracellular membrane but also
facilitate protein-protein interactions.
•
For farnsylated and geranylgeranylated proteins, the
prenyl group is attached to a specific C-terminal sequence.
CaaX where C is Cys, a is an aliphatic amino acid and X is
any amino acid.
•
•
•
•
The aaX portion is cleaved after the prenylation of the
protein.
If X is Ala, Met, or Ser, the protein is farnyslated
If X is Leu, the protein is geranylgeranylated
Page 404
Figure 12-30 Core structure of the glycosylphosphatidyl
inositol (GPI) anchors of proteins.
Glycosylphosphatidylinositol (GPI)
•
•
•
Anchor proteins to the exterior of the eukaryotic membrane.
Alternative to transmembrane polypeptides
Proteins destined to be anchored to the surface of the
membrane are synthesized with membrane spanning Cterminal sequences which are removed after GPI addition.
Figure 11–20 Plasma membrane proteins have a variety of functions.
Figure 9.19 Passive transport of solute molecules through a permeable
membrane
Figure 9.20 Three types of membrane transport
Figure 9.23 Glucose permease of erythrocyte membrane
Passive transport system - intracellular [glucose] =< plasma
[glucose] concentration.
Also transports epimers of glucose - mannose, galactose at slower
rates (20%)
Figure 9.23 Transport of sodium and potassium ions by Na+-K+
ATPase transporter (pump)
Three Na+ ions are transported out of the cell for every two K+ that
move inside
Lipases
•
•
How are lipids accessed for energy production?
Know the differences between the triacylglycerol lipase
and phospholipase A2 mechanisms.
•
Triacylglycerol lipase uses a catalytic triad similar to Ser
proteases (Asp, His, Ser)
Phospholipase A2 uses a catalytic triad but substitutes water
for Ser.
•
Page 911
Figure 25-3a Substrate binding to phospholipase A2. (a)
A hypothetical model of phospholipase A2 in complex
with a micelle of lysophosphatidylethanolamine.
Page 912
Figure 25-4a The X-ray structure of porcine
phospholipase A2 (lavender) in complex with the
tetrahedral intermediate mimic MJ33.
Figure 25-4bThe catalytic
mechanism of
phospholipase A2.
Page 912
What other
mechanism does this
look like?
What are the
differences?
Fatty acid binding proteins
•
•
•
Fatty acids form complexes with intestinal fatty acidbinding protein (I-FABP) which makes them more soluble.
Chylomicrons-transport exogenous (dietary) triacylglycerols
and chloestorl packaged into lipoprotein molecules from the
intestine to the tissues.
Chylomicrons are released into the bloodstream via transport
proteins named for their density.
•
VLDL (very low density lipoproteins), LDL (low density
lipoproteins) - transport endogenous (internally produced)
triacylglycerols and cholesterols from the liver to tissues
“Bad”
•
HDL (high density lipoproteins), - transport endogenous
cholesterol from the tissues to liver - “Good”
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Table 12-6 Characteristics of the Major Classes of
Lipoproteins in Human Plasma.
Page 442