Prof. Kamakaka`s Lecture 9 Notes

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Transcript Prof. Kamakaka`s Lecture 9 Notes

Lipids and Membranes
Membranes
All cell membranes share a characteristic
trilaminar appearance.
Two electron-dense layers separated by a less
dense central region.
Lipid composition of the plasma membrane and organelle membranes
Stearic and Oleic
Fatty acids are used as stored forms
of energy in cells.
A fatty acid is a carboxylic acid with a
long unbranched hydrocarbon (aliphatic)
chain
Lipids are natural products that are
insoluble in water.
Lipids are involved in
energy storage,
membrane composition
hormone biosynthesis.
Lipids are a broad group –
fats (triglycerides),
sterols,
fat-soluble vitamins.
Stearic
Oleic
Solid Vs Liquid
Saturated Vs Unsaturated
Simplest fatty acids are unbranched,
linear chains of CH2 groups linked by
carbon-carbon single bonds with one
terminal carboxylic acid group.
Saturated indicates that the maximum
possible number of hydrogen atoms are
bonded to each carbon.
An unsaturated fat is a fatty acid in
which there is at least one double bond
within the fatty acid chain.
Monounsaturated contains one double
bond, and polyunsaturated contains
more than one double bond.
TriGlycerides
The simplest lipids constructed
from fatty acids are the
triacylglycerols.
These are also called triglycerides,
fats or neutral fats.
Triacylglycerols are composed of 3
fatty acids, each in an ester linkage
with a single glycerol group. They
are nonpolar - and hence waterinsoluble - and have lower specific
gravity than water. (This is why oil and
water don’t mix, and why oil floats on the
surface of water)
Triglycerides are storage forms of fatty acids.
Fatty acids are strong acids and are stored as triacylgycerols
Fatty acids are richer in energy than carbohydrates
Fatty acids do not interact with water and are stored in anhydrous form (more compact)
In human bodies carb can sustain a human for a day while lipids can sustain a human for a couple of weeks
Common fats
Lipid functions
Lipids are used in
Fuel storage
Hormones
Signal transduction messenger
Membranes
Membrane lipids:
Phospholipid
Glycolipid
Cholesterol
Phospholipid
Phospho lipids have a charged group
The C1 and C2 of glycerol are esterified with fatty acids
C3 OH grp is esterified with phosphoric acid
In membranes often the PO4 is further esterified with an alcohol-choline, serine, inositol
Phosphorylcholine
Choline is a quaternary saturated amine
GlyceroPhospholipids
Cells continually degrade and replace
their membrane phospholipids.
Enzymes specific for each hydrolyzable
bond in a glycerophospholipid exist in
lysosomes within cells
Glycolipid
Sugar containing lipids
Derived from sphingosine
Sphingosine has three parts, a three
carbon chain with two alcohols an amine and
a hydrocarbon chain
Sphingomyelin has a sphingosine backbone and a
fatty acid is attached to the amine through amide
bond. Phosphate is attached through a phosphate
ester bond, and through a second phosphate ester
bond to choline.
Phosphoryl choline is replaced with a sugar
Sterols
Sterols are structural lipids present
in the membranes of most eukaryotic
cells.
Cholesterol is the major sterol in
animal tissues and is absolutely
necessary for membrane biogenesis
(especially in children (brain)).
All sterols have the 4 ring structure
and adopt a cylindrical structure
Vitamin D and Sterol
Liver
Vitamin D is one of several fat soluble vitamins, compounds that are essential
to human health but must be obtained from the diet.
Vitamin D forms in the skin by a reaction driven by sunlight; in the liver/kidney, it is
converted to a biologically-active hormone that regulates calcium uptake.
Micelle, membrane Vesicle
Membrane lipids are amphipathic-hydrophilic polar head and hydrophobic tail
Components of membranes
Liposomes
Lipid vesicles have low permeability for ions.
Na+ or K+ traverse a membrane more slowly
than water.
Permeability of molecules is correlated with
their relative solubility in water or non-polar
solvents.
Clinical uses of liposomes
DNA for gene therapy
Drug delivery to tumors (which have more
vascularization and therefore more
liposomes can be targeted to tumors).
Inclusion in liposome membranes of specific
cell surface proteins or antibodies against
tumor antigens increases specificity of
targeting.
Fluid mosaic
The fatty acyl chains in the interior of the membrane form a fluid, hydrophobic
region. Integral proteins float in this sea of lipid, held by hydrophobic interactions
with their non-polar amino acid side chains. Both proteins and lipids are free to move
laterally in the plane of the bilayer, but movement of either from one leaflet of the
bilayer to the other is restricted. The carbohydrate moieties attached to some
proteins and lipids of the plasma membrane are exposed on the extracellular surface
of the membrane.
Membrane proteins
Integral proteins are embedded in
membrane and often span the
bilayer
Proteins can span the membrane
via alpha helices composed on nonpolar side chains
(bacteriarhodopsin) or beta
sheets composed of non-polar side
chains (bacterialporin)
Peripheral proteins are primarily
bound to the head groups by ionic
and hydrogen bonds. These polar
interactions can be altered by
change in pH
Bacteriorhodopsin
Bacterialporin
Caveolin forces inward curvature of a membrane.
Each caveolin monomer has a central hydrophobic domain and three long-chain acyl
groups (red), which hold the molecule to the inside of the plasma membrane. When
several caveolin dimers are concentrated in a small region (a raft), they force a
curvature in the lipid bilayer
Phospholipid movement
FRAP
Lipids and proteins are in constant motion via lateral diffusion (raft).
Saturated fatty acids favor a rigid membrane
Double bonds of unsaturated fatty acids in membranes disrupts
ordered packaging of fatty acids and increases mobility of membranes.
Cholesterol forms complexes with specific sphingolipids forming thick
stable structures called lipid rafts
Transport
Ion movement
Channels and Carriers
Transmembrane diffusionchannels
In simple diffusion, removal of the
hydration shell is highly endergonic,
and the energy of activation (ΔG‡)
for diffusion through the bilayer is
very high
A transporter protein reduces the
ΔG‡ for transmembrane diffusion of
the solute. It does this by forming
noncovalent interactions with the
dehydrated solute to replace the
hydrogen bonding with water and by
providing a hydrophilic
transmembrane pathway.
Channels
animal cell membranes contain a very diverse set of ion channels.
Leakage channels are simplest type, permeability is constant. -potassium and chloride channels.
Ligand-gated ion channels are channels whose permeability is increased when chemical ligand
binds the channel. GABA receptor binds GABA and allows Cl to flow into nerve cells
Voltage-gated ion channels are channels whose permeability is influenced by the membrane
potential. NMDA receptor allows Ca to flow when electrical potential increases
Transmembrane potential is the difference in voltage between the interior and exterior of a cell.
Transport
Can be active (energy
requiring) or passive
Glucose transport
Glucose in blood plasma binds to a stereospecific site on T1
A conformational change from glucoseout • T1 to glucosein • T2, effecting the
transmembrane passage of the glucose
Glucose is released from T2 into the cytoplasm
This is facilitated diffusion
Membrane transport
Transporter proteins pump molecules across membranes
Small molecules cross a membrane based on a concentration gradient and their solubility
in the membrane
Lipophilic molecules like cholesterol pass by diffusion. Polar molecules like K+ cannot.
Membrane proteins form channels in the membrane that allow K+ to pass through via
passive transport.
K+ ion entering the channel can pass for 22 A while remaining solvated with water
(blue).
The pore diameter narrows to 3A (yellow) and K+ shed their water and interact with
carbonyl groups of pore amino acids- Gly and Thr
Only specific ions can go through specific channels
HCO3 and Cl antiport
Primary and secondary active transport
In primary active transport the
energy released by ATP hydrolysis
drives solute movement against an
electrochemical gradient
In secondary active transport, a
gradient of ion- often Na+, has
been established by primary active
transport.
Movement of Na down its
electrochemical gradient now
provides the energy to drive
cotransport of a second solute (S)
against its chemical gradient.
An electrochemical gradient is a spatial gradient across a membrane ofelectrical potential and chemical concentration.
Both components are due to ion gradients.
Active Membrane transport
Transporter proteins pump molecules across membranes
To pump Na+ against a concentration gradient (from areas of low Na+ conc to areas of
high Na+ conc) requires energy. Proteins in membrane use energy to move Na+ up a conc
gradient via active transport.
Active transport of Na+ out of cells and K+
into cells uses a Na+-K+ ATPase. Most ATP
in cells is used to perform this transport.
This Na+ ion gradient allows muscle cells to
be electrically excitable and contract.
K+ is a secondary antiporter.
Na K ATPase
Secondary transport
The direction of movement of Na and Ca ions (either inward or outward) depends upon the
electrical potential and the chemical gradient for the ions.
Transport
During ventricular systole (contraction)- the myocytes are depolarized (interior is less negative 60 millivolt) and have a positive membrane potential. The exchanger works such that Na + leaves
the cell and Ca++ enters the cell through the exchanger. Ca++ also enters the cell via Ca channels
and Na+ also leaves the cells via the Na/K ATPase pump.
Ca++ bind to the myofilaments activating contraction.
When the membrane potential is negative (interior is negative -80millivolt), the exchanger
reverses action and transports Ca++ out as Na+ enters the cell.
Thus during ventricular diasole (resting cells or relaxation of muscle)- the cells are polarized, Ca++
leaves the cell through the exchanger as well as by Ca-ATPase pumps. The flow of Na+ into the
muscle and Ca+ out of the muscle, terminates contraction.
The exact mechanism by which this exchanger works is unclear. It is known that calcium and
sodium can move in either direction via the exchanger.
Contraction-
more Na outside
more Ca inside
Relaxation-
more Na inside
more Ca outside
Transmembrane potential is the difference in voltage between the interior
and exterior of a cell.
Transport
Ca+
Na+-Ca+
Exchanger
Ca+
Ca+
Ca+
In heart failure, muscle contraction stops.
In heart failure, drugs (digitalis) are given that inhibit the Na+ATPase pump. Inhibition
of the pump increases Na+ in cells. This affects the exchanger because it normally
relies on low Na+ in the cell to pull more Na+ into the cell simultaneously pumping Ca+
out of the cell.
Now since the ATPase is inhibited, Na+ in the cell increases. This reduces the activity
of the exchanger. In the presence of the drug, there is a reduced Na+ gradient which
results in slower Ca+ expulsion from cell. This leads to increased Ca+ in the cells which
causes cells to contract more.
CFTR is a Cl- transporter in epithelial cells in the lungs. Reduction of Cl transport leads
to CF
CFTR
Pump
Membrane fusion