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Lipids and Membranes
Chapter 9
Lipids
Lipids fats oils…. Greasy molecules, mmmmm donuts.
Several levels of complexity:
• Simple lipids - a lipid that cannot be broken down to smaller
constituents by hydrolysis.
– Fatty acids, waxes and cholesterol
• Complex lipids - a lipid composed of different molecules held together
mostly by ester linkages and susceptible to cleavage reactions.
– acylglycerols - mono, di and triacyl glycerols ( fatty acids and
glycerol)
– phospholipids (also known as glycerophospholipids) - lipids which are
made of fatty acids, glycerol, a phosphoryl group and an alcohol.
Many also contain nitrogen
– glycolipids (also known as glycosphingolipids): Lipids which have a
spingosine and different backbone than the phospholipids
• Phospholipids:
• Two fatty acids covalently
linked to a glycerol, which is
linked to a phosphate.
• All attached to a “head
group”, such as choline, an
amino acid.
• Head group POLAR – so
hydrophilic (loves water)
• Tail is non-polar –hydrophobic
• The tail varies in length from
14 to 28 carbons.
Several levels of complexity:
• Precursor and derived lipids - these include several of the initial
long chain hydrocarbons and other molecules that make up lipids,
such as ketone bodies.
Lipids are defined as those molecules soluble in organic solvents and not
water
Properties of fatty acids
 Typically found as esters , mono,
di and tri -acylglycerols (good old
fashioned fat)
 Free fatty acids are found
associated with carrier proteins
such as albumin in blood
 These are amphipathic molecules
with various carbon chain lengths
 Can be up to 30 carbons long but
generally less than 20

Most common 12-24 carbons long
Properties of fatty acids
- Saturated fatty acids are
saturated with hydrogen. No
double bonds.
- 1/2 of animal fat has one
desaturation
- Unsaturated fatty acids contain at
least one double bond separated by
a methyl group. These are
typically cis- in nature. Trans
unsaturated fatty acids have been
linked to cancer and heart disease.
(the strength of the proof is not
clear).
- Most double bonds are separated
by two carbons
- Polyunsaturated fatty acids - duh
Nomenclature
- Trivial (greek) system, IUPAC system, omega system
- Common name most commonly used (trivial system)
- The systematic name for saturated acids ends in -anoic.
Unsaturated fatty acids ends in -enoic.
- The number one carbon is the carboxyl carbon
– Carbon #1 = alpha carbon
– Carbon #2 = beta carbon
– Carbon #3 = gamma carbon
- Omega vs. delta fatty acids
– Double bonds counted from the first carbon are delta
desaturations
– Double bonds counting from the methyl end are the omega
desaturations
– Omega nomenclature helps to identify physiological important
fats w3 - w6 (can not be intraconverted in body)
Nomenclature
- Common name most commonly used
- The systematic name for saturated acids ends in -anoic. Unsaturated fatty
acids ends in -enoic.
- The number one carbon is the carboxyl carbon
– Carbon #1 = alpha carbon
– Carbon #2 = beta carbon
– Carbon #3 = gamma carbon
- Omega vs. delta fatty acids
– Double bonds counted from the first carbon are delta desaturations
– Double bonds counting from the methyl end are the omega desaturations
Trivial
Oleic Acid
IUPAC
Carboxyl
Omega
Nomenclature
- Common name most commonly used
- The systematic name for saturated acids ends in -anoic. Unsaturated fatty
acids ends in -enoic.
- The number one carbon is the carboxyl carbon
– Carbon #1 = alpha carbon
– Carbon #2 = beta carbon
– Carbon #3 = gamma carbon
- Omega vs. delta fatty acids
– Double bonds counted from the first carbon are delta desaturations
– Double bonds counting from the methyl end are the omega desaturations
Trivial
Oleic Acid
IUPAC
9-octadecenoic acid
Carboxyl
Omega
Nomenclature
- Common name most commonly used
- The systematic name for saturated acids ends in -anoic. Unsaturated fatty
acids ends in -enoic.
- The number one carbon is the carboxyl carbon
– Carbon #1 = alpha carbon
– Carbon #2 = beta carbon
– Carbon #3 = gamma carbon
- Omega vs. delta fatty acids
– Double bonds counted from the first carbon are delta desaturations
– Double bonds counting from the methyl end are the omega desaturations
Trivial
IUPAC
Oleic Acid - 9-octadecenoic acid
Carboxyl
18:1 9
Omega
Nomenclature
- Common name most commonly used
- The systematic name for saturated acids ends in -anoic. Unsaturated fatty
acids ends in -enoic.
- The number one carbon is the carboxyl carbon
– Carbon #1 = alpha carbon
– Carbon #2 = beta carbon
– Carbon #3 = gamma carbon
- Omega vs. delta fatty acids
– Double bonds counted from the first carbon are delta desaturations
– Double bonds counting from the methyl end are the omega desaturations
Trivial
IUPAC
Oleic Acid - 9-octadecenoic acid
Carboxyl
Omega
18:1 9 18:1 9
Nomenclature
- Common name most commonly used
- The systematic name for saturated acids ends in -anoic. Unsaturated fatty
acids ends in -enoic.
- The number one carbon is the carboxyl carbon
– Carbon #1 = alpha carbon
– Carbon #2 = beta carbon
– Carbon #3 = gamma carbon
- Omega vs. delta fatty acids
– Double bonds counted from the first carbon are delta desaturations
– Double bonds counting from the methyl end are the omega desaturations
Trivial
IUPAC
Oleic Acid - 9-octadecanoic acid
Carboxyl
Omega
18:1 9 18:1 9
Linoleic Acid - 9, 12-octadecenoic acid
18:2 9,12 18:2 6
Nomenclature
- Common name most commonly used
- The systematic name for saturated acids ends in -anoic. Unsaturated fatty
acids ends in -enoic.
- The number one carbon is the carboxyl carbon
– Carbon #1 = alpha carbon
– Carbon #2 = beta carbon
– Carbon #3 = gamma carbon
- Omega vs. delta fatty acids
– Double bonds counted from the first carbon are delta desaturations
– Double bonds counting from the methyl end are the omega desaturations
Trivial
IUPAC
Oleic Acid - 9-octadecenoic acid
Carboxyl
Omega
18:1 9 18:1 9
Linoleic Acid - 9, 12-octadecenoic acid
18:2 9,12 18:2 6
Essential FA- those that humans can not make but are required to
Sustain growth - Linolenic 3 and Arachadonic 6
Common FA Names
Carbon #
12
14
16
18
16
18
20
Trivial Name
Lauric acid
Myristic acid
Palmitic acid
Stearic acid
IUPAC
Dodecanoate
Tetradecanate
Hexadecanoic acid
Octadecanoic acid
12:0
14:0
16:0
18:0
Palmitoleic acid 9-Hexadecenoic acid
16:1 9
Oleic acid
9,12 Octadecadienoic acid 18:2 9,12
Arachidonic acid
5,8,11,14 Eicosatetraenoic 20:4 5,8,11,14
Melting points and membrane fluidity. Both length and level of
unsaturation determine the stability of the hydrophobic
interactions and thus shift the transition phase - melting point
of membranes
- Double bonds - usually cis. This results in bends the chain.
- Reductions in hydrophobic effect reduce energy required to
disrupt the crystalin structure of a membrane or oil. Think of
animal fat with lower unsaturated fatty acids - butter and plant
oils that are polyunsaturated, corn oil.
- The longer the fatty acids the higher the melting point.
- Again the more hydrophobic interactions effects the more the
energy it takes to break the order. Decreases in the packing
efficiency decreases the mp
- The van der Waals forces then come apart more easily at lower
temperatures.
- Animal alter the length and unsaturated level of the fatty acids
in lipids (cholesterol too) to deal with the cold temps
Esterification
•
The general name for a chemical reaction in which two reactants
(typically an alcohol and an acid) form an ester as the reaction
product. Esters are common in organic chemistry and biological
materials, and often have a characteristic pleasant, fruity odor.
•
This leads to their extensive use in the fragrance and flavour industry.
•
Esterification is a reversible reaction. Hydrolysis- literally "water
splitting" involves adding water and a catalyst (commonly NaOH) to an
ester to get the sodium salt of the carboxylic acid and alcohol.
•
As a result of this reversibility, many esterification reactions are
equilibrium reactions and therefore need to be driven to completion
•
Esterifications are among the simplest and most often performed
organic transformations.
Lipids II
Triacylglycerols (Triglycerides)
- Esterification of glycerol takes place at each of the alcohol
moieties
- This is the major form of fatty acid storage. Found in adipose
tissue in specialized cells. These fat cells are filled with TAGs
and can grow in size.
- Release (hydrolysis) of fatty acids occurs under the control of
hormone sensitive lipase
- Fatty acids released into the bloodstream are carried via
albumin.
Triglycerides
- The acylated acyl chains are typically different at each position
of glycerol.
- Each of the three carbons on glycerol are different. The 1 and
3 carbons are steriochemically different and recognized as such
by enzymes. The carbons are labeled sn1, sn2, sn3
Triacylglycerols (TAGS)
- TAGs DAG and MAG. The sn3 carbon is typically removed
first.
- Saponification - hydrolysis by bases (KOH - potash) cleaves the
fatty acids from glycerol. Using KOH from wood ashes and
animal fat creates old-fashioned soaps. (divalent cations in
hard water cause the ppt of soaps)
- There is a large amount of energy available in the storage of
TAGs. These are highly reduced molecules with low amounts of
water associated. The result is a molecule that can undergo
repeated oxidation steps transferring the energy to form ATP.
The low water content increases the gram per gram energy
available vs. carbohydrates
- Polar bears can go for up to 8 months without eating. Most of
energy and water comes from the fats produced by the bear
and the fat ingested from seals.
Phospholipids
- Phospholipids are the largest constituent of the membrane
- Phospholipids serve two important purposes (different than TAGs)
structural and signaling. Although DAG is an important signaling
molecule as well
- You should know the different signaling lipids and there functions
- There are two general classes of phospholipids
- Glycerophospholipids, phospholipids or phosphate esters (same thing)
and the sphingolipids.
- Glycerophospholipids
-
- major lipid comonent of biological membranes
The sn 1 and sn2 positions on glycerol are esterified (red). The sn2 carbon
is typically unsaturated. Differences occur between tissues and organism
-The sn3 position is phosphorylated
(blue)
-The phosphoryl group can be
-modified with several different
alcohols.
-Common classes are shown in Table
9.2 pp249 of 3rd ed
-LEARN THEM
- Phosphatidic acid
high concentrations
is the base glycerophospholipid but is not found in
-Common head groups (the alcohol
derivatives) are
-serine, choline, ethanolamine,
glycerol and inositol.
•This divides glycerophospholipids
into
•basic
•neutral
•acidic lipids.
-The nomenclature is 1-acyl-2acyl-3-phosphatidyl "head group".
-Biological use –lung surfactant
phospholipases
• These are a set of hydrolytic enzymes which act on both the fatty
acid chains and the head group
• Phospholipase A2 excises C2 fatty acid group (red) forming a
Lysophospholipid - recognizes the sn-2 acyl bond
– Powerful detergent which lyses cells by disrupting membranes
• Bee and snake venoms rich in this enzyme
• Inflammatory responses
phospholipases
• Phospholipase C cleave phospholipids just before the phosphate group
• plays an important role in eukaryotic cell physiology, particularly
lipid signaling pathways in a calcium-dependent manner
• proliferation, differentiation, apoptosis, cytoskeleton remodeling,
vesicular trafficking, ion channel conductance, endocrine function
and neurotransmission.
Phospholipase C
•
Phospholipase C cleave phospholipids just before the phosphate group
generating inositol triphosphate (IP3) and diacylglycerol (DAG).
•
IP3 is soluble, and diffuses through the cytoplasm and interacts with IP3
receptors on the endoplasmic reticulum, causing the release of calcium and
raising the level of intracellular calcium.
•
DAG remains tethered to the inner leaflet of the plasma membrane due to
its hydrophobic character, where it recruits protein kinase C (PKC), which
becomes activated in conjunction with binding calcium ions
phospholipases
• Phospholipase D cleave phospholipids just after the phosphate group,
form phosphatidic acid (PA), releasing the soluble choline headgroup
into the cytosol
• Phosphatidic is extremely short lived and is rapidly hydrolised by the
enzyme PA phosphohydrolase to form diacylglycerol (DAG).
•
Phospholipids preferentially hydrolyze substrates that are located in
bilayer membreases. They carry our interfacial catalysis at the
boundry of water and a lipid phase
Plasmalogens
Different than the other
phosphoglycerides Has an ether lipid where the first
position of glycerol (sn1)binds a vinyl
residue (from a vinyl alcohol) with
the double bond next to the ether
bond.
The second carbon has a typical
ester-linked fatty acid, and the third
carbon usually has a phospholipid
head group like choline
These are typically involved in platelet aggregation & vasiodialation.
Protect the heart
Sphingolipids
-
-
Another class of phospholipids
Do not contain glycerol as a backbone instead an amino alcohol called
sphingosine.
Add one fatty acid and it is ceramide
- regulates differentiation, proliferation, programmed cell death
Add an head group (choline or ethanolamine) and it is a sphingophospholipid
These are very different in location and concentration than the
glycerolipids
Eicosanoids
- These are a diverse group of hormonelike molecules produced in
nearly all mammalian cells
- Can be formed from the action of
Phospholipase A2
- Stem from the greek word eikosi meaning twenty
- Because they act on the same organ they are produced in they are
autocrines, vs a paracrine which act distal to the site of origin
- Most are derived from arachidonic acid 20:4
D5,8,11,14
-
Leukotrienes are hydroxylated fatty acid derivatives of arachidonate
- Initially found in leukocytes - white blood cells
- Often congugated
- Secreted by damaged cells during anaphylaxis
- Promotes bronchioconstriction and vasioconstriction
- Acts as a chemotractant to bring white blood cells to fight
infection
-
Aspirin inhibits
the formation of
cyclic ecosanoids
-
The Serine in
the active site
of the enyme
cyclooxygenase
is acetlyated by
aspirin
Prostoglandins have a
cyclopentane ring and is
hydroxylated at various
carbons.
There are several versions
each with a different effect.
Different types and
concentrations of
prostaglandins are found in
different tissues.
•Induce inflammation and cause
fever and pain
•Ovulation and uterine
contraction during conception
and labor
•Antiplatelet aggregation
•Vasiodialation
•Smooth muscle contraction
-
-
Thromboxanes (TxB)
produced by
platelets to cause
aggregation at sites
of cardiovascular
injury.
Leads to clot
formation and foam
cell formation
(platelets
differentiate into
cells that cause
plauques in arteries)
-
-
Thromboxanes produced by
platelets Alterations in double
bonds in arachidonate still leads
to TxB formation but they are
less able to aggregate platelets
These fatty acids are found in
some cold fish oils omega 3 fatty
acids
Prostacyclin produced
by blood vessels and
inhibit platelet
aggregation
- These are
antagonistic to
thromboxanes
- The omega 3 fatty
acids leads to a more
potent antiaggregant
activity
Steroids
- Cholesterol plays an important role in membrane fluidity and the
starting material for steroids and vitamin D
- Six rings three cyclohexane and one cyclopentane
-Modified with
hydrophobic
functional groups on
carbons 10,13 and
17
-Inflexible
hydrophobic bulky
molecule
--OH on the 3rd
carbon - makes the
molecules ampipathic
-Found in all tissues
in the membranes
often acylated at
the OH
Function in membranes
- Cholesterol broadens the phase change from solid to fluid or oil like state.
- The stiff ring decreases coiling and movement of the fatty acid tails in the
phospholipids. This can have two effects on fluidity
-Below the melting
point - cholesterol
is too bulky to fit
into the rigid
crystal state. This
increases the
melting point
-Above the melting
point the cholesterol
still restricts the
movement of the
fatty acid tails.
Thus the melting
point is decreased
• Atherosclerosis - heart disease where plaque form blockages in
blood flow. Specialized cells macrophages are converted to
foam cells where they are filled primarily with cholesterol and
cholesterol esters. Eventually these cells can calcify and
harden ultimately blocking the flow of blood to the heart.
• Precursor for the steroids
Steroid hormones - do not act by binding receptors like other
hormones. These are lipid soluble hormones that are
transported through the plasma and interstitial fluids bound to
steroid carrier proteins (SCP). Once to the cells, the steroid
crosses the membrane and binds specifically to a cytosolic
steroid receptor. The complex often travels to the nucleus and
acts at the level of altering DNA-> RNA ->Protein production.
(transcription)
Steroid hormones
•
Glucocorticoids involved in
reducing
inflammation, pain
and carbohydrate
metabolism.
-
Can bind to
proteins which act
then bind to DNA
and alter gene
expression and
protein production
•
Mineralcorticoids required for normal
kidney function in the
regulation of K+ and
Na+ ion filtration
•
Glucocorticoids,
mineralcorticoids
and some
androgens are
produced in
adrenal cortex small organ just
above the kidney.
Over 50 varieties
found in this
tissue
Regulation of blood pressure and volume
When sodium ions levels are high- so a
high blood volume a glucocorticord
(cortisol) makes the heart release atrial
natriuretic hormone (ANH)
Kidneys excrete sodium ions and water
follows. Volume and pressure return to
normal.
When sodium ions levels are low- a low
blood volume makes kidneys secrete
renin (ENZYME)
Adrenal cortex secretes a
mineralocorticoid (Aldosterone), which
makes the kidneys reabsorb sodium ions
and thus water. Volume and pressure
return to normal.
Sex steroids;
Androgens and
estrogens.
Structures are
related and
formed from the
other. Effect of
these are
hormonal. Source
is generally from
the gonadal
tissues.
Membrane dynamics - Formation of lipid bilayers - these structures form due to the
insolubility in water.
-
When enough lipids are present, micelles form.
Eventually these can
fill out enough to form a bilayer where the polar heads face the
aqueous phase and the hydrophobic tails are buried in the nonpolar
phase
- Lipids easily diffuse
lateraly but rarely "flip"
due to the changes in
entropy changes that
must accompany such
a switch.
New - Lipid rafts and caveolae
•
Lipid rafts - Lipid rafts are specialized membrane domains enriched in
certain lipids cholesterol and proteins.
– three types of lipid rafts; caveolae, glycosphingolipid enriched
membranes (GEM), and polyphospho inositol rich rafts.
– The main role of rafts is in signal transduction where the rafts act
as an anchor for signaling protiens to assemble into “scafolds” and
the raft also acts as a binding site for actin related proteins.
•
Caveolae - Caveolae are flask shaped invaginations on the cell surface
that are a type of membrane raft, these are cave shaped and associated
with proteins called caveolin. Involved in receptor internalization and cell
signaling
The fatty-acid chains of lipids within the rafts tend to
be extended and so more tightly packed, creating
domains with higher order. It is therefore thought that
rafts exist in a separate ordered phase that floats in a
sea of poorly ordered lipids. Glycosphingolipids, and
other lipids with long, straight acyl chains are
preferentially incorporated into the rafts.