Module 8 - Lipids:

Lipids - General:
Structural Characteristics

Lipids:
- Are a diverse family of compounds that share the defining feature of insolubility in
water
- Category tends to be a catch-all for anything hydrophobic and insoluble in
water
- Tend to be of lower molecular weight than other classes of biomolecules
- Are distinct from other classes of biomolecules in that they form aggregates rather
than polymers
- They associate non-covalently in an aggregate

Functional Characteristics

Lipids play a number of diverse biological function including:

- Energy storage (fat in animals, oil in plants)
- Structural components of membranes
- There is more structural and functional diversity than what we give credit for
- Active roles
- Signalling (intracellular and extracellular)
- Enzyme cofactors and vitamins

Fatty Acids are Hydrocarbon Derivatives:

Fatty acids (general):
- Hydrocarbon w/ carboxylic head
- Carboxyl group and a hydrocarbon tail
- Carboxyl group has a charge associated w/ ir, hydrogen bonding capabilities,
is a polar group
- Hydrocarbon tail - just carbon and hydrogen, no charge, no hydrogen bonding
capabilities, is a non-polar hydrophobic group
- Is an amphipathic molecule
- Differ in length and degree of saturation
- Usually an even number of C’s (12-24)

Double bonds within fatty acids: (within hydrocarbon tails)

- Saturated (no double bonds present in tail)
- Unsaturated (1 double bond present in tail)
- Polyunsaturated (multiple double bonds in tail)
- Double bonds usually cis configuration (on the same side → introduce strong kinks)
- Double bonds usually separated by a methylene group (CH2), separate double bonds
Fatty Acid Nomenclature:
The nomenclature of fatty acids addresses three points of potential variability
- Length of tail (counting the number of carbons that is present)
- Presence or absence of double bonds within the tail (number of double bonds)
- Location of double bonds

(# carbons: #double bonds, 𝚫 double bond position)

- Position of double bonds indicated by 𝚫n, where n is the lowest numbered carbon
involved in double bond
- Carbon of the carboxyl group is the carbon one

Example one:
- It has 18 carbons
- It has 1 double bond
- Starting from the carbon 1 (carboxyl carbon), position of double bond is at C1
- = 18: 1: 𝚫9

Example two:
- It has 16 carbons
- It has 0 double bonds
- = 16: 0

Fatty Acid Structure:

- Hydrocarbon tails of fatty acids associate through hydrophobic and van der Waals
interactions
- Long chains have stronger associations than short chains
- Saturated chains (no double bonds) have stronger associations than
unsaturated
- Double bond causes a kink and cannot straighten out, therefore making
it harder to pack together
- What determines their ability to form solid structures is the length and the
double bonds
- Saturated fats are bad bc they’re more likely to form solids - they build up and
form plaques in your cardiovascular system
Association of Fatty Acids:
- The melting temperature of a fatty acid mixture reflects the length and degree of
saturation of the hydrocarbon tails
- Longer tails are more likely to form solids
- Double bonds have a greater influence than the length of the tail on fatty acid
associations
- The more double bonds introduced, the lower the melting temperature will
become
Fats and Oils as Energy Storage Molecules:
- Lipids represent critical long term energy storage molecules for plants and animals
- Glycogen stores short term energy storage
- Lipids occupy most of the intracellular space in adipocytes, the energy storage cells in
animal tissues
- Specialized cells called Adipocytes contain a big storage area for storage of
lipids
- The storage of fat under the skin also provides an insulating function for cold weather
animals
- Having a fat layer is like having a winter coat under your skin - keeps you
warm
- Fatty acids required for energy are storage as triacylglycerols

Triacylglycerols are Fatty Acid Esters of Glycerol:

- Triacylglycerols are the storage lipids in animals and plants
- Three fatty acids linked to glycerol through ester linkages
- Glycerol is a 3 carbon molecule, each carbon linked to a hydroxyl group and a
hydrogen (it's a carbohydrate)
- To each hydroxyl group we are linking on a fatty acid
- We’re taking the carboxyl group of the fatty acid and linking it onto a
hydroxyl group → called an ester linkage
- Simple triacylglycerols have the same three fatty acids at each position, complex
triacylglycerols have different fatty acids (differ in saturation and length)
- The ester linkage removes the polar carboxyl group to make a more hydrophobic
molecule
- When forming the ester linkage, we are getting rid of the negative charge that
previously existed on the carboxyl group
- This makes the molecule less polar
- This is what makes them long term storage units → they are non polar
molecules and have less water associated with them
A Perspective on Energy Storage Molecules:
- Different energy storage molecules serve different biological roles
- Fats represent the key molecules for long term energy storage
Source Duration

ATP < 1 second

Carbohydrate One day

Fats Many weeks

- On a gram per gram basis, there is 6x as much energy in fats than carbohydrates
- What are the characteristics of lipids that make them so effective as long term energy
storage molecules?

A Perspective on Energy Storage Molecules:

- Low oxidation state: Less oxygenated fuels burn more efficiently; triacylglycerols
have lower oxygenation state than carbohydrates
- Fats have more energy on a gram to gram basis because they are in an less
oxygenerated state
- Low hydration state: lipids are hydrophobic w/ limited interaction w/ water
providing a more compact, dehydrated energy storage form
- Hydroxyl groups are everywhere in a carbohydrate, therefore there is a lot of
water molecules. → Glycogen is a highly hydrated structure
- This means that we have to carry around the water weight w/ the
glycogen, and water contributes nothing in terms of energy
- In Triacylglycerol they are not carrying around water bc they are hydrophobic.
They are dehydrated → don’t have to carry around water weight

Making Soap from Fat:

- Treatment of fat w/ a strong base breaks the ester linkages to release free fatty acids
- This process is called saponification
- The amphipathic properties of free fatty acids make them effective in solubilization of
hydrophobic substances
- Fatty acids function as detergents and soaps through formation of micelles that
capture hydrophobic molecules

Better Living Through Science?

- A molecule that looks and tastes like fat, but cannot be processed by our digestive
system, has potential as a dietary substitute
- Olestra consists of 8 fatty acids linked to a sugar group
- Olestra looks and tastes like fats we crave, but passes through the digestive system
w/o being absorbed (no calories)
- We don’t have the machinery to break it down
- While olestra offered a low calorie alternative, there are some side effects . . .
Waxes Serve as Energy Reserves and Water Repellants:
- Waxes are esters of long chain fatty acids and long chain alcohols
- Waxes are very water insoluble and have high melting temps (60 - 100 C)
- Are extremely hydrophobic, perhaps one of the most hydrophobic substances
on earth
- They are widely distributed in nature as protective waterproof coatings on leaves,
fruits, animal skin, and feathers (like ducks → feathers are waterproof)

Structural Lipids in Membranes:

- Membrane bilayers define cells and regulate the composition of the intracellular
environment
- Although the structure seems simple, their structures are very complex
- There are dozens and dozens of different lipid molecules that are incorporated
into the structure → this relates to their properties (different functions)

- Formation of membranes in a spontaneous consequence of properties of the molecule

that compose them
- All of the membrane lipids have a polar head group and 2 hydrocarbon tails
associated w/ them
- This is important bc the overall shape of the structure of a polar head
and a single tail is a wedge . . . its most likely structure is a micelle
(this isn’t very useful for forming a membrane
- Once there is a head w/ two hydrocarbon tails, you have an area where
the polar head group and hydrocarbon tails are equal, and is more of a
rectangle than a wedge (now will spontaneously form a membrane)

Structural Lipids in Membranes:

- The lipid component of membranes tend to have similar overall shapes and properties
- Two hydrophobic tails and a hydrophilic head group
- Membrane lipids can be classified based on their backbone (glycerol vs sphingosine)
or by their polar head groups (phospho vs glyco)
- One category uses the glycerol backbone → building on a diacylglycerol
- Second category uses the sphingosine →
- Both have two hydrocarbon tail and a polar head → differ on the backbone

- Second way to classify is whether or not they have phosphate groups or sugar
groups in the polar head
Glycerophospholipids:
- Most abundant lipids in membranes
- Glycerol backbone w/ a phosphate at the C3 position (Glycerol-3-phosphate)
- Start w/ a molecule of diacylglycerol (fatty acids attached to carbon 1 and 2);
on carbon 3 position, there will be a phosphate group present
- Glycerol-3-Phosphate + 2 fatty acids = phosphatidate (or diacylglycerol 3 -
phosphate)
- Diacylglycerol - 3 - phosphate is also called phosphatidate or phosphatidic
acid
- The Phosphate group is the point of attachment for a variety of polar head groups

Glycerophospholipids: Continued . . .
- Variety of polar head groups for the glycerophospholipids
- Different heads can be linked on to glycerophospholipids
- Head groups can carry positive, negative, or neutral charge
- All are polar, but can carry different charges
- Most carry a charge
- Different head groups are likely associated w/ specialized function
- E.g. phosphatidylinositol is involved in intracellular signal transduction

Galactolipids and Sulfolipids:

- Phosphate availability is often limiting to plants → when there is not phosphate, we
can use sulfur groups or sugar groups (to attach to C3)
- To conserve use of phosphate for more critical applications (like nucleic acids) some
plants use sugar and sulphate polar head groups
- Plant cells often contain galactolipids
- One or two galactose groups liked to C3 of diacylglycerol
- Plants also contain sulfolipids

Sphingolipids:
- Sphingolipids are derived from sphingosine, a long chain amino alcohol
- Structurally sphingosine is similar to monoacylglycerol (a single hydrocarbon
attached to a three carbon backbone)
- Single fatty acid linked by amide bond to form ceramide
- We’re going to take a fatty acid and link it onto the amino group (linking a
carboxyl group w/ an amino group)
- This is forming the same sort of linkage as a peptide bond
- Structurally ceramide is similar to diacylglycerol

- Like glycerophospholipids, a variety of polar head groups can be attached to ceramide

- Common sphingolipids include:
- Sphingomyelin - phosphocholine
- Cerebrosides - glycosphingolipid (single sugar unit)
- Gangliosides - glycosphingolipids (multiple sugar units)
Glycosphingolipids Determine Blood Type:
- Cells are recognized as ‘self’ vs ‘non self’ based on patterns of surface exposed
carbohydrates
- Transfusion of an incompatible blood type causes severe immunological reaction
- Different blood types (A, B, O) reflect different sugar patterns as the head groups of
sphingolipids

Unique Membrane Lipids:

- Archaebacteria (extremophiles) live under conditions of high temp, pH and ionic
strength making it a challenge to maintain membrane integrity
- The membrane lipids of these extremophiles often contain:
- Ester linkages
- Branch points within the hydrocarbon tails - allow for a more complex
meshwork and giving a more durable structure
- Membrane spanning hydrocarbon tails composed from a single molecule

Sterols:
- Sterols are structural membrane lipids
- Sterols contain four fused ring steroid nucleus: 3 siz carbon rings and 5 carbon D ring
- These rings come together to form a steroid nucleus
- Ring system is rigid and nearly planar
- Blocky group w/ very little flexibility to it
- Non polar, no charge, no hydrogen bonding capability
- Sterols also serve as precursors for many biologically active products, for example,
testosterone

Cholesterol:
- One of the most famous sterols
- Cholesterol serves a number of critical biological functions such as mediating
membrane fluidity
- Also serves as a precursor of steroid hormones and bile salts
- Serves a precursor for important molecules such as glucocorticoids, sex
hormones, etc
- These are signalling molecules that are essential to your health →
contradictory to its stereotype

Cholesterol is also a structural component of membranes

How much cholesterol is a bad thing?
- The body can make its own cholesterol, as well as we can consume cholesterol
through food
- The discovery of statins (drug molecule) that targets one of the key enzymes involved
in the production of cholesterol (endogenous cholesterol)
- Inhibits cholesterol production and will reduce your cholesterol
- However, cholesterol is involved in many biological actions, including
lowering inflammation
- When people were lowering cholesterol through statins, many dangerous side
effects were coming out
- Question is: when do we start taking statins, and how much cholesterol is bad?

- Cholesterol is rigid, so in a membrane, the hydrocarbon tails that wave around hit
cholesterol and it dampens out their motion

Lipids as Signals, Cofactors, and Pigments:

- So far the lipids we have been considering have primarily passive roles (energy
storage and membrane structure)
- Active roles for the lipids include:
- Intracellular signalling molecules
- Hormones
- Enzyme cofactors
- Pigments
- Vitamins

Phosphatidylinositols Act as Intracellular Signal:

- Phosphatidylinositol 4,5 - bisphosphate on the inner membrane face
- A challenge to the cell is the membrane separates the inside from the outside -
this means on the inside of the cell, it has trouble seeing what’s going on
outside
- Signal transduction = taking an extracellular signal and turning it into a
intracellular response
- Phosphatidylinositol 4,5 - biphosphate is on the inner face (inside of the cell)
→ in response to an extracellular signal, there is going to be activation of the
enzyme phospholipase C
- Activation of phospholipase C in response to an extracellular signal triggers the
cleavage of head group to produce inositol 1, 4, 5 triphosphate which increases Ca 2+
- It recognizes and cuts the point of linkage of the polar head group to the
diacylglycerol ( i.e. it will cut off the polar head group)
- The polar head group will float away and will serve as as a signalling
molecule → it does this by binding to a receptor on the endoplasmic reticulum
(ER) and when it does that, it causes the Er to release calcium into the cytosol
- Calcium then activates protein-kinase C
 - Diacylglycerol gets left behind in the membrane, and will diffuse within the
membrane. The protein-kinase complex is associated w/ the membrane, and
the diacylglycerol will be able to bind to regulatory sites on it which will cause
further activate the protein-kinase C complex (which adds phosphate groups
onto things)
- Both Ca 2+ and diacylglycerol activate specific intracellular pathways and processes
- By adding phosphate groups onto things
This is a dual function molecule → it can contribute to the overall
architecture of the membrane, but can also serve a higher order role in signal
transduction

Eicosanoids:
Eicosanoids
- Paracrine hormones (act on cells near point of production)
- They act where they are produced
- Derivatives of C20 polyunsaturated fatty acids (arachidonic acid)
- Three classes of eicosanoids
- Have completely distinct biological functions, but are derived from the exact
same molecule (arachidonic acid)

1) Prostaglandins - constriction of blood vessels

a) When having fever, inflammation, or pain, its due to production of
prostaglandins
2) Thromboxanes - involved in blood clot formation
a) You need to maintain a certain fluidity of blood, as well as have blood clot
formation when bleeding
3) Leukotrienes - smooth muscle contraction
a) Involved in smooth muscle contraction → such as digestion, where they
contract muscle to digest foods

- We start w/ arachidonic acid, there’s a couple of shared steps that then go on to the
formation of prostaglandins or thromboxanes, or there’s a different set of steps that
form leukotrienes
- When we take aspirin, it blocks enzymes that are a common step of both
prostaglandins and thromboxanes
- It will decrease levels of prostaglandins so you’ll have less pain and fever
- However, it also will decrease production of thromboxanes → blood thinner
- Something that is administered to people at high risk of stroke or heart failure,
is aspirin to make the blood thinner to make it easier on the heart to pump
blood
Steroid Hormones:
- Hydrophobic oxidized sterol derivatives
- Effects how it will be carried through blood
- Bc they are very hydrophobic, they have very low solubility in water/ blood →
need carrier proteins
- Carried through bloodstream by carrier proteins
- Pass through plasma membrane to bind receptors in the nucleus
- When molecules are based on a sterol backbone, they are very hydrophobic,
and can pass directly through the outer membrane and nuclear membrane to
influence patterns of transcription directly
- They can bind to transcription factors associated w/ the nucleus
- Alter patterns of gene expression and metabolism

Lipid Vitamins:
- Four lipid vitamins: A, D, E, and K
- Fat soluble vitamins – differ from water vitamins in terms of risk
- If you take in excess of water soluble vitamins (such as C and B), you’re just
going to excrete them out
- If you take in excess of fat soluble vitamins, they tend to be stores in fatty
tissues and will accumulate
- All contain rings and long, aliphatic side chains
- All are highly hydrophobic
- The lipid vitamins differ widely in their functions

Vitamin D:
- Vitamin D regulates Ca 2+ uptake and deposition
- Uptake from the gut and deposition into the skeleton
- Skeleton is dynamic and is always turning over. A main component of the
bone structure is calcium
- Vitamin D can be obtained from the diet or produced endogenously
- Endogenous production occurs in a series of reactions, one of which requires UV light
- Vitamin D can be made in the body through exposure to sunlight
- In Canada, we often have vitamin D deficiencies bc we are not being exposed
to UV light
- This is especially a concern w/ Canadian babies, bc their skeleton is
developing quickly. → recommended to supplement their diet w/ vitamin D
- Insufficient vitamin D is associated w/ skeletal defects (Rickets)
- This can reversed (due to the fact that bone structure is always being turned
over) w/ improvements of diet and exposure to sunlight
- Excessive vitamin D can cause calcification of soft tissues
- Darker skin helps to protect from UV light to avoid excessive endogenous
vitamin D production
Vitamin A
- Vitamin A is obtained from liver, egg yolks, and milk products
- Some animals have sufficient vitamin A in their lives to present a danger to humans in
they were to consume them
- Vitamin A exists in 3 forms: alcohol (retinol), aldehyde, and retinoic acid
- Retinal (aldehyde) is a light sensitive compound w/ a role in vision
- Red eye in photos results from retinal

Vitamin E (alpha-tocopherol)
- A reducing reagent that scavenges oxygen free radicals
- May prevent damage to fatty acids in membranes
- Often used as an additive in cosmetics
- Deficiency causes scale skin, muscular weakness and sterility

Vitamin K:
- Required for synthesis of blood coagulation proteins
- Allows blood to form clots
- K is for coagulation
- In 1920s warfarin was used as rat poison where it caused rodents to suffer
uncontrolled bleeding
- Rats bump into things and essentially bleed out on the inside bc they can no
longer form blood clots
- Vitamin K analogues (such as warfarin) are now given to individuals who suffer
excessive blood clotting