Part I => CARBS and LIPIDS
§1.4 LIPIDS
§1.4a Lipid Classification
§1.4b Biological Membranes
Section 1.4a:
Lipid Classification
Synopsis 1.4a
- Lipids are hydrophobic molecules (such as fats, oils and waxes) that
usually harbor some degree of amphiphilic character—ie they have
both polar and apolar regions
- Unlike the other three major classes of biomolecules (proteins,
nucleic acids, and carbohydrates), lipids do not polymerize
- Lipids perform a wide variety of structural and regulatory functions—
such as gate keepers (lipid bilayers), energy reservoirs (fuels), and
chemical messengers (steroid hormones)—of the cell
- Biologically-relevant lipids can be subdivided into five major classes:
(1) Fatty acids—carboyxlic acids with long aliphatic tail
(2) Triglycerides—glycerol derivatives of fatty acids
(3) Phospholipids—phosphoglycerol derivatives of fatty acids
(4) Sphingolipids—derivatives of ceramides
(5) Steroidolipids (steroids)—derivatives of sterane
(1) Fatty Acids: Carboxylic Acids ᴙ Us!
- Fatty acids are carboxylic acids with a long aliphatic tail with
the molecular formula CxHy-COOH, where x is usually in the
range 10 < x < 30, and y depends on the degree of saturation
- Fatty acids are categorized according to whether they lack
(saturated) or harbor (unsaturated) one or more C=C bonds
- Fatty acids are assigned the x:m symbol, where x is the number
of C atoms and m is the number of C=C double bonds
- Saturated fatty acids harbor greater conformational flexibility
than their unsaturated counterparts due to the relatively free
rotation about each C-C bond
- Unsaturated fatty acids with one or more C=C double bonds exist as cis-trans stereoisomers—most
naturally-occurring unsaturated fatty acids harbor the cis-conformation (with the trans-conformer
being more dominant in processed foods—eg unnatural trans-fats!)
- Unsaturated fatty acids can adopt 2n cis-trans stereoisomers, where n is the number of C=C bonds
- Naturally-occurring fatty acids have an even number of C atoms (eg 12, 14, 16, 18, and so forth)—
they are biosynthesized via concatenation of C-C units!
- The melting point (mp) of fatty acids increases with increasing x but decreases with increasing m
(1) Fatty Acids: Common Members
x:m
(2) Triglycerides: Fatty Acid Esters of Glycerol
Esterification
(RCOOH)
- Fatty acids rarely exist in their free form and usually occur as esterified derivatives of glycerol—via
esterification of the carboxylic group (-COOH) of fatty acids with the hydroxyl (-OH) groups of glycerol
- Fatty acid esters (usually with different fatty acid R groups) are called triglycerides (or triacylglycerols)
- Most oils and fats in plants and animals are largely a mixture of various triglycerides—differing only in
the chemical nature of the fatty acid R groups—triglycerides are the major constituents of cooking
oils and fats
- Only difference between oils and fats is their state of matter (liquid versus solid) @ room
temperature—oils are usually rich in unsaturated fatty acids, while fats are largely composed of their
saturated counterparts
- Triglycerides are largely stored in the adipose tissue where they function as “high” energy
reservoirs—due to being more reduced (or less oxidized) than their carbohydrate and protein
counterparts, thereby yielding significantly more energy per unit mass upon oxidative metabolism
- Humans can survive on water alone for months—thanks to the “free energy” stored in triglycerides!
(2) Triglycerides: Common Members
A triglyceride with three different
fatty acids—palmitoleate (16:1),
linoleate (18:2), and stearate (18:0)
(3) Phospholipids: Fatty Acid Esters of Phosphoglycerol
Phosphorylation
(ATP)
Esterification
(RCOOH)
- Phospholipids (or glycerophospholipids) are fatty acid derivatives of phosphoglycerol (or
glycerol-3-phosphate)—with only two (designated C1 and C2) of the three C atoms of glycerol
esterified to fatty acid R groups
- Additionally, the phosphate moiety attached to C3 atom is derivatized with another functional
group called X (which is usually polar)
- Unlike triglycerides, phospholipids are thus highly amphiphilic (or amphipathic)—they harbor
partial characters of both hydrophobicity (hydrocarbon tails of fatty acids) and hydrophilicity
(phospho moiety):
amphiphilic => amphis (both/dual) + philia (attraction/compatibility)
amphipathic => amphis (both/dual) + pathos (to suffer/indulge/harbor)
- Such amphiphilic virtue of phospholipids renders them ideally suited to serve as major
components of “biological membranes”—and hence the feasibility of multicellular life!
(3) Phospholipids: Common Members
The “myo” prefix has nothing to do with the
“muscle” but rather myo-inositol indicates
one of many stereoisomers !
(3) Phospholipids: Unsaturated Chains are Bent
Phosphatidylcholine
(Chemical Structure)
Phosphatidylcholine
(3D Model)
(4) Sphingolipids: Derivatives of Ceramides
X
Esterification/
Etherification
(XOH)
Acylation
(RCOOH)
Ceramide
Sphingolipid
- Ceramides are fatty acid amides of sphingosine (an amino alcohol)—wherein a fatty acid group R
is acylated onto the –NH3+ group to generate a ceramide
- Sphingolipids are derivatives of ceramides in which the variable functional group X is conjugated
either via a phosphoester or ether linkage to one of the –OH groups
- Along with phospholipids, sphingolipids form a major component of biological membranes (with
particular abundance in the brain and around the central nervous system)—where they also play
key roles in signal transduction and molecular recognition
- Sphingolipids are subdivided into three major classes depending on the nature of moiety X:
X = phospho(choline/ethanolamine)
=>
Sphingomyelins (neuronal lipids)
X = Monosaccharide
=>
Cerebrosides (neuronal lipids)
X = Oligosaccharide*
=>
Gangliosides (brain lipids)
*One or more of these sugars must be a sialic acid (a 9-C sugar)!
(4) Sphingolipids: Major Classes
Cerebrosides and gangliosides are
also glycolipids—see §1.3
(4) Sphingolipids: Sphingomyelin Conformation
Chemical Structure
3D Model
(4) Sphingolipids: Ganglioside Conformation
Chemical Structure
3D Model
(5) Steroidolipids: Sterane Derivatives
Cyclopentane
+
Perhydrophenanthrene
Cyclopentanoperhydrophenanthrene
(Sterane)
- Steroidolipids (or simply steroids) are derivatives of cyclopentano-perhydro-phenanthrene
(or simply sterane)
- Sterane is a 17-carbon polycyclic hydrocarbon comprised of four non-planar rings
(designated A-D) fused together
- There are hundreds of distinct steroids (all derived from sterane) found in animals and plants
- A notable example of steroids is cholesterol—that also serves as a precursor for the
biosynthesis of so-called steroid hormones
(5) Steroidolipids: Cholesterol
Esterification
(RCOOH)
Cholesterol
Cholesteryl stearate
- Cholesterol is the most abundant sterane in animals with numerous functions
- Cholesterol is the third major component (after phospholipids and sphingolipids) of biological
membranes—typically comprising 30-40%(mol/mol) of total membrane lipids
- Owing to its greater rigidity (due to the fused ring system) than phospholipids and
sphingolipids, cholesterol is critical for both the structural integrity and dynamic fluidity (?!!)
of biological membranes
- Within biological membranes, cholesterol can also be esterified to form cholesteryl fatty acids
- In mammals, cholesterol serves as the metabolic precursor of a wide variety of chemical
messengers that have come to be known as “steroid hormones”
(5) Steroidolipids: Steroid Hormones
Cortisol
(Adrenal glands)
Aldosterone
(Adrenal glands)
Testosterone
(Testes)
Estradiol
(Ovaries)
Progesterone
(Ovaries)
- Steroid hormones are endocrine hormones that regulate numerous physiological functions central to homeostasis
- Steroid hormones (highly hydrophobic/lipophilic) exert their effects by virtue of their ability to diffuse through the membrane
and binding to their specific intracellular (cytoplasmic and nuclear) receptors called steroid hormone receptors (SHRs)
- SHRs are a subfamily of nuclear receptor superfamily—a group of transcription factors that become activated upon the
binding of a ligand such as a hormone or a vitamin
- Steroid hormones are subdivided into five major classes according to their physiological functions:
Class
Example
Receptor
Major stimuli
Principal Function
Glucocorticoids
Cortisol
Glucocorticoid receptor
Stress, hypoglycemia
Metabolism and inflammation
Mineralocorticoids Aldosterone
Mineralocorticoid receptor Hypotension, acidosis
Osmoregulation—salt and
water balance
Androgens*
Testosterone
Androgen receptor
Exercise, being stress-free Male sex steroid
Estrogens*
Estradiol
Estrogen receptor
Exercise, being stress-free Female sex steroid
Progesterones*
Progesterone
Progesterone receptor
Exercise, being stress-free Menstruation, pregnancy &
embryogenesis
*Produced in both males and females but in reciprocal quantities!
Exercise 1.4a
- How do lipids differ from the three other major
classes of biological molecules?
- Explain the trend in melting point with increasing
fatty acid chain length and number of double bonds
- Summarize the structures and physical properties of
fatty acids, triglycerides, phospholipids, sphingolipids,
and steroids
- Summarize the functions of steroid hormones
Section 1.4b:
Biological Membranes
Synopsis 1.4b
- In water, amphiphilic molecules such as phospholipids
associate (but do not solubilize/dissolve!) into a lipid bilayer
to form a homogenous solution—cf the mixing of water with
oil (aggregation) vs salt/sugar (solubilization)!
- The ability of amphiphilic substances to form micelles or
bilayers so as to shield their hydrophobic groups while
exposing their hydrophilic groups to water is driven by the
“hydrophobic effect”
- In addition to lipids, a wide plethora of so-called integral
membrane proteins (IMPs) penetrate the lipid bilayer and
laterally “swim” along the plane of the bilayer
- IMPs contain a transmembrane structure consisting of αhelices or a β-barrel with a hydrophobic surface
- The dynamic arrangement and interactions of membrane
lipids and proteins are described by the “fluid mosaic model”
Fatty Acids: Amphiphilic Nature
Apolar Tail
Polar Head
- Most biomolecules harbor both hydrophilic and hydrophobic characters—ie they possess
polar (eg polarized and/or charged) and apolar regions/segments
- Such biomolecules with hybrid character—such as fatty acids (eg palmitate)—are said to
be “amphiphilic” or “amphipathic”:
amphi  both
philia  attraction/liking
phobia  disliking/repulsion
pathos  to suffer/harbor
- Do amphiphiles such as fatty acids aggregate or solubilize in water?!
Lipids: Artificial Membrane Systems
- In amphiphiles such as fatty acids, the
polar head interacts with water via Hbonding while the apolar tails exclude
water on thermodynamic grounds
- Accordingly, amphiphiles aggregate in
water in an highly ordered manner
- Such
ordered
aggregates
of
amphiphiles form four distinct type of
artificial/synthetic membrane systems:
(1) Micelles (monolayers)
(2) Bicelles (bilayers)
(3) Liposomes (bilayers)
(4) Nanodiscs (bilayers)
- Formation of such artificial membrane
systems is driven by the hydrophobic
effect–ie the ability to exclude water
from their apolar tails!
(1) Detergent Micelles (Monolayers)
Polar Head
Central
Cavity
Water
Apolar Tail
SDS
(detergent)
SDS
(amphiphile)
Spherical Micelle
(monolayer)
- In aqueous solution, single-tailed detergents (amphiphilic) such as sodium
dodecyl sulfate (SDS) and fatty acids associate (or aggregate) into higherorder structures called micelles—m for monolayer!
- Such arrangement allows the non-polar (apolar) tails to avoid contact with
water while allowing their polar head groups to interact with the solvent
- Formation of such micelles is driven by the fact that it is thermodynamically
more favorable for the non-polar detergent tails to exclude water and
engage in van der Waals contacts with the neighboring tails in addition to
being entropically favorable (T∆S > 0)
- The central cavity may also become filled with water depending on the
concentration of detergent molecules
Micelle
(3D model)
(2) Lipid Bicelles (Bilayers)
Polar
Head
Water
Apolar
Tails
Phospholipid
(amphiphile)
Disk-like Bicelle
(bilayer)
Bicelle
(3D model)
- In a manner akin to the formation of detergent micelles, double-tailed amphiphilic molecules such as
phospholipids associate (or aggregate) into higher-order disc-like structures called bicelles—b for bilayer!
- Unlike less crowded single-tailed detergents, unfavorable steric clashes between double-tailed lipids
require them to pack into what are essentially disk-like bilayers (bicelles) in lieu of monolayers
(micelles)—albeit with monolayers at the edges!
- Within such a bicelle, lipid heads stick out on the surface on each side, while tails align up in a more or
less extended conformation against each other internally to generate what is predominantly a “lipid
bilayer”—this is the physicochemical basis of the assembly of biological membranes!
- The ability of such amphiphilic molecules to exclude water from their non-polar surfaces is of course (!)
called the “hydrophobic effect”—it is also the basis of folding of proteins into 3D shapes!
(3) Liposomes (Bilayers)
Central
Cavity
Lipid Bilayer
Nutrient Delivery
- When disrupted by physical treatments such as sonication (agitation with ultrasonic waves with
λ ~ mm), phospholipid bicelles (lipid bilayers) form liposomes—3D spherical structures fully
enclosed by a single lipid bilayer with a central aqueous cavity
- Such liposomes not only serve as artificial membranes for research but can also be used as a
vehicle for the delivery of hydrophilic nutrients and drugs (encapsulated in the central cavity)
that do not readily diffuse through the cell membranes
- Conversely, hydrophobic nutrients and drugs can also be delivered to specific tissues by virtue
of the fact that they readily dissolve into the lipid bilayer of the liposomes
- Upon reaching their target site, liposomes fuse with biological membranes, thereby emptying
their contents into the inside of the cell
(4) Nanodiscs (Bilayers)
Membrane
scaffold proteins
(MSPs)
Lipid bilayer
- Nanodiscs are comprised of a central phospholipid bilayer wherein the outer
boundary/perimeter of apolar tails is shielded by amphipathic proteins called
“membrane scaffold proteins (MSPs)” in a double-belt fashion
- MSPs are usually modified apolipoproteins—proteins involved in lipid metabolism—that
harbor amphipathic character
- Nanodiscs serve as excellent artificial membranes for research in that they represent a
more native system for the stabilization/folding of membrane proteins than lipsomes,
bicelles and micelles
- Nanodiscs may look like lipid bicelles (!)—but nanodsics differ from bicelles in that while
the former represent relatively homogeneous structures, the latter are highly
heterogenous (poorly defined 3D architectures)
Lipid Bilayer Is a 2D Fluid
Lateral Diffusion
Transverse Diffusion (Flip-flop)
- Owing to the ability of lipids to rapidly exchange with each other within the plane of the same
bilayer leaflet (lateral diffusion), biological membranes are highly dynamic and fluid structures
- On the other hand, exchange of lipids across the bilayer leaflets (transverse diffusion) is
extremely rare due to thermodynamic constraints—such flip-flop requires the outer polar head
to rotate and become momentarily immersed in the apolar environment of lipid tails at the core
of the bilayer
- The lipid tails within the core of the bilayer are under constant motion due to the free rotation
about the C-C bond, while the motion of head groups is relatively restricted due to steric clashes
or unfavorable polarity
- Because of the mobility of lipids primarily within the plane of the same bilayer leaflet, the lipid
bilayer is often described as a two-dimensional (2D) fluid—cf the mobility of terrestrial animals
(2D) vs birds/fish (3D)!
Lipid Bilayer Experiences Phase Transition
Liquid Solution
Viscous fluid with high mobility (T > Tm)
Liquid Crystal
Gel-like solid with an ordered array (T < Tm)
- Although a pre-requisite for the living cell, the fluidity of lipid bilayer is highly dependent upon
temperature (T) and lipid composition
- Lipid bilayer undergoes a dramatic phase transition in vitro from being a highly viscous fluid (liquid
solution) to a gel-like solid (liquid crystal) as the temperature is lowered to and below a certain
threshold value (usually around 25°C)—this is called transition temperature (Tm)—the temperature
at which the bilayer “melts” (cf water-ice phase transition)!
- Tm is highly dependent upon both the chain length (x) and degree of saturation (m) of fatty acids of
membrane lipids—longer the chain length and/or higher the degree of saturation, higher the Tm!
- Changing the composition of fatty acids of membrane lipids can attune the Tm of lipid bilayer (so as
to maintain its fluidity at ambient temperature)—a necessity for cold-blooded animals such as fish
- Fortunately, biological membranes experience little or negligible aforementioned bilayer phase
transition—how so? Enter cholesterol!
Effect of Cholesterol on Phase Transition
50
40
30
20
10
Cholesterol
0
Phospholipids
T / °C
- By virtue of its ability to snug in between phospholipids, cholesterol serves as a “fluidity
buffer” and either broadens or completely abolishes the phase transition observed in lipid
bilayers in vitro in response to changes in temperature!
- When T > Tm, cholesterol (due to its highly rigid fused ring system) decreases bilayer fluidity
by interfering with the motions of lipid tails
- When T < Tm, cholesterol increases bilayer fluidity by disrupting close packing of lipid tails
Lipid Bilayer Harbors Membrane Proteins
Integral Membrane Proteins
Peripheral Membrane Protein
Extracellular
Lipid
Bilayer
Peripheral Membrane Protein
monotopic
polytopic
Cytoplasmic
- In addition to lipids, proteins also constitute a major component of biological membranes—
such proteins are referred to as “membrane proteins”
- Membrane proteins are classified into “integral” or “peripheral” depending on the nature of
their interactions with the lipid bilayer
- Integral membrane proteins (IMPs) traverse through the lipid bilayer once (monotopic) or
multiple times (polytopic)—IMPs are highly hydrophobic and insoluble (precipitate out) in water
- Peripheral membrane proteins (PMPs) adhere to the surface of either the inner or outer leaflet
of the bilayer via association with lipid head groups or non-transmembrane regions of IMPs—
PMPs are water-soluble
Integral Membrane Proteins (IMPs)
Extracellular
Bacteriorhodopsin
(polytopic α-helical)
OmpF
(antiparallel β-barrel)
Lipid
Bilayer
Cytoplasmic
- IMPs are essentially amphiphiles—the protein regions (or transmembrane segments) immersed within
the milieu of the bilayer are predominantly composed of non-polar amino acid residues, while
intervening regions (loops) residing on the extracellular and cytoplasmic faces are by and large
dominated by polar and charged residues
- Transmembrane segments traversing lipid bilayers (biological membranes) usually adopt two major
folds or topologies—α-helical or β-barrel
- β-barrel transmembrane proteins are essentially comprised of a large multi-stranded β-sheet that twists
and coils to form a closed hollow channel—so as to allow passive diffusion of nutrients, salts and water
- α-helical transmembrane proteins can either traverse through the bilayer once (monotopic) or multiple
times (polytopic) to form the so-called helical bundle—and they conduct a multitude of roles from
signal transduction (cell surface receptors) to energy generation (proton pumps)
Peripheral Membrane Proteins (PMPs)
- PMPs adhere to the surface of either the inner or outer leaflet of the bilayer via association with lipid
head groups or non-transmembrane regions of IMPs
- PMPs are essentially “water-soluble” proteins that impart structural and functional versatility upon
biological membranes—eg attachment of spectrin, actin and ankyrin to the inner leaflet of biological
membranes not only serves as the “membrane skeleton” that gives the cell shape but also provides a
framework for the smooth integration and operation of signaling networks running from the nucleus
to the events occurring at the cell surface
Fluid Mosaic Model
- Lipid bilayer can be described as a “mosaic”—a composite structure made up of a heterogeneous mixture
of constituent components such as lipids and proteins arranged in an “orderly” manner—the latter are
further decorated with oligosaccharides to form what are called “glycoproteins” or “proteoglycans”
- In addition to the ability of lipids to freely exchange within the same leaflet of lipid bilayer, integral
membrane proteins also undergo a similar lateral diffusion along an axis perpendicular to the plane of the
bilayer—they essentially “float” in a “hydrophobic sea” of lipid bilayer!
- Given such 2D fluid of the bilayer with lipids and proteins constantly on the move, the lipid bilayer is best
envisioned as a “fluid mosaic”—such a model accounts for most of its biological properties!
Asymmetric Distribution of Lipids
Asymmetric Distribution of Lipids in the Cell Membrane of Human Erythrocyte
- Protein components of biological membranes are not evenly distributed on both sides—eg the
oligosaccharide moities of glycoproteins are almost exclusively attached to their extracellular regions
(where they play a central role in mediating cell-cell interactions)
- In a similar manner, lipids are also asymmetrically distributed on each face of the lipid bilayer—eg
sphingomyelin and phosphatidylcholine are predominantly located in the extracellular leaflet of
erythrocytes, whereas phosphatidylethanolamine and phosphaitdylserine are on the cytoplasmic face
- Such asymmetric distribution of lipids is necessary to attune specific cell types for their specific needs
and physiological functions
Exercise 1.4b
- Why do glycerophospholipids and sphingolipids—but not fatty
acids—form bilayers?
- Explain why lateral diffusion of membrane lipids is faster than
transverse diffusion
- What factors influence the fluidity of a bilayer?
- What are the two types of secondary structures that occur in
transmembrane proteins?
- Describe the fluid mosaic model
Good Fats vs Bad Fats
GOOD FATS are essential for the regulation of metabolism and include:
(1) naturally-occurring foods that harbor cis- and unsaturated fatty acids
(2) foods such as vegetable oil, nuts, fish
BAD FATS can lead to heart disease and include:
(1) processed foods that harbor trans- and saturated fatty acids
(2) foods such as red meat, dairy products, fried foods