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Lipids
Lipids: Structurally Diverse Class
• Insoluble in water
• Good solubility in nonpolar solvents
Function as:
• Storage molecules
• Structural molecules
• Signaling, Cofactors, Pigments
Classification of Lipids
Based on the structure and function
• Lipids that contain fatty acids (complex lipids)
– Storage lipids and membrane lipids
• Lipids that do not contain fatty acids: cholesterol,
terpenes, carotenoids, ...
Lipids that do not contain fatty
Based on the structure and function
Steroids (cholesterol), terpenes, carotenoids, ...
Lipids that do not contain fatty
Steroids derived from cholesterol
Lipids that do not contain fatty
Some other biologically active isoprenoid compounds
or derivatives
Lipids that do not contain fatty
Lipids as pigments in plants and bird feathers
Lipids that contain fatty acids
Phospho/glyco lipids and triacylglycerols (fat)
(or sfingosin)
Fatty Acids
• Carboxylic acids with hydrocarbon chains containing from 4
to 36 carbons
• Almost all natural fatty acids have an even number of
carbons
• Most natural fatty acids are unbranched
• Saturated: no double bonds between carbons in the chain
• Monounsaturated: one double bond between carbons in the
alkyl chain
• Polyunsaturated: more than one double bond in the alkyl
chain
Two conventions for naming fatty acids
Fully saturated Stearic acid, 18:0
Unsaturated Oleic acid, 18:1(Δ9)
Conformation of Fatty Acids
• The saturated chain tends to adopt extended
conformations
• The double bonds in natural unsaturated
fatty acids are commonly in cis configuration
• This introduces a kink in the chain
The packing of fatty acids into stable aggregates
Solubility and Melting Point of Saturated Fatty Acids
• Solubility
decreases as the
chain length
increases
• Melting point
increases as the
chain length
increases
Melting Point and Double Bonds
• Saturated fatty acids pack in a fairly orderly way
– extensive favorable interactions
• Unsaturated cis fatty acid pack less regular due to
the kink
– Less extensive favorable interactions
• It takes less thermal energy to disrupt disordered
packing of unsaturated fatty acids:
– unsaturated cis fatty acids have a lower melting point
Trans Fatty Acids
• Trans fatty acids are formed by partial
hydrogenation of unsaturated fatty acids
• A trans double bond allows a given fatty acid to
adopt an extended conformation.
• Trans fatty acids can pack more regularly, and
show higher melting points than cis forms
Trans Fatty Acids in Foods
• Consuming trans fats increases risk of
cardiovascular disease
– Avoid deep-frying partially hydrogenated vegetable
oils
– Current trend: reduce trans fats in foods
Triacylglycerols (fats and oils)
Triacylglycerols (fats and oils)
Glycerol
Triacylglycerol
Triacylglycerols (fats and oils)
• Majority of fatty acids in biological systems are found in
the form of triacylglycerols
• Solid ones are called fats
• Liquid ones are called oils
• Triacylglycerols are the primary storage form of lipids
(body fat)
• Triacylglycerols are less dense than water: fats and oils
float
Fats Provide Efficient
Fuel Storage
• The advantage of fats over polysaccharides:
– Fatty acid carry more energy per carbon because they
are more reduced
– Fatty acids carry less water along because they are
nonpolar
• Glucose and glycogen are for short-term energy needs,
quick delivery
• Fats are for long term (months) energy needs, good
storage, slow delivery
Membrane lipids
Membrane lipids
Biological membrane – double layer of lipids
Membrane lipids – amphiphatic (hydrophobic and
hydrophylic end)
Membrane lipids
• Glycerolphospholipids – phospholipids
• Glycerolglycolipids – glycolipids, plant lipids
• Sulpholipids – sulfated glycolipids
• Tetraether lipids – archaea unique membrane lipids
• Sphingolipids
• Sterols – other lipid compounds of membranes
Phospholipids
• Primary constituents of cell membranes
• Two fatty acids form ester linkages with first and
second hydroxyl group of L-glycerol-3-phosphate
Phospholipids
Glycolipids and Sulfolipids
• Lipids of plant chloroplasts organells
• Sugar-containing lipids
• Mainly galactosyldiacylglycerols
Tetraether lipids
• Unique archaea lipid
• Long chain branched hydrocarbons
• Linked at each end to glycerol by ether bond
Sphingolipids
• The backbone of sphingolipids is NOT glycerol
• The backbone of sphingolipids is a long-chain
amino alcohol sphingosine
• A fatty acid is joined to sphingosine via an amide
linkage rather than an ester linkage as usually
seen in lipids
Sphingolipids
• A polar head group
is connected to
sphingosine by a
glycosidic or
phosphodiester
linkage
• The sugarcontaining
glycosphingolipids
are found largely in
the outer face of
plasma membranes
Cholesterol
Cholesterol
The major sterol in animal tissues
Nonpolar hydrocarbon sidechain
Bacteria cannot synthesize
sterols
Membranes and membrane
transport
Membrane Bilayer
The membrane bilayer consists of a two
leaflets of lipid monolayers
– Hydrophilic head groups
interact with water
– Hydrophobic fatty acid
tails are packed inside
– One side faces the
cytoplasm
– Another side faces the
extracellular space or the
inside of membraneenclosed organelle
Functions of Membranes
• Define the boundaries of the cell
• Allow import and export
– Selective import of nutrients (e.g. lactose)
– Selective export of waste and toxins (e.g. antibiotics)
• Retain metabolites and ions within the cell
• Sense external signals and transmit information into the cell
• Provide compartmentalization within the cell
– separate energy-producing reactions from energy-consuming ones
– keep proteolytic enzymes away from important cellular proteins
• Produce and transmit nerve signals
• Store energy as a proton gradient and support synthesis of
ATP
The Composition of Membranes
• The properties of head groups and hydrophobic
tails determine the properties of membranes
• Different tissues have different membrane lipid
head group compositions
• Different organels have different membrane lipid
head group compositions
• Different layers of membrane have different
membrane lipid head group compositions
The Composition of Membranes
Tissues
Lipid composition is different in different organisms and in
different tissues of the same organism:
• Type of lipids varies
• Ratio of lipids to proteins varies
• Abundance and type of sterols varies, prokaryotes lack
sterols
The Composition of Membranes
Organels
Plasmtická a organelové membrány krysích hepatocytů
The Composition of Membranes
Membrane layers
• Bilayer is asymmetric
• Outer leaflet is often more
positively charged
• Phosphatidylserine outside
has a special meaning:
– Activates blood clotting
– Marks the cell for
destruction
Organisms can Adjust the
Membrane Composition
• Membrane properties are determined by the ratio of
unsaturated to saturated fatty acids
• To maintain constant fluidity, cells need more saturated
fatty acids at higher temperature
Fatty acid composition of E. coli cells cultured at different temperatures
Two basic types of membrane proteins
• Integral membrane
proteins
• span the lipid bilayer,
• Peripheral membrane
proteins
• associated with the
membrane by electrostatic
interactions or hydrogen
bonding
Integral membrane proteins
• Hydrophobic interaction of membrane
spanning region with lipids
• Various types and architecture of
membrane spanning regions
• Frequent presence of Tyr and Trp
residues at the interface between lipid
and water
Lipid Anchors
• Some membrane proteins are lipoproteins; they
contain a covalently linked lipid molecule
• The lipid part can become part of the membrane
• The protein is now
anchored to the
membrane
The Fluid Mosaic Model
Fluid Mosaic Model of Membranes
• Lipids form a viscous, two-dimensional solvent
into which proteins are inserted and integrated
more or less deeply
• Integral proteins are firmly associated with the
membrane, often spanning the bilayer
• Peripheral proteins are weakly associated and
can be removed easily
– Some are non-covalently attached
– Some are linked to membrane lipids
Membrane dynamics
Physical Properties of Membranes
• Dynamic and flexible structures
• Can exist in various phases and undergo
phase transitions
• Not permeable to large polar solutes and ions
• Permeable to small polar solutes and
nonpolar compounds
Membrane Phases
• Depending on their composition and the
temperature, lipid bilayer can be in gel or fluid
phase
– Gel phase: individual molecules do not move
around
– Fluid phase: individual molecules can move
around
• Heating causes phase transition from the gel to
fluid
• Under physiological conditions, membranes are
more fluid-like than gel-like
Membrane Dynamics:
Lateral Diffusion
• Individual lipids undergo fast lateral diffusion
within the leaflet
Membrane Dynamics:
Transverse Diffusion
• Spontaneous flips from one leaflet to another
are rare because the charged head group,
which is normally well-solvated, must
transverse the apolar region
Membrane Diffusion: Flippases
• Special enzymes — flippases — catalyze
transverse diffusion
• Some flippases use energy of ATP to move
lipids against the concentration gradient
Membrane Rafts
• Lipid distribution in a single leaflet is not random
• Some regions contain clusters of
glycosphingolipids with longer than usual tails
• These regions are more ordered and contain
specific doubly- or triply-acylated proteins
• Rafts allow segregation of proteins in the
membrane
Membrane Rafts
Membrane Fusion
• Membranes can fuse with each other without
losing continuity
• Fusion can be spontaneous or proteinmediated
• Examples of protein-mediated fusion are
– Entry of influenza virus into the host cell
– Release of neurotransmitters at nerve synapses
Spontaneous membrane fusion
Membrane transport
Transport Across Membranes
Transport Across Membranes
• Some solutes passively diffuse through the lipid
membrane
• Passive diffusion - only gases and small
uncharged hydrophobic molecules
• Diffusion of polar molecules involves desolvation
and thus has a high activation barrier
• Facilitated transport across the membrane with a
help of proteins that provide an alternative
diffusion path – membrane transporters
• Active transport on a cost of energy of ATP
Classes of Transport Systems
• Facilitated transport
(uniporters)
• Active transport – Primary
active transport
(ATP-powered pumps)
• Cotransport - Secondary
active transport
(symporters, antiporters)
Classes of Transport Systems
Glucose facilitated uniport
Glucose active symport
Role of Na+K+ ATPase
P-class proton pumps
• maintaining the intracellular
concentrations of Na+ and K+
• generating the membrane
potential
• electrical signaling in neurons
• gradient of Na+ drives the
uphill cotransport of solutes
Lipid Metabolism
Respiration: Stage 1
Respiration: Stage 2
Respiration: Stage 3
Lipid Catabolism
Oxidation of Fatty Acids is a
Major Energy-Yielding Pathway in
Many Organisms
• About one third of our energy needs comes from dietary
triacylglycerols
• About 80% of energy needs of mammalian heart and liver
are met by oxidation of fatty acids
• Many hibernating animals, such as grizzly bears relay
almost exclusively on fats as their source of energy
Fats Provide Efficient Fuel Storage
• The advantage of fats over polysaccharides:
– Fatty acid carry more energy per carbon
because they are more reduced
– Fatty acids carry less water along because they
are nonpolar
• Glucose and glycogen – fast and short-term
energy needs
• Fats and fatty acids – slow and long term
(months) energy needs
Dietary Fatty Are Absorbed in the
Vertebrate Small Intestine
Hydrolysis of Fats Yields Fatty
Acids and Glycerol
• Hydrolysis of triacylglycerols is catalyzed by lipases
• Triacylglycerols are digested into fatty acids and glycerol to
be transported across intestinal mucosa
• They are converted back to triacylglycerols to be carried in
blood in a for of chylomicrons
• In cappilaries triacylglycerols are again converted to fatty
acids and glycerol and transported to cells
• Fatty acids are oxidized or re-esterified to triacylglycerols for
storage
Stored Triacylglycerols
Glycerol from Fats Enters
Glycolysis
Glycerol from Fats Enters
Glycolysis
• Glycerol kinase activates glycerol at the expense of ATP
• Subsequent reactions recover more than enough ATP to
cover this cost
• Allows limited anaerobic catabolism of fats
Fatty Acid Transport into
Mitochondria
• Fats are degraded into fatty acids and glycerol in the
cytoplasm
• -oxidation of fatty acids occurs in mitochondria
• Small (< 12 carbons) fatty acids diffuse freely across
mitochondrial membranes
• Larger fatty acids are transported via
acyl-carnitine / carnitine transporter
• Fatty acids are first converted into Fatty Acyl-CoA
Acyl-carnitine / Carnitine Transport
Complete Fatty Acid Oxidation
3 stages of Fatty Acid Oxidation
• Stage 1 consists of oxidative conversion of twocarbon units of fatty acids into acetyl-CoA with
concomitant generation of NADH
• Stage 2 involves oxidation of acetyl-CoA into CO2
via citric acid cycle with concomitant generation
NADH and FADH2
• Stage 3 generates ATP from NADH and FADH2
via the respiratory chain
The -Oxidation Pathway
Four steps
Each pass removes
one acetyl moiety in
the form of:
acetyl-CoA
Step: 1
Dehydrogenation of Alkane to Alkene
Step: 1
Dehydrogenation of Alkane to Alkene
• Catalyzed by isoforms of acyl-CoA dehydrogenase
(AD) on the inner mitochondrial membrane
– Very-long-chain AD (12-18 carbons)
– Medium-chain AD (4-14 carbons)
– Short-chain AD (4-8 carbons)
• Analogous to succinate dehydrogenase reaction in
the citric acid cycle
• Electrons are passed into the mitochondrial
respiratory chain
Trifunctional Protein (TFP)
• The last three steps are catalyzed by inner
mitochondrial membrane multienzyme complex
• Processes fatty acid chains with 12 or more
carbons
• Shorter fatty acid chains are oxidation - by soluble
enzymes in the matrix
Step: 2
Hydration of Alkene
Step: 2
Hydration of Alkene
• Catalyzed by two isoforms of enoyl-CoA
hydratase:
– Soluble short-chain hydratase
– Membrane-bound long-chain hydratase (TFP)
• Adds water across the double bond yielding
alcohol
• Analogous to fumarase reaction in the citric acid
cycle
Step: 3
Dehydrogenation of Alcohol
Step: 3
Dehydrogenation of Alcohol
• Catalyzed by -hydroxyacyl-CoA
dehydrogenase
• The enzyme uses NAD+ cofactor as the hydride
acceptor
• Produced NADH enters respiratory chain
• Analogous to malate dehydrogenase reaction in
the citric acid cycle
Step: 4
Transfer of Fatty Acid Chain
Step: 4
Transfer of Fatty Acid Chain
• Catalyzed by acyl-CoA acetyltransferase
(thiolase)
• The net reaction is thiolysis of carbon-carbon
bond
Fatty Acid Catabolism for Energy
• Repeating the above four-step process six more
times results in the complete oxidation of
Palmitic acid into eight molecules of acetyl-CoA
– FADH2 is formed in each cycle (7 total)
– NADH is formed in each cycle (7 total)
• Acetyl-CoA enters citric acid cycle and is further
oxidizes into CO2
– This makes more GTP (1), NADH (3) and FADH2 (1)
NADH and FADH2 Serve
as Sources of ATP
Yield of ATP during Oxidation of One Molecule of Palmitoyl-CoA to CO2 and H2O
Ketone Bodies
Formation of Ketone Bodies
• Entry of acetyl-CoA into citric acid cycle requires
oxaloacetate
• When oxaloacetate is depleted, acetyl-CoA is
converted into ketone bodies
• The first step is reverse of the last step in the oxidation: thiolase reaction joins two acetate
units
Liver as the Source of Ketone
Bodies
• Production of ketone bodies increases during
starvation
• Ketone bodies are released by liver to
bloodstream
• Organs other than liver can use ketone bodies
as fuels
• Too high levels of acetoacetate and hydroxybutyrate lower blood pH dangerously
Lipid Biosynthesis
Lipids Fulfill a Variety of
Biological Functions
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Storage of energy
Constituents of cellular membranes
Anchors for membrane proteins
Cofactors for enzymes
Signaling molecules
Pigments
Detergents
Transporters
Antioxidants
Catabolism and Anabolic of Fatty
Acids Proceed via Different
Pathways
• Catabolism of fatty acids
– produced acetyl-CoA
– reducing power to NADH, FADH2
– location: mitochondria
• Anabolism of fatty acids
– requires malonyl-CoA and acetyl-CoA
– reducing power from NADPH
– location: cytosol in animals, chloroplast in plants
Overview of Fatty Acid Synthesis
• Fatty acids are built in several passes
processing one acetate unit at a time
• The acetate is coming from activated
malonate in the form of malonyl-CoA
• Each pass involves reduction of a
carbonyl carbon to a methylene carbon
Synthesis of Malonyl-CoA
• The three-carbon precursor for fatty acid
synthesis is made from acetyl-CoA and CO2
Overview of Fatty Acid Synthesis
Fatty Acid Synthesis
• Overall goal is to attach a two-carbon acetate unit from
malonyl-CoA to a growing chain and then reduce it
• Reaction involves cycles of four enzyme-catalyzed steps
– Condensation of the growing chain with activated acetate
– Reduction of carbonyl to hydroxyl
– Dehydration of alcohol to trans-alkene
– Reduction of alkene to alkane
Acyl Carrier Protein
Fatty Acid Synthase
• Two thiols participate in the fatty acid synthesis
– Thiol from 4-phosphopantethine in Acyl Carrier Protein
– Thiol from cysteine in fatty acid synthase
Assimilation of Two-Carbon
Units
Acetyl condensate
with malonyl into
acetoacetyl located
at ACP
Reduction of Carbonyl Group
reduction of C3 on acetoacetyl
group to D--hydroxybutyryl
NADPH as a electron donor
Dehydration
Water is removed from C-2 and
C-3 of the D--hydroxybutyryl to
yield a double bond
Second Reduction
Finally the double bond
is reduced (saturated) to
form acyl-ACP
NADPH is the electron
donor
• The acyl group is then transferred from ACP to
Fatty acid synthase
• and the ACP is re-charged with new malonyl from
malonyl-CoA
New cycle starts by
condensation with
malonyl on ACP
Fatty Acid Synthesis - summary
• Overall goal is to attach a two-carbon acetate unit from
malonyl-CoA to a growing chain and then reduce it
• Reaction involves cycles of four enzyme-catalyzed steps
• The growing chain is attached to the enzyme via a
thioester linkage
• During condensation, the growing chain is transferred to
the acyl carrier protein
• After the second reduction step, the elongated chain is
transferred back to fatty acid synthase
Enzymatic Activities in Fatty
Acid Synthase
• Condensation with acetate
– -ketoacyl-ACP synthase (KS)
• Reduction of carbonyl to hydroxyl
– -ketoacyl-ACP reductase (KR)
• Dehydration of alcohol to alkene
– -hydroxyacyl-ACP dehydratase (DH)
• Reduction of alkene to alkane
– enoyl-ACP reductase (ER)
• Chain transfer
– Malonyl/acetyl-CoA ACP transferase
Acyl Carrier Protein
• Contains a covalently attached
prothetic group 4’-phosphopantethiene
• The acyl carrier protein shuttles
the growing chain from one active
site to another during the four-step
reaction
Localisation of fatty acis metabolism
Catabolism – Fatty acid oxidation
• animals - Mitochondria
• plants – Peroxisomes
Anabolism – Fatty acid biosynthesis
• animals – Cytosol
• plants - Chloroplasts
Synthesis of Unsaturated Fatty
Acids
• Animals can readily introduce one double bond to palmitate
and stearate
• Vertebrates cannot introduce additional double bonds
between C10 and methyl-terminal
• We must obtain linoleate and -linolenate with diet; these
are essential fatty acids
Plants, algae, and some insects
synthesize linoleate from oleate
Vertebrate Fatty Acyl Desaturase
is a Mixed Function Oxidase
• O2 is an terminal acceptor of electrons
• Two electrons come from saturated fatty acid
• Two electrons come from NADPH via
Cytochrome b5
Biosynthesis of Triacylglycerols - I
• Glycerol 3-phosphate is formed
• Acylation of two hydroxyl groups
of glycerol 3-phosphate
Biosynthesis of Triacylglycerols - II
Diacylglycerol 3-phosphate (phosphatidic
acid) is a precursor for
• triacylglycerols
• glycerophospholipids