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Lipids

are a chemically diverse class of biomolecules characterized by their insolubility in H2O

that means lipids are generally NON-POLAR and HYDROPHOBIC

some lipids, however, are AMPHIPATHIC (part of the molecule is polar and part is non-polar)

They are generated primarily from fatty acids.

1. Fatty acids

2. Triacylglycerols

3. Phospholipids

4. Glycolipids

5. Sterols

Fatty Acids

Fatty acids are carboxylic acids with hydrocarbon chains Saturated fatty acids DO NOT contain carbon-carbon double bonds

Unsaturated fatty acids contain carbon-carbon double bonds (C=C)

Cellular oxidation of fatty acids to CO2 and H2O is highly exergonic, and fatty acids serve as stored forms of energy

Fatty acids are components of several of the other classes of lipids

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Fatty Acids: effects of saturation

Degree of saturation affects physical properties

Saturated fatty acids - solid at

RT

Unsaturated fatty acids are oily

liquids at RT

Different melting points.

Naturally occurring unsaturated fatty acids tend to have cis double bonds.

Trans fatty acids are produced in dairy animals or hydrogenation of oils.

Examples of Fatty Acids & Nomenclature

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Triacylglycerols

the simplest lipids constructed from fatty acids

triacylglycerols are composed of three fatty acids covalently joined to glycerol through ester linkages.

most naturally occurring triacylglycerols are mixed, meaning they contain 2 or more different fatty acids.

Triacylglycerol

+ 3 fatty acids

Food and triglycerides Butter and other spreads, vegetable oils, animal fats

Triglycerides are also found in skin creams, hair conditioners,

shoe polish, soaps, etc

Soaps Triglycerides + heat + NaOH Glycerols + Na salt of Fatty acid

(Soaps)

Triglycerides and energy Triglycerides are more reduced than glucose and can provide twice the energy

during oxidation.

Triglycerides are hydrophobic, stored with less water than glycogen.

Stored in adipocytes - fat cells, rich in lipases

Can be carried in the blood by serum albumin

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Two types of backbones are usedone is based on glycerol; the other on the long chained amino alcohol sphingosine

Phospholipids or glycolipids with a sphingosine

backbone are called sphingolipids

Lipid Backbones

Backbone for glycerophospholipids

H

H

Phospholipids and Glycolipids

structural lipids of biological membranes

they are amphipathic in nature similar in their basic structures: BACKBONE + at least one FATTY ACID + something else

Backbone

Fatty acid

Something else

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membrane phospholipids are mostly this type based on glycerol (3-phosphate) backbone Two fatty acids in ester linkage

Glycerophospholipids

Polar groups for glycerophospholipids

Phosphatidyl ethanolamine / choline/ serine major constituents of membranes

Phosphatidyl inositol, important signalling molecule in membrane

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Sphingolipids - based on sphingosine backbone

Sphingolipids

Blood groups are part determined by membrane

sphingolipids on blood cells

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Small number of glycerophospholipids have ether instead of ester

Released from basophils,

stimulates platelet

aggregation.

Ether linkage

Sterols are structural lipids present in the membranes of most eukaryotic cells

cholesterol is the major sterol in human tissues

in eukaryotic cells, sterols are synthesized from simple five carbon subunits called isoprenes

Cholesterol

have four fused carbon rings

Steroid hormones are derivatives of cholesterol

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Steroids are made of isoprene (2-methyl-1,3-butadiene)

Pharmacy Students - BC1443

Practical Tutorial:

Friday, February 14th, 10-12am, LG52

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Liposomes and Membranes

Electron microgram of

mitochondrion and bacterial cell

Lipids component formation of higher levels of structure

FATTY ACIDS FORM MICELLES

PHOSPHOLIPIDS FORM

BILAYERS : BIOLOGICAL MEMBRANES

TRIANGULAR

VAN DER WAALS RADIUS

COOH

12-200

MOLECULES

HYDROPHILIC HEADS

HYDROPHOBIC

TAILS

RECTANGULAR

VAN DER WAALS RADIUS

PHOSPHOLIPID

BILAYER

(EXTENDS

INDEFINITELY)

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Lipid bilayer confers certain properties

Forms closed structures

Impermeable to water-soluble molecules

Extremely stable, yet fluid-like flexible- in nature.

1) Unsaturated - fluidity

2) Saturated - fluidity

3) Cholesterol (rigid) - fluidity

The composition of lipids in a membrane affect the

structure of the membrane (fluidity and curvature) activity of membrane enzymes and transport systems (i.e. membrane proteins!)

Biological Membranes

Composed of amphipathic lipids

arranged in bilayers with

proteins either spanning or

associated with the resulting

membranes

Fluid mosaic model: free

movement of lipids and

proteins within the plane of

the membrane (unless

attached to scaffolds)

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Membrane asymmetry organization in cells

Both the plasma membrane and internal membranes have cytosolic and exoplasmic faces

This orientation is maintained during membrane trafficking proteins, lipids, glycoconjugates facing the lumen of the ER and Golgi get expressed on the

extracellular side of the plasma membrane

Lipid composition of individual monolayers varies!

Asymmetric distribution of lipids in

monolayers arises because of:

1) Site of synthesis

Sphingomyelin synthesized on exoplasmic face of Golgi.

Glycerophospholipids synthesized on cytosolic face of ER.

2) Action of flippases

integral membrane enzyme that catalyzes the movement of lipids

between the outer and inner leaflets

Cells control the lipid composition

of membranes

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Transverse vs. lateral movement of

phospholipids within membranes

Type I: one TM helix, amino terminal

outside membrane.

Type II: one TM helix, amino terminal

inside membrane.

Type III: multiple TM domains.

Type IV: several Tm-domain proteins

assembled to form channels.

Type V:attached by covalently bound

lipids.

Type VI: TM helix and lipid anchor.

Membrane Proteins *

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Biological Membranes - Functions

Barrier maintaining the functional and structural integrity of cells and organelles (compartmentalization).

Regulate the import and export of solutes.

Maintenance of membrane potential.

Endocytosis, exocytosis, phagocytosis

Signal transduction

Pure lipid bilayer Impermeable to most solutes

Gases + small polar/ uncharged molecules can cross

by passive diffusion

Most molecules cannot cross (ions, amino acids, ATP, large uncharged/ polar molecules)

Molecule Transport across the Bilayer

Most molecules need help to cross membranes by relying on proteins to make the membrane selectively permeable

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Transmembrane Signalling

Phosphatidylinositols act as Intracellular

Signals

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Transmembrane Signalling

Transmembrane transport proteins:

Make membranes permeable to specific ions and large molecules

Speed up transport of slowly diffusing molecules (ex. water, urea)

How do they work?

Provide a pathway through the membrane that avoids contact with the hydrophobic core of the membrane bilayer

Generally specific for one molecule or a few related molecules

Membrane Transport Proteins (>1000)

Passive (simple) and facilitated

diffusion DOWN the con-

centration gradient

Active transport, UP (against)

the concentration gradient, and

therefore REQUIRES energy

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Membrane Transport Proteins: ATP-powered Pumps

ATP-powered Pumps

Use energy from ATP hydrolysis to transport molecules against their concentration / electrochemical gradients active transport

ATP-powered Pumps: P-class

Na+/K+ ATPase of the plasma membrane

Hydrolysis of 1 ATP per transport cycle coupled to:

Transport of 3 Na+ out of cell and 2 K+ into cytosol

Na+ / K+ ATPase makes a major

contribution towards establishing and

maintaining the ionic gradients across

membranes (and associated

membrane potentials Vm) that are

essential for normal function of ion

channels, transporters and some

signalling pathways.

ATP pumps are not restricted to the plasma membrane (eg. Ca2+ -ATPase in

sacroplasmic reticulum)

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2. Ion channels

Transport ions down their electrochemical gradients

Facilitated Diffusion i.e. no energy required

(but runs down ionic gradients generated by

pumps)

Na+, Cl-, Ca2+, K+ (very important for Vm)

Ion Permeability (K+-Channel)

Pore is only 10 A long

P-loop in each subunit (selectivity filter): Glu and Asp - negative charges (2 per unit) Carbonyl dipoles from TVGY 4 x 4 solvation of cations

Central cavity lake Enough H2O molecules for 2 shells Hydrophobic AA around Energy of K+ lowered by 44 kcal/mol

K+ ions prefer the pore than solution

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3. Membrane Transport Proteins:

Uniporters

Transport molecules down their concentration gradients

Facilitated Diffusion

Example: GLUT family of Glucose transporters (12 proteins)

Transport glucose down its concentration gradient into cells Best characterised is GLUT1 from erythrocyte plasma membrane

Allows red blood cells to take up glucose from blood Accounts for 2% of plasma membrane protein in red blood cells Once in cell, glucose is converted to glucose-6-phosphate

3. Membrane Transport Proteins:

Cotransporters

Use the energy stored in the electrochemical gradient of Na+ and H+ to power the movement of small molecules or ions against their concentration

gradients

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Transmembrane Transport depends on

The concentration (chemical) gradient of the molecule across the membrane

AND the electrical potential (voltage) across the membrane

The electrochemical gradient, determines the energetically

favourable direction of movement.

Exocytosis & Endocytosis