Lipids and Biological Membranes

Lipids: Found in all living organisms Especially important as components of biological membranes Defined functionally, not structurally, as compounds that are totally or sparingly soluble in water

The simplest lipids are the fatty acids: monocarboxylic acids of the general formula R-COO; R=hydrocarbon tail - O - C = O } polar head C 2 group C 2 } C non- polar 2 hydrocarbon tail C 2 C 3 a m p h i p a t h i c

Fatty acids may contain double bonds (unsaturated) or may be without double bonds (saturated) - O - C = O C 2 C 2 C 2 C 2 C 3 SATURATED - O - C = O C 2 C 2 C- C- C 3 CIS - O - C = O C 2 C 2 -C C- C 3 TRANS

In naming fatty acids, the position of the double bonds is indicated by the symbol n, where n is the lowest numbered carbon atom of the double bonded pair. Shorthand notation: 2 numbers separated by a colon, the first refers to the number of carbons, the second to the number of double bonds. Example: 16 carbon fatty acid with double bonds between carbons 5 & 6, 10 &11 is given as: 16:2 (5,10)

Fatty Acids differ by: 1. Length of their hydrocarbon chains 2. Position and presence of C=C bonds

The length of the chain and degree of unsaturation influence the melting temperature of the fatty acid. carbon skeleton common name melting temp ( o C) 12:0 lauric acid 44.2 18:0 stearic acid 69.6 18:1 18:2 oleic acid 13.4 linoleic acid -5

Packing of hydrocarbon tails is affected by the degree of saturation } van der Waals interactions } inefficient packing due to cis double bonds

Fatty acids generally occur esterified to other molecules Fats and oils in plants and animals consist of mixtures of triacylglycerols (triglycerides or neutral fats) which are fatty acid triesters of glycerol. Used as energy reserves and are the most abundant class of lipids. Not components of membranes.

-C O -C O -C O glycerol O + - O-C-R 1 O + - O-C-R 2 + O - O-C-R 3 3 fatty acids O -C-O-C-R 1 O -C-O-C-R 2 O -C-O-C-R 3 triacylglycerol triacylglycerols are NOT amphipathic!

Simple triacylglycerols contain only one type of fatty acid (ex., tristearoylglycerol) Mixed triacylglycerols contain two or three different types of fatty acids. A soap is a salt of a fatty acid. Soaps are produced by hydrolyzing animal fat (which is mostly triacylglycerols) with a base such as NaO or KO (to produce the Na or K salts of the fatty acids).

Glycerophospholipids Major lipid components of membranes Consist of glycerol, 2 fatty acids, and a phosphate-x group O -C-O-C-R 1 O -C-O-C-R 2 O -C-O-P-O O -----X

If X=; phosphatidic acid (small amounts in membranes) Most X groups=polar alcohols (choline; serine; ethanolamine) -C 2 -C 2 -N 3 + ethanolamine -C 2 -C 2 -N + (C 3 ) 3 choline

C1 usually has a C16 or C18 saturated fatty acid C2 often has a C16 to C20 unsaturated fatty acid These gp s represent a family of compounds containing the same polar head group but different fatty acids esterified at C1 and C2

Dipalmitoylphosphatidylcholine O -C-O-C-(C 2 ) 14 C 3 O -C-O-C-(C 2 ) 14 C 3 O -C-O-P-O-C 2 -C 2 -N + (C 3 ) 3 O Lung Surfactant

The venoms of some poisonous snakes contain phospholipases, enzymes that break down phospholipids. Eastern diamondback rattlesnake and Indian cobra venoms contain phospholipase A 2 which hydrolyzes the fatty acid from C 2 of glycerophospholipids. The product of this reaction, lysolethicin, dissolves the membranes of red blood cells thus killing the victim.

Sphingolipids Present in animal and plant membranes Abundant in the central nervous system Derivatives of the C18 amino alcohols sphingosine and dihydrosphingosine

sphingosine O-C 2 -C-C-C-C-(C 2 ) 12 -C 3 + 3 N O dihydrosphingosine O-C 2 -C-C-C-C-(C 2 ) 12 -C 3 + 3 N O

N-fatty acyl derivatives of sphingosine are Ceramides Ceramides are the parent compounds of all sphingolipids O-C 2 -C-C-C-C-(C 2 ) 12 -C 3 N O O-C } fatty acid at C2 R

Three Families of Sphingolipids: 1) Sphingomyelins O-C 2 -C-C-C-C-(C 2 ) 12 -C 3 N O O-C R

Three Families of Sphingolipids: 1) Sphingomyelins phosphocholine or phosphoethanolamine linked through the PO 4 group O-C 2 -C-C-C-C-(C 2 ) 12 -C 3 N O O-C R The myelin sheath which electrically insulates nerves is very rich in sphingomyelin.

2) Cerebrosides ceramides with a single sugar residue attached via the hydroxyl at C1 O-C 2 -C-C-C-C-(C 2 ) 12 -C 3 N O-C R O

2) Cerebrosides ceramides with a single sugar residue attached via the hydroxyl at C1 b-glucose or b-galactose linked through a glycosidic bond O-C 2 -C-C-C-C-(C 2 ) 12 -C 3 N O-C R galactocerebrosides most prevalent in nervous tissue; glucocerebrosides in other tissues O

3) Gangliosides contain oligosaccharide chains in which at least one sugar residue is sialic acid C 3 O=C N R O O=C-O - O R = CO CO C 2 O sugar chain is linked through a glycosidic bond at C1, just as in the cerebrosides

Glycosphingolipids (particularly gangliosides) primarily are components of cell surface membranes and constitute a major fraction of brain lipids They are of great medical importance: -They are receptors for hormones that regulate growth and differentiation. Also regulate cell-cell interaction and tissue immunity. -Membrane lipid composition changes during tumor formation. -They are present in nerve endings and appear important in nerve impulse transmission. -Genetic disorders result in defects in ganglioside metabolism (Tay-Sachs).

Waxes: Long chain alcohols esterified to long-chain fatty acids. O-C=O The fatty acid is usually saturated. Water-repellant coating for skin, leaves, feathers.

Terpenes: Formed from combinations of two or more molecules of isoprene. -C=C 2 2 C=C-C 3 Flavors such as lemon, menthol; phytol, a component of chlorophyll; lycopene, the carotenoid in tomato, are all terpenes.

Steroids ave a cyclic nucleus of 4 saturated, fused rings designated A,B,C,D C D A B Cyclopentanoperhydrophenanthrene!

Cholesterol major component of animal membranes most abundant steroid in animals is a sterol due to hydroxyl group at C3 (weakly amphipathic) fused ring system imparts rigidity precursor to steroid hormones (sexual development; pregnancy; lipid, protein & carbohydrate metabolism salt balance) esterification of fatty acids to C3-O forms cholesteryl esters (found in lipoproteins in blood)

Cholesterol C 3 C C 2 C 2 C 2 C C3 C 3 aliphatic side chain at C17 C 3 C 3 C D polar O group at C3 O A B

Properties of Lipid Aggregates Amphipathic molecules form micelles in aqueous solution above their critical micelle concentration (cmc)

Phospholipids tend to form bilayers in aqueous solution because their fatty acyl chains do not pack well into micelles. Single bilayers form liposomes.

Fluid Mosaic Model phospholipid heads of fatty acids carbohydrate portion of glycoprotein cholesterol integral protein fatty acyl tails of fatty acids peripheral protein with lipid anchor

Glycophorin Major red blood cell membrane protein as a single membrane-spanning α-helix Carbohydrate moieties on outside determine ABO and MN blood group antigenic specificity and also act as receptors for the influenza virus

N 2 Lipid-Anchored Proteins COO COO N-myristolylation occurs at an N-terminal glycine residue Anchoring through palmitic acid residues occurs at cysteine residues

mouse cell human cell fuse cells wait Experiment of Frye and Edidin uman cells labelled with red fluorescent dye were fused with mouse cells labelled with green fluorescent dye. After time, rapid mixing of the fluorescently labelled cell surface proteins was observed. This demonstrated the lateral diffusion of protein components in the membrane

Transport Across Biological Membranes A wide variety of molecules and ions must be transported across membranes. Some small uncharged molecules cross membranes by simple diffusion. Large and/or highly charged molecules are transported by a variety of mechanisms.

Passive Transport Facilitated diffusion: The protein assisted diffusion of a molecule or ion down its concentration gradient. Transport is effected by membrane transport proteins: integral proteins that span both leaflets of the bilayer. These proteins are either pores or gates. Pore: water-filled hole through which appropriately sized molecules can pass in either direction.

Gate: binds molecule on one face of bilayer; undergoes conformational change allowing release of molecule on the other side. Glucose Permease (erythrocytes):

A single transporter may transport more than one molecule. Antiport: transport of two molecules in opposite directions across a membrane. Symport: transport of two molecules in the same direction across a membrane. Band 3 protein: Found in human red blood cells. Transports CO 3 - out and Cl- into the cell (down their concentration gradients). A type of antiporter.

Active Transport The net movement of a molecule up or against its concentration gradient. Active transporters are always gates; never pores. The hallmark feature of active transport is that it requires a source of energy.

Primary active transport: Fueled by primary energy sources such as the hydrolysis of ATP. Na + /K + ATPase: Transports two K+ into the cell and three Na+ out for every molecule of ATP hydrolyzed. ydrolyzes approx. 100 molecules of ATP per minute. Maintains intracellular [K+] at 100mM (5-10mM extracellular) and intracellular [Na+] at 10mM (140mM extracellular).

Secondary active transport: Driven by ion gradients. Flow of ions down their concentration gradient provides a source of free energy to used to pull molecules into the cell against their concentration gradients. Lactose Permease: Found in E. coli. Carries out 1:1 symport of + and lactose. The influx of + down its conc. gradient pulls lactose into the cell up its conc. gradient.