Lipids I

Fatty acids and simple lipidsComplex lipids

Medical Chemistry Lecture 11 2007 (J.S.)

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Lipidsare – naturally occurring compounds, of animal or plant origin, – because of their hydrophobicity, soluble in organic solvents

(only sparingly, if at all, soluble in water).

Structure of lipids from the chemical point of view:

Esters (or amides) of long-chain fatty acids with aliphatic or alicyclic) alcohols or aminoalcohols.

Two major biological function of lipids:– Triacylglycerols (fats) are nutrients, the turnover about 100 g per day in

adult humans, the only source of essential fatty acids, and a vehicle allowing intake and

resorption of lipophilic vitamins. Fat represents an energy reservoir in animal bodies and oily fruits of plants.– Phospholipids and glycolipids form lipid dilayer of biomembranes, the turnover about 2 g / d in adult humans.

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Major classes of lipids

Simple lipids Triacylglycerols (fats) Waxes Ceramides

Complex lipids Phospholipids Glycolipids

Derived "lipids"Eicosanoids (originate by transformation of polyunsaturated fatty acids)Isoprenoid compounds – squalene, dolichol, carotenoids, cholesterol, phytosterols, calciols and other steroidsAccompanying compounds – lipophilic vitamins (tocopherols,

phylloquinone, retinol)

amphipathic molecules(tensides)

hydrophobic molecules

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Classification of fatty acids (FA):– saturated – monounsaturated (monoenoic) – polyunsaturated (PUFA, containing two or more double

bonds)– short-chain fatty acids ( C4 – C10 )

– medium-chain ( C8 – C10 ) – long-chain fatty acids ( C12 )

Fatty acids – general propertiesFatty acids– are aliphatic monocarboxylic acids– contain an even number of carbons because they are synthesized

from two-carbon units (acetyl-CoA)– may have saturated chains (containing no double bonds)

or unsaturated chains (one or more double bonds,nearly all of the cis configuration and not conjugated)

– are non-polar due to their aliphatic chains (practically water-insoluble)

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The common naturally occurring fatty acids

Number of carbonsand double bonds

Common name Systematic name

Saturated fatty acids4:0 Butyric butanoic

6:0 Caproic hexanoic

8:0 Caprylic octanoic

10:0 Capric decanoic

12:0 Lauric dodecanoic

14:0 Myristic tetradecanoic 16:0 Palmitic hexadecanoic

18:0 Stearic octadecanoic

20:0 Arachidic eicosanoic

22:0 Behenic docosanoic

24:0 Lignoceric tetracosanoic

Unsaturated fatty acids16:1 (9) Palmitoleic cis -hexadec-9-enoic

18:1 (9) (n–9) Oleic cis-octadec-9-enoic

18:2 (9,12) (n–6) Linoleic cis ,cis -octadeca-9,12-dienoic

18:3 (6,9,12) (n–6) -Linolenic cis ,cis -octadeca-6,9,12-trienoic

18:3 (9,12,15) (n–3) -Linolenic all -cis -octadeca-9,12,15-trienoic

20:4 (5,8,11,14) (n–6) Arachidonic all -cis -eicosa-5,8,11,14-tetraenoic

20:4 (5,8,11,14,17) (n–3) (Timnodonic) EPA all -cis -e icosa-5,8,11,14,17-pentaenoic

(n–7)

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18 : 3 (n–3)

C OO–18 15 12 9

n n-3 n-6 n-9

Linolenic acid (unionized form)Linolenate (ionized form)

18 : 3 (9,12,15)

positions of double bonds (numbering from the carboxyl carbon number 1)

number of double bonds

total number of carbon atoms

Nomenclature of unsaturated fatty acids

Example: all-cis-Octadeca-9,12,15-trienoic acid (systematic name)

Common trivial name

occasionally also 18:3 (3)

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18:1 (n-9)

16:0

Saturated long-chain fatty acidsare solid

Presence of unsaturated acids- lowering of the temperature

of thawing

The presence of cis double bonds is the cause of "bent“ molecules:

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Polyunsaturated fatty acids (n-6 and n-3)are essential for animals

In higher animals, only the desaturases are known which generatedouble bonds at carbons 9, 6, 5, and 4.

Fatty acids containing double bonds beyond C-9 (acids n-6 and n-3) are synthesized by plants. They are essential dietary constituents for animals and serve as precursors of eicosanoids (prostanoids and leukotrienes).Providing the dietary intake is sufficient (vegetable seed oils, resp. fish), linoleate and α-linolenate act as precursors of other essential polyenoic acids such as arachidonate (n-6) and eicosapentaenoate (n-3), from which eicosanoids are formed.

Linoleate 18:2 (9,12)

γ-Linolenate 18:3 (6,9,12)

Eicosatrienoate 20:3 (8,11,14)

Arachidonate 20:4 (5,8,11,14)

6-desaturation

elongation

5-desaturation

α-Linolenate 18:3 (9,12,15)

Octadecatetraenoate 18:4 (6,9,12,15)

Eicosatetraenoate 20:4 (8,11,14,17)

Eicosapentaenoate 20:5 (5,8,11,14,17)

6-desaturation

elongation

5-desaturation

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Polyunsaturated fatty acids of lipids exposed to oxygen may be subjectsof auto-oxidation initiated by light or by metal ions – the primary cause ofdeterioration of fat (rancidity).

In vivo, similar undesirable lipid peroxidation is initiated by free radicals,mostly by the hydroxyl radicals •OH. Lipid peroxidation is a chain reactionproviding a supply of further free radicals (RO•, ROO•).

malondialdehyde

(•OH) (O2 )

hydroperoxide

further products(ethane, unsaturated hydrocarbons, higher unsaturated aldehydes, etc.)

endoperoxide

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Trans-fatty acids are present in certain foods.

The presence of trans-fatty acids in human nutrition seems to be harmful(e.g., an unfavourable effect on cholesterol metabolism). Most arise as a by-product during the "hardening" of vegetable oils into margarinesby means of metal-catalyzed hydrogenation.An additional contribution comes from the ingestion of ruminant fat that containstrans-fatty acids (beef tallow 3-7 %, butter 3 %) arising from the action ofmicroorganisms in the rumen.

The shape of trans-unsaturated acids resembles that of saturated fatty acids:

cis-unsaturated

trans-unsaturated saturated FA

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sn-glycerol

Glycerol (propane-1,2,3-triol)– a component of triacylglycerols (fats and oils) and glycerophospholipids

Alcohols as constituents of lipids:

Glycerol is a symmetrical (non-chiral) compound. Derivatives,in which two of the carbons bind different groups, are chiral.In lipid chemistry, it is required to number the carbon atoms

of glycerol unambiguously and the –sn– (stereospecific numbering) system isused:

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1

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Sphingosine(4E)-sphingenine (systematic name (2S,3R,4E)-2-aminooctadec-4-ene-1,3-diol)contains 18 carbons atoms, trans-double bond in position 4, amino group at position 2, and two hydroxyls at position 1 and 3.

CH–CH–CH2–OH

NH2

OH

The group name sphingosine is used also for dihydrosphingosine (sphinganine)and the C16, C17, C19, and C20 homologs of sphingenine and sphingosine.

Long-chain aliphatic alcoholsare constituents of waxes, e.g.

hexadecan-1-ol (cetyl alcohol, palmityl alcohol) – in spermaceti,octadecan-1-ol (stearyl alcohol),hexacosan-1-ol (ceryl alcohol) - in bees-wax.

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Simple lipidsTriacylglycerols (fats and vegetable oils)WaxesCeramides

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Triacylglycerolsare esters of glycerol and fatty acids.Natural fats and oils (butterfat, lard, olive oil, etc.) consists not of a singletriacylglycerol, but of a complex mixture of triacylglycerols. A smallportion of diacyl- and monoacylglycerols may be included.

For example:

1-stearoyl-2-oleoyl-3-palmitoyl-sn-glycerol

Triacylglycerols TGDiacylglycerols DGMonoacylglycerols MG, e.g.

2-oleoyl-glycerol (a 2-monoacylglycerol)

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Physical properties of triacylglycerols

The melting points of triacylglycerols depend on the degree of unsaturationof bound acyls.A triacylglycerol containing all saturated fatty acids of 12 carbons andmore is a solid fat at body temperature.Oils contain a higher percentage of unsaturated fatty acids than do fats.

The more double bonds are present in the fatty acid portion of the triacylglycerol, the lower is its melting point.

The reason for the effect of saturation or unsaturation on the melting pointof triacylglycerols is in the bent structure of unsaturated fatty acyls. In fully saturated triacylglycerols, the long, saturated chains have extended conformations that can pack together fairly regularly (numerous dispersion inter-molecular interactions), as in a crystal. Unsaturated triacylglycerols cannot align in a crystalline array, the substance therefore remains a liquid.

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Fatty acid composition of some fats and oils

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Chemical transformations of fats and oils

Converting of vegetable oils into fats which are solid or semi-solid at room temperature – "fat hardening"

Interesterification (intermolecular exchange of acyl residues in triacylglycerols) between vegetable oils and solid fats (coconut fat, hog lard, beef tallow) is a process that provides fats or oils with new properties without the accumulation of trans-FA.

The spreadable fats obtained from either vegetable oils or solid animal fat are known as margarines. The fat in margarine, which is 80 – 40 % by weight, contains emulsified water and the emulsion is stabilized by emulsifiers ( 0.5 % mono- and diacylglycerols, crude lecithin, etc.). The product may be also stirred and shaken with skim milk to mimic butter's appearance.

An old process (developed in 1902) is based on the hydrogenation of unsaturated triacylglycerols using nickel as a catalyst.A drawback of the hydrogenation is the extent of undesirable stereoisomerization -production of trans-monounsaturated fatty acids.

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Hydrolysis of triacylglycerols

Soap (alkali salts of long-chain fatty acids) is an anionic tenside.

Ester bonds in triacylglycerolscan be hydrolyzed by boiling with mineral acids or alkaline hydroxides.

Hydrolysis by acids will give glycerol and free fatty acids.

Alkaline hydrolysis is called saponification, because triacylglycerols areconverted into glycerol and the alkaline salts of fatty acids – soaps.

In the small intestine, hydrolysis of ingested fats is catalyzed by pancreatic lipase(at pH value about 7.5 – 8.8). The hydrolysis is not complete, two natural tensidesare produced:

two molecules of soap (an anionic tenside) and 2-monoacylglycerol (a non-ionic tenside).

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The processes responsible for the development of rancidity include– oxidations (see Lipid peroxidation) that produce hydroperoxides and

many secondary products as hydrocarbons, aldehydes, carboxylic acids, and

– hydrolysis of ester bonds (namely due to bacterial action) that releases free short-chain fatty acids with an unpleasant odour.

Rancidity of fats and oils

Lipid peroxidation of unsaturated lipids can be retarded by– exclusion of oxygen– storage at low temperature in the dark– addition of antioxidants to food.

After certain time, fats containing unsaturated fatty acyls turn rancid.The process is accelerated, if fats are exposed to oxygen, heat, light,contain microorganisms, mould, trace amount of metals, or high proportionof water.

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– Fats should not cover more than 30 % energy intake.

– Restriction of fats that contain large amount of saturated fatty acids (often accompanied by cholesterol).

– Enhanced intake of olive or rapeseed oil as well as of emulsified margarines (instead of butter).

– Avoid intake of trans-fatty acids, burnt fat, reasonable amount of fried food.

Fats and oils in nourishment – recommendations:

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E.g., small amount of waxes is secreted by sebaceous glands of mammals. Lanolin is the fatty substance extracted from sheep's wool; it is a complex mixture

of waxes, long-chain alcohols and free and esterified sterols used as basis of ointments

Spermaceti (hexadecyl palmitate) – a liquid wax contained in heads of sperm-whale (cachalot).

Beeswax – one of the major components is hexacosyl hexacosanoate.

are natural mixtures of esters of saturated long-chain fatty acidsand aliphatic long-chain primary alcohols.

Waxes (cerides)

Ceramides (N-acylsphinghosines)

Although free ceramides are not found in animal tissues, they represent thebasal lipidic structure of all types of sphingolipids.

Complex lipids

Phospholipids Glycerophospholipids Plasmalogens

Sphingophospholipids

GlycolipidsSphingolipids

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Schematic structures of complex lipids

The "head“ group

GlycolipidsSphingophospholipids

The "head“ group

Plasmalogens

The "head“ group

Glycerophospholipids

Sphingolipids:

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The major glycerophospholipids

The "head“ group

The simplest glycerophospholipid is phosphatidic acid (phosphatidate, 1,2-diacyl-sn-glycerol 3-phosphate).Only very small amounts of phosphatidateare present in membranes. However, themolecule is a key intermediate in the biosynthesisof the glycerophospholipids.

Glycerophospholipids

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1,2-diacyl-sn-glycerol 3-phosphatePhosphatidic acid

Phosphatidyl is the name of a remainder obtained by taking off –OH group.

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Alcohols – the hydrophilic head groupsattached to phosphatidate through ester bondsin various types of glycerophospholipids

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+

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All phospholipid types are natural tensides– the main lipid constituents of membranes

Dipolar (amphoteric) glycerophospholipids – phosphatidyl choline – phosphatidyl ethanolamine - each of them has one negative and one positive

electric charge

Acidic glycerophospholipids – phosphatidyl serine - two negative and one positive electric charge

– phosphatidyl inositol - one negative electric charge

– bisphosphatidyl glycerol - two negative electric charges

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Phosphatidyl inositol(up to 20 % membrane phospholipids)

Phosphorylation of PI generates phosphatidyl inositol 3,4-bisphosphate (PIP2)which is an intermediate of the phosphatidyl inositol cycle that generatesby hydrolytic splitting two intracellular messengers IP3 and diacylglycerol.

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Lysophospholipids (2-deacylphospholipids)are intermediates of phospholipid metabolism

Plasmalogens (mostly plasmenyl cholines)

are a group of 1-O-(alken-1-yl)-2-O-acylglycerophospholipids,enol-ether lipids. They represent about 10 % phospholipids in brain and muscles..

alk-1-enylenol-ether bond

acyl

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Glycerophospholipids are– essential structural components of all biological membranes,– essential components of all types of lipoproteins in extracellular fluids,– supply polyunsaturated fatty acids for the synthesis of eicosanoids,– act in anchoring of some proteins to membranes,– serve as a component of lung surfactant– phosphatidyl inositols are precursors of second messengers (PIP2, DG),

etc.

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Anchoring of proteins to membrane

The linkage between the COOH-terminusof a protein and phosphatidylinositol fixedin the membrane lipidic dilayer exist inseveral ectoenzymes (alkaline phosphatase,acetylcholinesterase, some antigens).

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Lung surfactant

The major component of lung surfactant is dipalmitoylphosphatidylcholine.

It contributes to a reduction in the surface tension within the alveoli (air spaces) of the lung, preventing their collapse in expiration. Less pressure is needed to re-inflate lung alveoli when surfactant is present.

The respiratory distress syndrome (RDS) of premature infants is caused, at least in part, by a deficiency in the synthesis of lung surfactant.

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Sphingolipids – schematic structure

A glycolipidA sphingophospholipid

The "head“ group

CeramideN-Acylsphingosine

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Sphingosine (trans-2-aminooctadec-4-ene-1,3-diol).

Ceramides are N-acylated sphingosines. The acyl residue is attached to the amino group of sphingosine by an amide link:

The acyl residue has often 24 carbon atoms (lignoceric acid or its derivatives).

Ceramide is the lipidic part of all types of sphingolipids.

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Glycolipidsare ceramides to which a saccharide component is attached by glycosidicbond: monoglycosylceramides – cerebrosides, oligoglycosylceramides,acidic sulphoglycosylceramides, and sialoglycosylceramides – gangliosides.

Sphingolipids Sphingophospholipids are esters of ceramide-1-phosphate and ethanolamine or (mostly) choline. Ceramide phosphocholines are called sphingomyelins.

Phosphocholine

β-D-Glucopyranosyl

Cerebroside:

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Sphingophospholipids

Sphingomyelin is the most abundant sphingophospholipid and isfound in myelin (the fatty substance of the sheath around neurons.

phosphoryl group choline

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Cerebroside(1-O-glucosylceramide)

Glycolipidsare important in nerve tissues and in the plasma membrane. They occurparticularly in the outer leaflet of the plasma membrane, where theycontribute to cell surface saccharides (glycocalyx).

β-D-glucopyranosyl

The most simple glycolipids are cerebrosides – monoglycosylceramides

Glucosylceramide is the predominant glycolipid in extraneuronal tissues, whilegalactosylceramide is a major glycolipid of brain and other nervous tissue.

Galactosylceramides can be sulfated and the products – sulfoglycolipids(sulfatides) are present in high amounts in myelin.

Complex saccharidic component that contain in addition one or more moleculesof sialic acid is present in gangliosides

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Saccharidic components of glycolipids - examples:

Cerebroside Ceramide–(1←1β)Glc

Oligoglycosylceramide Ceramide–(1←1β)Glc (4←1β)Gal

Sulfoglycosphingolipid Ceramide–(1←1β)Glc-3´-sulfate

Gangliosides GM3 (monosialoganglioside type III)

Ceramide–(1←1β)Glc-(4←1β)Gal (3←2α) NeuAc

GM2 Ceramide–(1←1β)Glc-(4←1β)Gal-(4←1β)GlcNAc

(3←2α) NeuAc

GM1 Ceramide–(1←1β)Glc-(4←1β)Gal-(4←1β)GlcNAc-(3←1β)Gal (3←2α) NeuAc

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Ganglioside GM2

Ceramide–(1←1β)Glc-(4←1β)Gal-(4←1β)GlcNAc

(3←2α)NeuAc

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In spite of the difference in the structures of glycerophosphoplipids and sphingophospholipids, the over-all shape of the both types ofphospholipid (as well as of glycolipid) molecules is very similar:

Glycerophospholipid Sphingophospholipid Simplified icon of a phospholipid or glycolipid molecule

Polar head

Two hydrophobicchains

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A flat micelle, a bimolecular lipid layer

Rapid lateral diffusion(a fluid mosaic)

Very slow transverse diffusion(flip-flop)

Membrane proteins areinserted in lipid bilayeror bound to either surface.

Phospholipids (and glycolipids) are the main lipid constituents of membranes:

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