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LIPIDS

1. Simple - esters of fatty acids with various alcohols


a. fats - esters of fatty acids with glycerol
Oils are fats in the liquid state
b. waxes - esters of fatty acids with higher molecular weight monohydric alcohols
2. Complex - esters of fatty acids containing groups in addition to an alcohol & a fatty acid
a. phospholipids = fatty acid + alcohol + phosphoric acid residue
- have nitrogen-containing bases & other substituents
Ex: glycerophospholipids - alcohol is glycerol
Sphingophospholipids - alcohol is sphingosine
b. glycolipids / glycosphingolipids = fatty acid + sphingosine + carbohydrate
c. other complex lipids - sulfolipids, aminolipids, lipoproteins
3. Precursor & derived lipids
- fatty acids, glycerol, steroids, other alcohols, fatty aldehydes & ketone bodies, hydrocarbons, lipid-soluble vitamins, & hormones

Neutral lipids - uncharged


- acylglycerols / glycerides, cholesterol & cholesteryl esters

FATTY ACIDS ARE ALIPHATIC CARBOXYLIC ACIDS


Free fatty acids - unesterified
Neutral fats & oils - esterified
- straight-chain derivatives containing an even # of C atoms
Saturated - no double bond
Unsaturated - 1 or more double bonds

FATTY ACIDS ARE NAMED AFTER CORRESPONDING HYDROCARBONS


- named after the hydrocarbon with the same # & arrangement of C atoms
- Saturated - anoic
Unsaturated - enoic
- C atoms are numbered from the carboxyl C
- terminal methyl C is known as the ω or n-carbon

SATURATED FATTY ACIDS CONTAIN NO DOUBLE BONDS


- based on acetic acid (CH3-COOH) as the 1st member of the series in which CH2 is added between the terminal CH3 & COOH groups

UNSATURATED FATTY ACIDS CONTAIN 1 OR MORE DOUBLE BONDS


1. Monounsaturated acids- 1 double bond
- monoethenoid, monoenoic
2. Polyunsaturated acids - 2 or more double bonds
- polyethenoid, polyenoic
3. Eicosanoids - derived from 20 C polyenoic fatty acids
a. prostanoids
- prostaglandins
*synthesized in vivo by cyclization of the center of the C chain of 20 C polyunsaturated fatty acids (arachidonic acid) to
form a cyclopentane ring
*E type - has a keto group in position 9
F type - hydroxyl group in position 9
- prostacyclins
- thromboxanes
*have the cyclopentane ring interrupted with an O atom (oxane ring)
b. Leukotrienes
-cause bronchoconstriction as well as being potent proinflammatory agents & play a part in asthma
c. lipoxins
(b&c) - 3rd group of eicosanoid derivatives formed via the lipoxygenase pathway
- characterized by 3 or 4 conjugated double bonds

MOST NATURALLY OCCURRING UNSATURATED FATTY ACIDS HAVE CIS DOUBLE BONDS
Saturated - C chains form a zigzag pattern when extended, as at low temperatures
- at high temperatures, some bonds rotate causing chain shortening which explains why biomembranes become thinner
Unsaturated - geometric isomerism occurs depending on the orientation of atoms or groups around the axes of double bonds which do not
allow rotation
1. Cis - acyl chains are on the same side of the bond
- naturally occurring unsaturated long-chain fatty acids
- molecules being bent 120 degrees at the double bond
- oleic acid - L shape
- increase in # of cis double bonds leads to a variety of possible spatial configurations of the molecule
- arachidonic acid - 4 cis double bonds & has kinks or U shape
2. Trans - acyl chains are on opposite sides
- elaidic acid - straight
- trans double bonds alter spatial relationships
- trans fatty acids are present in certain foods arising as a by-product of the saturation of fatty acids during hydrogenation
or hardening of natural oils in the manufacture of margarine

PHYSICAL & PHYSIOLOGICAL PROPERTIES OF FATTY ACIDS REFLECT CHAIN LENGTH & DEGREE OF UNSATURATION
- the melting points of even-numbered-C fatty acids increase with chain length & decrease according to unsaturation
- triacylglycerol containing 3 saturated fatty acids of 12C or more is solid at body temperature
- if fatty acid residues are 18:2, it is liquid below 0°C
- membrane lipids, which must be fluid at all environmental temperatures, are more unsaturated than storage lipids

TRIACYLGLYCEROLS / TRIGLYCERIDES ARE THE MAIN STORAGE FORMS OF FATTY ACIDS


- sn (stereochemical numbering) system is used to # the C atoms of glycerol
- C 1 & 3 of glycerol are not identical when viewed in 3D
- glycerol is always phosphorylated on sn-3 by glycerol kinase to give glycerol 3-phosphate & not glycerol 1-phosphate

PHOSPHOLIPIDS ARE THE MAIN LIPID CONSTITUENTS OF MEMBRANES


- derivatives of phosphatidic acid in which the phosphate is esterified with the OH of a suitable alcohol
- phosphatidic acid - intermediate in the synthesis of triacylglycerols & phosphoglycerols but not found in great quantity in tissues
- most phospholipids have a saturated acyl radical in the sn-1 position but an unsaturated radical in the sn-2 position of glycerol

1. Phosphatidylcholines / Lecithins
- most abundant in cell membrane
- contain choline - nervous transmission (acetylcholine) & as a store of labile methyl groups
- ex: dipalmitoyl lecithin - effective surface-active agent
- major constituent of the surfactant preventing adherence (due to surface tension) of the inner surfaces of
the lungs
- its absence from the lungs of premature infants causes respiratory distress syndrome
- phosphatidylethanolamine (cephalic) & phosphatidylserine (in most tissues) differ from phosphatidylcholine only in that
ethanolamine or serine replaces choline
2. Phosphatidylinositol
- precursor of 2nd messengers
- inositol is present as the stereoisomer, myoinositol
- ex: phosphatidylinositol 4,5-biphosphate - important constituent of cell membrane phospholipids
- cleaved into diacylglycerol & inositol triphosphate which both act as internal signals or
signal messengers
3. Cardiolipin
- major lipid of mitochondrial membranes
- precursor of phosphatidylglycerol which gives rise to cardiolipin
4. Lysophospholipids
- intermediates in the metabolism of phosphoglycerols
- phosphoglycerols containing only 1 acyl radical
- ex: lysophosphatidylcholine / lysolecithin - metabolism & interconversion of phospholipids
- also found in oxidized lipoproteins
- has been implicated in some of their effects in promoting atherosclerosis
5. Plasmalogens
- occur in brain & muscle
- resemble phosphatidylethanolamine but possess an ether link on the sn-1 C instead of ester link found in acylglycerols
- alkyl radical is an unsaturated alcohol
6. Sphingomyelin
- found in the nervous system
- on hydrolysis, yield a fatty acid + phosphoric acid + choline + sphingosine (complex amino alcohol)
- no glycerol is present
- ceramide = sphingosine + fatty acid
- also found in glycosphingolipids

GLYCOLIPIDS / GLYCOSPHINGOLIPIDS ARE IMPORTANT IN NERVE TISSUES & IN THE CELL MEMBRANE
- widely distributed in every tissue of the body
- occur in the outer leaflet of the cell membrane where they contribute to cell surface carbohydrates
- found in animal tissues
- contain ceramide & 1 or more sugar
- ex: galactosylceramide - major glycosphingolipid of brain & nervous tissue
- contain a C24 fatty acids such as cerebronic acid
- sulfogalactosylceramide / sulfatide - high amount in myelin
- glucosylceramide - predominant simple glycosphingolipid of extraneural tissues; small amount in brain
- gangliosides - complex glycosphingolipids derived from glucosylceramide that contain in addition 1 or more molecules of sialic acid
- present in nervous tissues in high concentration
- have receptor
- GM3 - simplest ganglioside found in tissues
= ceramide + glucose + galactose + neuraminic acid
- GM1 - more complex ganglioside derived from GM3
- receptor in human intestine for cholera toxin
- neuraminic acid - principal sialic acid found in human tissues

STEROIDS PLAY MANY PHYSIOLOGICALLY IMPORTANT ROLES


- all have a similar cyclic nucleus resembling phenanthrene (rings A,B,C) to which a cyclopentane ring (D) is attached
- a simple hexagonal (benzene) ring denotes a completely saturated 6C ring with all valences satisfied by hydrogen bonds
- methyl side chains are shown as single bonds unattached at the farther methyl end
*positions 10 & 13 (C atoms 18 & 19)
- a side chain at position 17 is usual
- sterol - has 1 or more hydroxyl groups & no carbonyl / carboxyl groups

1. Cholesterol
- best known steroid because of its association with atherosclerosis
- precursor of a large # of equally important steroids that include bile acids, adrenocortical hormones, sex hormones, vit. D,
cardiac glycosides, sitosterols of plants, & some alkaloids
- widely distributed in all cells of the body but particularly in nervous tissue
- major constituent of cell membrane & of plasma lipoproteins
- often found as cholesteryl ester where the OH group on position 3 is esterified with a long-chain fatty acid
- occurs in animals but not in plants
2. Ergosterol
- vit. D precursor
- occurs in plants & yeast
- when irradiated with UV light, acquires antirachitic properties consequent to the opening of ring B
3. Polyprenoids
- share the same parent compound as cholesterol
- not steroids
- synthesized like cholesterol from 5C isoprene units
- ex: ubiquinone - a member of respiratory chain in mitochondria
Dolichol - long-chain alcohol which takes part in glycoprotein synthesis by transferring carbohydrate residues to
asparagines residues of the polypeptide
- plant-derived isoprenoid compounds include rubber, camphor, fat-soluble vitamins (A,D,E,K) & beta-carotene (provitamin A)

BECAUSE OF ASSYMETRY IN THE STEROID MOLECULE, MANY STEREOISOMERS ARE POSSIBLE


- each of the 6C rings of the steroid nucleus is capable of existing in the 3D conformation either of a “chair” or “boat”
- chair - more stable
- naturally occurring steroids
- rings can be either cis or trans
-

LIPID PEROXIDATION (AUTO-OXIDATION) IS A SOURCE OF FREE RADICALS


- responsible not only for deterioration of foods (rancidity) but also for damage to tissues in vivo where it may be a cause of
cancer, inflammatory diseases, atherosclerosis & aging
- molecular precursor is the hydroperoxide product ROOH
- catalyzed in vivo by heme compounds & lipoxygenases found in platelets & WBC
- other products of auto-oxidation or enzymic oxidation of physiologic significance include
oxysterols (cholesterol) & isoprostanes (prostanoids)
1. Initiation
2. Propagation
3. Termination

ANTIOXIDANTS
*food additives
propyl gallate
butylated hydroxyanisole (BHA)
butylated hydroxytoluene (BHT)
*naturally occurring
Vit. E (tocopherol) - lipid-soluble
Urate & vit. C - water-soluble
Beta-carotene - at low PO2
1. Preventive - reduce the rate of chain initiation
Catalase & other peroxides that react with ROOH
Chelators of metal ions - EDTA & DTPA (diethylenetriaminepentaacetate)
2. Chain-breaking - interfere with chain propagation
superoxide dismutase - acts in the aqueous phase to trap superoxide free radicals O2•
Urate
Vit. E - acts in the lipid phase to trap ROO radicals
AMPHIPATIHIC LIPIDS SELF-ORIENT AT OIL:WATER INTERFACES
Fatty acids, phospholipids, sphingolipids, bile salts, cholesterol - contain polar groups
1. Lipid Bilayer
2. Micelles
- critical concentration of lipids is present in aqueous medium
*facilitate absorption of lipids from the intestine
Aggregations of bile salts into micelles & liposomes
Formation of mixed micelles with the products of fat digestion
3. Liposomes
- formed by sonicating an amphipathic lipid in an aqueous medium
- consist of spheres of lipid bilayers that enclose part of the aqueous medium
- carriers of drugs in the circulation when combined with tissue-specific antibodies (cancer therapy)
- used for gene transfer into vascular cells
- carriers for topical & transdermal delivery of drugs & cosmetics
4. Emulsions
- larger particles formed usually by non-polar lipids in an aqueous medium
- stabilized by emulsifying agents such as amphipathic lipids (lecithin) which form a surface layer separating the main bulk of the non-
polar material from the aqueous phase

METABOLISM OF ACYLGLYCEROLS & SPHINGOLIPIDS


Dipalmitoyl lecithin - major component of lung surfactant
Inositol phospholipids in cell membrane - precursors of hormone 2nd messengers
Alkyl phospholipids - platelet activating factor
Glycosphingolipids form part of the glycocalyx of the cell surface
- cell adhesion & cell recognition
- receptors for bacterial toxins
- ABO blood group substances

CLINICAL ASPECTS
Lung surfactant - respiratory distress syndrome
dipalmitoylphosphatidylcholine
Phospholipids & sphingolipids
1. Demyelinating diseases - Multiple Sclerosis
- loss of both phospholipids (ethanolamine plasmalogen) & sphingolipids from white matter
- lipid composition of white matter resembles that of gray matter
- CSF shows raised phospholipids levels
2. Sphingolipidoses (lipid storage diseases)
- often manifested in childhood
- part of a larger group of lysosomal disorders
*complex lipids containing ceramide accumulate in cells (neurons) causing neurodegeneration & shortening the life
span
*rate of synthesis of stored lipid is normal
*enzymatic defect is in lysosomal degredation pathway of sphingolipids
*extent to which the activity of affected enzyme is decreased is similar in all tissues
a. Tay Sachs - hexosaminidase A -blindedness, muscular weakness
b. Krabbe’s - beta-galactosidase - myelin almost absent
c. Gaucher’s - beta-glucosidase -erosion of long bones; - enlarged liver & spleen
d. Niemann-Pick - sphingomyelinase - enlarged liver & spleen; - fatal in early life
e. Farber’s - ceramidase - hoarseness, dermatitis, skeletal deformation; - fatal in early life
- Multiple sulfatase deficiency - accumulation of sulfogalactosylceramide, steroid sulfatases & proteoglycans owing to a
combined deficiency of arylsulfatases A,B,C & steroid sulfatases

Reference:
Harper’s Biochemistry 28th edition

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