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
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
