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Kerasin : R = lignoceric acid (C3HCOOH) , acetate Cerebron (Phrenosin) = God...

Kerasin : R = lignoceric acid (C3HCOOH) , acetate Cerebron (Phrenosin) = God Otac, tos lignocerica , Neuron : I double bond a deic acid Oxynerion : Oh Chatterjea, M. N., and R. Shinde. Textbook of Medical Biochemistry. 8th ed., Jaypee Brothers Medical Publishers, 2012. Chapter 4. Chemistry of Lipids 59 CLINICAL IMPORTANCE There is no glycerol, no phosphoric acid and no nit- sphingolipid o Des glycerol rogenous base. Thus, a cerebroside, on hydrolysis, yields: (a) Dipalmityl lecithin (DPL): D PL acts as a surfactant and A sugar, usually galactose, but sometimes glucose lowers the surface tension in lung alveoli. The lung alveoli Hydrolysis A high molecular weight fatty acid and bride Palmitoyl COA Serine Sphingosine contains 2 types of cells. + 1 Type-I: These are thin cells which line the much of alveolar The alcohol, sphingosine or dihydrosphingosine. -3 CH-CHsurface, Thus they contain nitrogens though there is no SECTION TWO HO = and CH-ICHalee-CHe NH-c-umi9 These are granular pneumocytes, round cells Type-II: A nitrogenous base. eCH - and contain lamellar inclusions. These inclusions contain 4) depends on FA types Types of cerebrosides: Individual cerebrosides are differ- 'He -o surfactant, x - D PL, which is secreted from these cells by entiated by the kinds of fatty acids in the molecule. Four exocytosis. Surface activity is that phenomenon whereby the surface types of cerebrosides have been isolated and their fatty Xi H - tension of the air-alveolar : lining interfa ce is lowered with Ceramide acids have been identified. They are: expiration due to presence Phosphocholine - : of DPL. In absence sphingomyelin of normal e myelin surface sheath Kerasin: Contains normal lignoceric acid, C23H47 activity, if DPL is absent, the alveolar radius becomes smaller glycolipids Glucosylcereboside COOH as fatty acid. Lignoceric acid is synthesi- Glucose - · with expirations, the wall tension rises and the alveoli zed from ‘acetate’, by repeated condensation of C2 disac - (oc-Gall collapse. Absence;of DPL, Lactosylceramide in premature foetus, produces units. Complex oligosac collapse of lung alveoli, Ganglioside which produce &Mrespiratory distress - · 2 Cerebron (Phrenosin): Contains hydroxy lignoceric syndrome (hyaline-membrane disease). (b) Lecithin-Sphingomyelin Ratio (L/S ratio): L/S ratio in acid, also called cerebronic acid. This fatty acid is Amniotic fluid has been used for the evaluation of fetal directly formed by hydroxylation (at 2 position) of Cerebroside (ceramide Glands Ex Glucosylceramide I sats lignoceric acid. · + lung maturity. Prior to 34 we eks gestation, , the amniotic fluid Intermediate glycolipid lecithin and sphingomyelin concentrations are approximately Nervon: Contains an unsaturated homologue of - peripheral equal. After this time, system there issheath + myelin a marked incre ase in lecithin nervous lignoceric acid called nervonic acid (C23H45 COOH). ~ and L/S ratio incre ases to gre ater than 5 at term. Nervonic acid has one double bond, appears to be A L/S ratio of > 2 or > 5 indicate adequate foetal lung I monounsat formed by elongation of oleic acid, i.e. from a C18 to maturity a nd sugg e sts th at re spiratory distre ss after delivery is not likely to develop. a C24 monounsaturated fatty acid. D elivery of a premature low weight fetus, with L/S ratio Oxynervon: Contains hydroxy derivative of nervonic approximately 1 or Reticula in non-medullated nerve fibres. en do the lial c ells viz., liver, sple e n, bon e m arrow a nd also brain. Structure: A cerebroside is considered to be built on the C omplex lipids appe ar to collect within mitochondria of following: the R E cells. Biochemically, there is characteristically elevation in serum acid phosphatase level. FA of high molecular weight Clinical features: Adults as well as infants are affected. Sphingosine Usually galactose but (a) In infancy and childhood: Fairly acute onset, with rapid course and de ath in several ye ars. The infant loses weight, sometimes may be glucose. Gaucher's Disease (ARI Cerebosides· white matter · Acid phosphatase & B-glucocerebrosidase : lysosomal · myelin · Kerasin & · medullated nerves infant ; MR - Gla a dult ; hepatospleenomegaly bone pair progressive anaemia Leuco(WBCs ① encoonwoncell livan cell so o : thrombin Brisi (platlet/  · Ganglioside (sphingosine + heteropolysac I > - cell membrane receptors > - gray matter > - OM1 , GM2 GM3 8 I NANA (N-acetylneuraminic acid) , 60 Chemistry of Biomolecules fails to grow, progressive mental retardation. Initially ther* Structure: Although the exact structures of the ganglio- sides are not definitely established. On hydrolysis, gang- e is spasticity, later on followed by flaccidity. liosides yield the following: (b) In adult: Progressive enlargement of sple en (spleno- A long chain FA (usually C18 to C24). megaly) which may re ach to umbilicus or below. C harac- teristic bone pain due to marrow cells replaced by histiocytes Alcohol-sphingosine. A carbohydrate moiety which usually contains: SECTION TWO loaded with the lipids. As a result le ads to progressive anaemia, leucopenia and thrombocytopenia , tendency to – Glucose and/or galactose, get secondary infections and ble eding tendency. – One molecule of N-acetyl galactosamine, and – At least one molecule of N-acetyl neuraminic 2. GANGLIOSIDES acid (NANA) (also called ‘sialic acid’). Brain gangliosides are known to be complex and Klenk, in 1942, isolated from beef brain, a new class of mono-, di-, trisialogangliosides containing 1 to 3 sialic carbohydrate rich glycolipids which he called as gang- acid residues have been described. liosides. Gangliosides have been isolated from ganglion cells, neuronal bodies and dendrites, spleen and RBC Types of gangliosides: Over 30 types of gangliosides have stroma. The highest concentrations are found in gray been isolated from brain tissue. matter of brain. Gangliosides are the most complex of Four important types are: the glycosphingolipids. They are large complex lipids, GM-1, GM-2, GM-3 and GD-3. Their structures are their molecular weights varies from 180,000 to 250,000. shown in Figure 4.20. 1 1 GM3 Fig. 4.20: Structure of some common gangliosides Ganglioside gray matter · Nana bitsion sitin & M3 ; Gal-du NANA Ome GalNAc-Gal-fir ; ANA GD ~ Oml ; Gal-GalNAc-Gal-er Gal-Glu I ↳ NANA NANA-NANA Cholera toxin  late White matter sulpholipids. Infant + CNS Metachromatic Leucodystrophy ↓ motion & sulphatase (Aryl sulfatase Al ↓ speech + optic ↑Sulfatide · (gal-ceramide Cz - 504 Adult : Psychia normal cerebroside : sulfatide = 3 : 1 dementia (hosr, = 1 :4 MD Chemistry of Lipids 61 CLINICAL IMPORTANCE 3. SULPHOLIPIDS The simplest and common ganglioside found in tissues Lipids material containing sulphur has long been known is GM 3, which contains ceramide, one molecule of to be present in various tissues and has been found in glucose, one molecule of galactose and one molecule of liver, kidney, testes, brains and certain tumours. neuraminic acid (NeuAc). Most abundant in white matter of brain. Several SECTION TWO Gm1 is a more complex ganglioside derived from Gm3 types of sulfur containing lipids have been isolated from is of considerable biologic interest, as it is now known to brain and other tissues. In general, they appear to be be the receptor in human intestine for cholera toxin. sulfate esters of glycolipids, the sulphate group is esterified with OH gr. of hexose moiety of the molecule. Biomedical Importance CLINICAL ASPECT G angliosides are mainly components of ‘membranes’. The Ganglioside sugar units and sialic acid sections of the molecule are “water- 1. Metachromatic Leucodystrophy (MLD): It is an ↓ soluble” (i.e. “hydrophilic”) and –vely charged, where as the inherited disorder in which sulfatide accumulates in receptors site ceramide portion is ‘lipid soluble’ (i.e. “hydrophobic”). The latter various tissues. Sulphatide is formed from ‘galactocere- ↓ appe ars to be embedded in the membrane lipids, where as broside’ through esterification of OH group on C3 of s ceramide the hydrophilic se ctions, with its charge d units protrude s galactose with H2SO4 (SO4 at C3 of Gal). Ratio of cerebro eve h membrane externally towards the medium. The gangliosides, therefore, side: to sulphatide in brain normally is 3:1. In this can serve as specific membrane binding sites (receptor ↓ san sites) for circulating hormones and thereby influence various disorder, it is altered to 1:4. biochemical processes in the cell. Enzyme deficiency: Deficiency of enzyme sulphatase 2 called as Aryl sulfatase A. CLINICAL ASPECT (a) Tay-Sachs Disease (GM2 Gangliosidosis) Accumulation of gangliosides in brain and nervous tissues takes place. The affected ganglioside is G M 2. The Enzyme deficiency is hexosaminidase A. Types: Two clinical types are seen. Inheritance: Autosomal recessive. (a) Late infantile type: Usually manifests before 3 years, N or m a l d e gra d a tio n of G M 2 r e q uir e s th e a ctio n of gross involvement of CNS: a specific hydrolyzing enzyme hexosaminidase A , which Defects in locomotion, weakness, ataxia, hypotonus, re move s th e termin al G al-N A c. S ubs e qu e ntly th e oth er and paralysis components are hydrolysed by other specific enzymes. In Difficulties in speech absence of the enzyme H exosaminidase A , G M 2 cannot be There may be optic atrophy. degraded and accumulates. (b) Adult type: Initially associated with psychiatric This rare inherited disorder is associated with: Progressive development of idiocy and blindness in manifestations but subsequently progressive dementia. infants soon after birth. This is due to widespre ad injury 2. Fabry’s disease: An inherited disorder, a lipid storage to ganglion cells in brain (cerebral cortex) and retina. disease (lipidosis). A cherry-red spot about the macula, seen ophthal- Inheritance: X-linked dominant, full symptoms only moscopically, is pathognomonic a nd is c a us e d by in males. d e stru ctio n of r e tin a l g a n glio n c e lls, e x p o sin g th e Enzyme deficiency: α -galactosidase. The enzyme is underlying vasculature. found normally in liver, spleen, kidney, brain and There may be seizures and association of macrocephaly. small intestine. & B-galactosidase - Prognosis is bad, usually de ath follows: Nature of lipid that accumulates ceramide trihexo- (b) GM1 Gangliosidosis side (globotriosyl ceramide) ↑ GMI It is due to a deficiency of the enzyme β -galactosidase, Clinical manifestations: Skin rash (reddish purple), ↑ glycoprotein le ading to accumulation of G M 1 gangliosides, glycoproteins Pain in lower extremities (painful neuropathy), Lipid and the mucopolysaccharide karatan sulphate. accumulates in the endothelial lining of blood vessels, ↑ haratan sulphate The inheritance pattern and symptoms are similar to Tay- may produce vascular thrombosis. Progressive renal S ach’s dise ase. failure–due to extensive deposition of lipids in glome- ruli. Occasionally manifestations of cardiac enlarge- Table 4.1 gives the differentiation of cerebrosides and ment. Eye involvement: Corneal opacities, cataracts, gangliosides. vascular dilatation. Tay Sachs Disease (ARI disease Fabry's (xD) - & hexosaminidase A X ·? C-galactosidase 3 Nac vos Sma Isfargos IGM2 - GM3) · ceramide trihexoside (globotriosyl ceramide / · GM2 · skin rash (100-20s) painful neuropathy , cerebral , · Idiocy , blindness > - Retina + cortex Vascular thrombosis /Stonew , renal failure · Cherry red spot in macula laconisone , eye (Retinal ganglion cells his I · Onion-skin lysosome  62 Chemistry of Biomolecules Table 4.1: Similarities and differentiation of cerebrosides and gangliosides Cerebrosides Gangliosides I. Similarities 1. Both are compound lipids ~ 2. Both are glycolipids and contain carbohydrates - 3. Both contain sphingol (sphingosine) as an alcohol SECTION TWO 4. Both are found in large quantities in brain and nervous tissue ~ 5. Both do not have glycerol, phosphoric acid, and nitrogenous base. II. Dissimilarities 1. O ccur in white matter of brain and in myelin she aths 1. Highest concentration in grey matter of brain 2. Not found in embryonic brain but develops as 2. Found in ganglion cells, neuronal bodies and medullation progresses dendrites 3. Function : Nerve conduction in myelin sheath 3. Transfers biogenic amines 4. C arbohydrate content—usually galactose sometimes 4. C arbohydrate content is more. In addition to glucose glucose/galactose, contains O ne mole of G al-N A C, O ne or more of N-acetyl neuraminic acid (N A N A)-(sialic acid) 5. Long chain fatty acids are—Lignoceric acid and 5. C ontains long chain fatty acids C 18 to C 24 nervonic acid/and their O H-derivatives 6. O n basis of FA content 4 types of cerebrosides viz. 6. More than 30 types have be en isolated. Four kerasin, cerebron (phrenosin), nervon, and important types are: G M-1, G M-2, G M-3, G D-3 oxynervon 7. C erebrosides on prolonged hydrolysis with B a(O H)2 , 7. Not so FA is removed and yield psychosin 8. C erebrosides are degraded by the enzyme 8. G M-2 gangliosides are degraded by the enzyme glucocerebrosidase , a lysosomal enzyme hexose aminidase A , G M-1 gangliosides are degraded by β -galactosidase. 9. Inherited deficiency of “enzyme” 9. Inherited deficiency of β-glucocerebrosidase produces the dise ase a. E nzyme “H exosaminidase A” produces Gaucher’s disease Tay-Sach’s disease (G M-2 gangliosidosis) b. E nzyme β-galactosidase produces GM-1 gangliosidosis 10. Do not act as cell membrane receptors 10. G angliosides can serve as a ‘specific membrane binding site’ on cell membrane for circulating hormones and thereby influences various metabolic processes in cells 3. Krabbe’s Disease Diagnosis: Depends on the determination of galacto- An inherited disorder of lipid metabolism, a lipid cerebrosidase activity in leucocytes and cultured skin storage disease (lipidosis) fibroblasts. β -galacto- Prognosis: Fatal. Enzyme deficiency: Galactocerebrosidase (β Table 4.2 summarises some of the sphingolipidosis sidase). The enzyme normally catalyzes the hydrolysis with enzymes involved nature of lipid accumulating and of galactocerebrosides and it splits the linkage clinical symptoms. between ceramide and galactose AMPHIPATHIC LIPIDS Lipids as such are insoluble in water, since they contain a predominance of “nonpolar” hydrocarbon groups. But fatty acids, phospholipids (PL), bile salts, and to a lesser extent cholesterol contain “Polar” groups. Hence, the part of the molecule is hydrophobic or water insoluble and part is hydrophilic or water soluble. Such molecules are Nature of lipid accumulating: Galactosyl ceramide called amphipathic. Clinical manifestations: Orientation of amphipathic lipids: Amphipathic lipids – Severe mental retardation in infants get oriented at oil-water interfaces with the polar groups – Total absence of myelin in central nervous system in the water phase and the non-polar groups in the oil – Globoid bodies found in white matter of brain. phase (Fig. 4.21A). Note: Galactocerebroside is an important component of Membrane bilayers: Orientation of amphipathic lipids myelin as above forms the basic structure of biological mem- branes (Fig. 4.21B). Krabbe's Disease & B-galactosidase ↑ Galactosyl ceramide · MR · white · matter/myclin Globoid · cells  Chemistry of Lipids 63 Table 4.2: Some examples of sphingolipidoses Disease + Foam , el Enzyme deficiency Lipid accumulating (see key below) Clinical symptoms · Zebra bodies Niemann-Pick disease Sphingomyelinase C er + p-choline sphingomyelin E nlarged liver and sple en, mental + cherry retardation, fatal in e arly life Gaucher’s disease - β -glucosidase - C er + Glc glycosylceramide E nlarged liver, massive splenomegaly, SECTION TWO erosion of long bones, mental retardation in infants Tay-Sachs disease ↑ Hexosaminidase B ↑ C er – Glc – G al(N euAc) + G al N A C Mental retardation, muscle we akness, G M 2 ganglioside blindness Metachromatic ~ Arylsulphatase A - C er – G al – G al + O S O 3 Mental retardation, demyelination, - leukodystrophy 3 sulfogalactosyl ceramide psychologic disturbances in adults - Fabry’s disease α -Galactosidase C er – Glc – G al + G al Skin rash, renal failure (full symptoms Globotriaosyl ceramide only in males X-linked recessive) Krabbe’s disease β -Galactosidase C er + G al galactosyl ceramide Mental retardation myelin almost absent Key : C er – C eramide Glc – Glucose G al – G alactase N eu-Ac – N-acetyl neuraminic acid + D enotes site of deficient enzyme re action ↳ Given Figs 4.21A to D: Formation of lipid bilayer membrane, micelle, and liposomes from amphipathic lipids  64 Chemistry of Biomolecules Micelles: When a critical concentration of these amphi- drugs in the circulation, targeted to specific organs, e.g. in pathic lipids is present in an aqueous medium, they cancer therapy, form micelles. Micelles formation, facilitated by bile ii. They are being used for gene transfer into vascular cells, salts, is prerequisite for fat digestion and absorption and from the intestine (Fig. 4.21C). iii. As carriers for topical and transdermal delivery of drugs Liposomes: Liposomes are formed by sonicating an and cosmetics. SECTION TWO amphipathic lipid in an aqueous medium. Characteristic of liposomes: They consist of spheres Emulsions: They are larger in size and formed usually of lipid bilayers that enclose part of the aqueous by non-polar lipids (e.g. T-G) are mixed with water medium (Fig. 4.21D). (aqueous medium). They are stabilised by emulsi- fying agents such as amphipathic lipids (e.g. Uses of Liposomes phosphatidyl choline) which form a surface layer i. T h e y are of pote ntial clinic al us e , p articularly wh e n separating the main bulk of non-polar material from combined with tissue-specific antibodies, as carriers of the water. · antibodies sive / · is gene I. Questions (Essay type and short notes) 5. The smell of the fat turned rancid is due to: a. Presence of vit E b. Presence of quiniones 1. What are lipids? Classify them giving suitable example. c. Phenols d. Volatile fatty acids 2. Describe the chemistry and functions of phospholipids. e. Cholesterol. 3. Describe the chemistry and functions of cholesterol. 6. Phospholipids are important cell membrane components 4. Describe the chemistry and functions of lecithin. because: 5. Describe classification of lipids and write in details about a. They have glycerol phospholipids. b. They can form bilayers in water 6. What are phospholipids? Describe the classification and c. They have both polar and nonpolar portions functions of phospholipids. d. They combine covalently with proteins Differentiate e. All of above. a. Phospholipids are glycolipids 7. Which one of the following is not a phospholipid? b. Cerebrosides and gaugliosides a. Lecithin b. Plasmalogen c. Lysolecithin d. Gangliosides Short Notes e. Cephalin a. Glycolipids b. Essential fatty acids 8. A fatty acid which is not synthesised in human body and c. Sphingomyelin d. Cholesterol has to be supplied in the diet: e. Cerebrosides f. Phospholipids a. Palmitic acid b. Oleic acid g. Reacidity h. Lipoproteins c. Linoleic acid d. Stearic acid e. Valeric acid. II. MCQs (Give one correct answer) 9. In cephalin choline is replaced by: 1. Depot fats of mammalian cells comprise mostly of: a. Serine b. Ethanolamine a. Cholesterol b. Cholesterol esters c. Betaine d. Sphingosine c. Phospholipids d. Cerebrosides e. Inositol e. Triacylglycerol 10. The triacyl glycerol present in plasma lipoproteins are 2. When choline of lecithin is replaced by ethanolamine the hydrolysed by: product is a. Lingual lipase b. Pancreatic lipase a. Spingomyelin b. Cephalin c. Co-lipase d. Lipoprotein lipase c. Plasmalogens d. Lysolecithin e. Adipokinetic lipase. e Phosphatidic acid. 11. Phosphatides occur in: 3. Which of the following is a hydroxyl fatty acid: a. Myelin sheath b. Stablilises chylomicrons a. Oleic acid b. Ricinoleic acid c. In erythrocyte d. All of the above c. Caproic acid d. Stearic acid e None of the above. e. Arachidonic acid. 12. Which of the following is not essential fatty acid? 4. Acrolein test is answered by: a. Oleic acid b. Linoleic acid a. Cholesterol b. Glycerol c. Arachidonic acid d. Linolenic acid c. Glycosides d Sphingol e. All of the above. e. Saturated fatty acid.  จากคลิป Sphingolipidoses · Tay-Sachs Disease Tom Has ITay Sachs- : Hexaminidases · Niemann-Pick Disease Nice Shirt 1 Niemma-Pick : Sphingomyelinase / , · Metachromatic leukodystrophy Most Are Saffron (MLD : Anyl Sulfatase Al · Fabry Disease Few Are Green (Fabry : 2 -gal. A · Krabbe Disease · Gaucher Disease & M2 galNAc-gal-glu-cer NNA nexaminidase & Tay-Sachs > Cherry-red Macula V ~ Neuro degrade & M3 gal-glo-cer NANA gal-era -MS in child ~ glo-ceramide & Fabry (XRI > Renal ↓ - gal. A ceramide sulfatides DMCLD glucocerebroside gal-gal-glu-cer trihexoside any I sulfatase glucocerebrosidase ? Saucher > Bone & (B) V V g a lactocerebroside < ceramide < sphingomyelin ceramide-phosphocholine gal-cer g alac to cerebrosidase sphingomyelinase Niemann-Pick & Krabbe & : Cherry-red macula f ~ E) oboid cells Hepatospleenomegaly Tay-Sachs : Hexosaminidase A Niemann-Pick : Sphingomyelinase ↓ & Cherry red macula t neurodegrade 19. 280115s/ hyper reflexia + spasticity · Onion-skin lysosomes · Hepatospleenomegaly , Zebra bodies , Foam cells Krabbe : galactocerabosidase Retachromatic Leucodystrophy Fabry 2-gal A : (MLDI 4 : Aryl Sulfatase · Optic atrophy , Blindness # ebrile episodes · Globoid Cells ↓ ⑨ * Angiokeratomas Burning pain / · neuropathy ↑ M * Renal Failure Youth death white matter Gaucher : glucocerabosidase lesion ↓ in child HSM Multiple sclerosis · (MS) · Bone I Osteoporosis & zosirie. crumpled tissue paper · ↳ doneon cell iuateisier Eicosanoids จากคลิป = Local hormones C26 : 1 1 9 W -) = Palmitoleic acid Arachidonic acid 28 : 1 *a W-9 = Oleic acid 28 : 2 19 , 12 W -6 = Linoleic acid V W - C18 : 3 19 , 1413 W - 3 = X- Linolenic acid Prostaglandins Thromboxanes Leukotrienes 220 : 4 W - 6 = Arachidonic acid - Co : s W-3 = EPA (Eicosapentaenoic ac eicosanoids 20 ↳ engin methyl Eicosanoid synthesis I in - & SN1 Sat Fat HeC g = & Cell membranes Hch O ! ~ - SNz = unsat Fat Phospholipase Az loin Arachidonic acid on HC 3 O 0-X wo SN3 = Phosphate + X NSAIDS I W (non-steroid Antin Arachidonic acid I flammatory Drug) Cyclooxygenase Lipoxygenase 1 COX) cox - 1 Cox-2 LOX , inflammatory 2 L ↳ L wer : Doses Prostagland in He Leukotriene An I - 2 - 34 V V (WBC) v Prostaglandins Thrombox anes Leukotrienes · Fe · Az · By sCy , Dy g Ey · Prostacyclin IPGTz) Function of eicosanoids PLE2 · Pain + Inflammatory PG12 1 Prostacycling & or nociceptors - pain signal · Vasodilation ↓ , Platelet aggregation · Hypothalamus - chemical release * syn. thrombocyte I plate let, · a fever TXAe 1 Thromboxanes) stomach , mucus production · Vasoconstriction ↑ Platelet aggregation · , · Kidney> Vasodilation , a renal blood flow 1900 piron serie uterus · < ↑ smooth muscle contraction & & A.. · form prostate Drugs from Eicosanoid & Is isolated from seminal fluid produced Induction of labor in the gland · prostate LTB4 keeping the ductus · · Immune - neutrophils arteriosus open & chemotaxis LTC4 Da Ey Immune Eosinophils · > & airway narrowing (broncho constriction ↑ LTC 1 Asthma * Montelukast Leukotriene receptor blockage :