LIPIDA oleh: Drs. Immanuel Meliala., M.Si., Apt Family of Lipids.

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2 LIPIDA oleh: Drs. Immanuel Meliala., M.Si., Apt

3 Family of Lipids

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6 Introduction Definition: water insoluble compounds Most lipids are fatty acids or ester of fatty acid They are soluble in non-polar solvents such as petroleum ether, benzene, chloroform (except C:4 butiric acid) Functions Energy storage Structure of cell membranes Thermal blanket and cushion Precursors of hormones (steroids and prostaglandins) Types: Fatty acids Neutral lipids Phospholipids and other lipids

7 Fatty acids Carboxylic acid derivatives of long chain hydrocarbons –Nomenclature (somewhat confusing) Stearate – stearic acid – C 18:0 – n-octadecanoic acid –General structure:

8 Fatty acids Common fatty acids n = 4 butyric acid (butanoic acid) n = 6 caproic acid (hexanoic acid) n = 8 caprylic acid (octanoic acid) n = 10 capric acid (decanoic acid)

9 Fatty acids common FA’s: n = 12: lauric acid (n-dodecanoic acid; C 12:0 ) n = 14: myristic acid (n-tetradecanoic acid; C 14:0 ) n = 16: palmitic acid (n-hexadecanoic acid; C 16:0 ) n = 18; stearic acid (n-octadecanoic acid; C 18:0 ) n = 20; arachidic (eicosanoic acid; C 20:0 ) n= 22; behenic acid n = 24; lignoceric acid n = 26; cerotic acid

10 Fatty Acids C=16.tapi TL beda.

11 Pengaruh ikatan rangkap thd titik lebur Asam lemak titik lebur(ºC) 16:00 16:11 18:063 18:116 18:2-5 18:3-11 20:075 20:4-50

12 Fatty acids Fatty acids can be classified either as: –saturated or unsaturated –according to chain length: short chain FA: 2-4 carbon atoms C=2? medium chain FA: 6 –10 carbon atoms long chain FA: 12 – 26 carbon atoms essential fatty acids vs those that can be biosynthesized in the body: –linoleic and linolenic are two examples of essential fatty acid

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17 Unsaturated fatty acids Monoenoic acid (monounsaturated) Double bond is always cis in natural fatty acids. This lowers the melting point due to “kink” in the chain

18 Unsaturated fatty acids Dienoic acid: linoleic acid

19 Unsaturated fatty acids Various conventions are in use for indicating the number and position of the double bond(s)

20 Unsaturated fatty acids Polyenoic acid (polyunsaturated)

21 Unsaturated fatty acids Monoenoic acids (one double bond): 16:1, 9  7: palmitoleic acid (cis-9-hexadecenoic acid 18:1, 9  9: oleic acid (cis-9-octadecenoic acid) 18:1, 9  9: elaidic acid (trans-9-octadecenoic acid) 22:1, 13  9: erucic acid (cis-13-docosenoic acid) 24:1, 15  9: nervonic acid (cis-15-tetracosenoic acid)

22 Unsaturated fatty acids Trienoic acids (3 double bonds) 18:3;6,9,12  6 :  -linolenic acid (all cis-6,9,12- octadecatrienoic acid) 18:3; 9,12,15  3 :  -linolenic acid (all-cis-9,12,15- octadecatrienoic acid) Tetraenoic acids (4 double bonds) 20:4; 5,8,11,14  6: arachidonic acid (all-cis- 5,8,11,14-eicosatetraenoic acid)

23 Unsaturated fatty acids Pentaenoic acid (5 double bonds) 20:5; 5,8,11,14,17  3: timnodonic acid or EPA (all-cis-5,8,11,14,17-eicosapentaenoic acid)* Hexaenoic acid (6 double bonds) 22:6; 4,7,10,13,16,19  3: cervonic acid or DHA (all-cis-4,7,10,13,16,19- docosahexaenoic acid)* Both FAs are found in cold water fish oils

24 Fatty Acids Properties –Saturated fatty acids are solid at room temperature and have a high melting point –Unsaturated fatty acids are liquid at room temperature and have a low melting point Naturally-occuring fatty acids -Cis form -Not conjungated---isolated double bond -Even numbered fatty acids

25 Lipids are non-polar (hydrophobic) compounds, soluble in organic solvents. Most membrane lipids are amphipathic, having a non-polar end and a polar end. Fatty acids consist of a hydrocarbon chain with a carboxylic acid at one end. A 16-C fatty acid: CH 3 (CH 2 ) 14 - COO - Non-polar polar A 16-C fatty acid with one cis double bond between C atoms 9-10 may be represented as 16:1 cis  9.

26 Some fatty acids and their common names: 14:0 myristic acid; 16:0 palmitic acid; 18:0 stearic acid; 18:1 cis  9 oleic acid 18:2 cis  9,12 linoleic acid 18:3 cis  9,12,15  -linonenic acid 20:4 cis  5,8,11,14 arachidonic acid 20:5 cis  5,8,11,14,17 eicosapentaenoic acid (an omega-3) Double bonds in fatty acids usually have the cis configuration. Most naturally occurring fatty acids have an even number of carbon atoms.

27 There is free rotation about C-C bonds in the fatty acid hydrocarbon, except where there is a double bond. Each cis double bond causes a kink in the chain. Rotation about other C-C bonds would permit a more linear structure than shown, but there would be a kink.

28 Properties of fats and oils fats are solids or semi solids oils are liquids melting points and boiling points are not usually sharp (most fats/oils are mixtures) when shaken with water, oils tend to emulsify pure fats and oils are colorless and odorless (color and odor is always a result of contaminants) – i.e. butter (bacteria give flavor, carotene gives color)

29 Examples of oils Olive oil – from Oleo europa (olive tree) Corn oil – from Zea mays Peanut oil – from Arachis hypogaea Cottonseed oil – from Gossypium Sesame oil – from Sesamum indicum Linseed oil – from Linum usitatissimum Sunflower seed oil – from Helianthus annuus Rapeseed oil – from Brassica rapa Coconut oil – from Cocos nucifera

30 Non-drying, semi-drying and drying oils based on the ease of autoxidation and polymerization of oils (important in paints and varnishes) the more unsaturation in the oil, the more likely the “drying” process –Non-drying oils: Castor, olive, peanut, rapeseed oils –Semi-drying oils Corn, sesame, cottonseed oils –Drying oils Soybean, sunflower, hemp, linseed, tung, oiticica oils

31 Neutral lipids Glycerides (fats and oils) ;glycerides –Glycerol –Ester of glycerol - mono glycerides, diglycerides and triglycerides Waxes – simple esters of long chain alcohols

32 GLYCERIDES Function: storage of energy in compact form and cushioning

33 Stereospecific numbering carbon 2 of triglycerides is frequently asymmetric since C-1 and C-3 may be substituted with different acyl groups by convention we normally draw the hydroxyl group at C-2 to the left and use the designation of sn2 for that particular substituent C-1 and C-3 of the glycerol molecule become sn1 and sn3 respectively

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37 Metabolisme lemak Mulut: lingual lipase: spesipik pada posisi 1,3 dan asam lemak rantai pendek, dan dapat diserap langsung ke hati dan dimetaboliser Lambung : gastric lipase: spesifik pada 1,3 dan asam lemak rantai sedang masih dapat diserap ke hati Usus halus: pancreatic lipase: spesifik 1,3 dan asam lemak rantai panjang Hasil akhir: asam lemak bebas dan 2-MAG diserap melalui kelenjar limpha, asam lemak jenuh panjang menaikkan kolesterol plasma

38 Pengaruh posisi terhadap absorbsi Pada posisi 1,3 asam lemak akan dibebaskan menjadi asam lemak asam lemak bebas; Jika asam lemak pendek akan cepat diserap ke hati Jika asam lemak rantai panjang dan jenuh akan bereaksi dengan kalsium dalam makanan dan mengendap sehingga terbuang bersama faeces

39 Pengaruh posisi palmitat terhadap resiko penyakit jantung koroner Palmitat pada posisi sn-2 akan meningkatkan lipida darah Palmitat pada posisi 1,3, tidak akan menaikkan lipida darah, karena akan terbebas dalam pencernaan sehingga akan beraksi dengan kalsium kemudian bersama faeces dikeluarkan Mis. Lard alami: palmitat 65% pada posisi sn- 2, setelah diinteresterifikasi menurunkan kadar trigliserida darah

40 WAXES simple esters of fatty acids (usually saturated with long chain monohydric alcohols) Beeswax – also includes some free alcohol and fatty acids Spermaceti – contains cetyl palmitate (from whale oil) –useful for Pharmaceuticals (creams/ointments; tableting and granulation) Carnauba wax – from a palm tree from brazil – a hard wax used on cars and boats

41 Bee’s wax Spermaceti source Carnauba wax source

42 Waxes Examples of long chain monohydric alcohols found in waxes

43 WAXES Fatty acids + Long chain alcohol Important in fruits: 1.Natural protective layer in fruits, vegetables, etc. 2.Added in some cases for appearance and protection. Beeswax (myricyl palmitate), Spermaceti (cetyl palmitate)

44 Phospholipids the major components of cell membranes –phosphoglycerides Phospholipids are generally composed of FAs, a nitrogenous base, phosphoric acid and either glycerol, inositol or sphingosine

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46 Phospholipid

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48 Phospholipids join a bilayer to form a cell membrane. Polar Head Nonpolar Tail The Cell Membrane

49 Glycolipid Phospholipids join a bilayer to form a cell membrane. The Cell Membrane

50 Phospholipids Phospholipid: alcohol + phosphate +fatty acid Glycerophospholid: glycerol + 2 fatty acids + phosphate/amino alcohol –Lecithins and cephalins abundant in brain & nerve tissue, egg yolks, wheat germ, and yeast –Forms cell membranes

51 Phospholipids Sphingolipid: sphingosin + fatty acid + phosphate/amino alcohol –A phospholipid with sphingosin instead of the glycerol –Important in the myelin sheath that surrounds most nerve fibers Glycolipid: glycerol + 1 fatty acid + sugar –In cell membranes –Function in cell adhesion & self-identity markers

52 Phospholipids Lipidoses, lipid diseases –Excess accumulation of sphingolipid or glycolipid –Caused by an absent, mismade, or deficient enzyme that breaks down the lipid

53 Phosphatidyl inositol Commonly utilized in cellular signaling

54 Sphingolipids Based on sphingosine instead of glycerol

55 Sphingomyelin (a ceramide) It is a ubiquitous component of animal cell membranes, where it is by far the most abundant sphingolipid. It can comprise as much as 50% of the lipids in certain tissues, though it is usually lower in concentration than phosphatidylcholine

56 Ether glycerophospholipids Possess an ether linkage instead of an acyl group at the C-1 position of glycerol –PAF ( platelet activating factor) –A potent mediator in inflammation, allergic response and in shock (also responsible for asthma-like symptom –The ether linkage is stable in either acid or base –Plasmalogens: cis ,  -unsaturated ethers –The alpha/beta unsaturated ether can be hydrolyzed more easily

57 Ether glycerophospholipids end of the first of two

58 glycolipids There are different types of glycolipids: cerebrosides, gangliosides, lactosylceramides

59 GLYCOLIPIDS Cerebrosides One sugar molecule –Galactocerebroside – in neuronal membranes –Glucocerebrosides – elsewhere in the body Sulfatides or sulfogalactocerebrosides A sulfuric acid ester of galactocerebroside Globosides: ceramide oligosaccharides Lactosylceramide –2 sugars ( eg. lactose) Gangliosides Have a more complex oligosaccharide attached Biological functions: cell-cell recognition; receptors for hormones

60 Gangliosides complex glycosphingolipids that consist of a ceramide backbone with 3 or more sugars esterified,one of these being a sialic acid such as N-acetylneuraminic acid common gangliosides: G M1, G M2, G M3, G D1a, G D1b, G T1a, GT 1b, G q1b

61 Ganglioside nomenclature letter G refers to the name ganglioside the subscripts M, D, T and Q indicate mono-, di-, tri, and quatra(tetra)-sialic- containing gangliosides the numerical subscripts 1, 2, and 3 designate the carbohydrate sequence attached to ceramide

62 Ganglioside nomenclature Numerical subscripts: 1. Gal-GalNAc-Gal-Glc-ceramide 2. GalNAc-Gal-Glc-ceramide 3. Gal-Glc-ceramide

63 A ganglioside (G M1 )

64 Cardiolipids A polyglycerol phospholipid; makes up 15% of total lipid-phosphorus content of the myocardium – associated with the cell membrane Cardiolipids are antigenic and as such are used in serologic test for syphilis (Wasserman test)

65 Sulfolipids also called sulfatides or cerebroside sulfates contained in brain lipids sulfate esters of cerebrosides present in low levels in liver, lung, kidney, spleen, skeletal muscle and heart function is not established

66 Lipid storage diseases also known as sphingolipidoses genetically acquired due to the deficiency or absence of a catabolic enzyme examples: Tay Sachs disease Gaucher’s disease Niemann-Pick disease Fabry’s disease http://www.ninds.nih.gov/disorders/lipid_storage_diseases /lipid_storage_diseases.htmhttp://www.ninds.nih.gov/disorders/lipid_storage_diseases /lipid_storage_diseases.htm

67 Blood groups determined by various glycolipids on RBCs A antigens B antigens H antigens not recognized by anti-A or anti-B antibodies (found on type O blood cells)

68 Cholesterol and cholesterol esters

69 STEROID NUMBERING SYSTEM

70 STEREOCHEMISTRY OF STEROIDS

71 Cholesterol sources, biosynthesis and degradation diet: only found in animal fat biosynthesis: primarily synthesized in the liver from acetyl-coA; biosynthesis is inhibited by LDL uptake degradation: only occurs in the liver

72 Cholesterol and cholesterol esters The hydroxyl at C-3 is hydrophilic; the rest of the molecule is hydrophobic; also 8 centers of asymmetry

73 Cholesterol and cholesterol esters Functions: -serves as a component of membranes of cells (increases or moderates membrane fluidity -precursor to steroid hormones -storage and transport – cholesterol esters

74 Functions of cholesterol serves as a component of membranes of cells (increases or moderates membrane fluidity) precursor to steroid hormones and bile acids storage and transport –cholesterol esters

75 Prostaglandins and other eicosanoids (prostanoids) local hormones, unstable, key mediators of inflammation derivatives of prostanoic acid

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78 SUBSTITUTION PATTERN OF PROSTANOIDS

79 Functions of eicosanoids Prostaglandins – particularly PGE 1 – block gastric production and thus are gastric protection agents Misoprostol (Cytotec) is a stable PGE 1 analog that is used to prevent ulceration by long term NSAID treatment PGE 1 also has vasodilator effects –Alprostadil (PGE 1 ) – used to treat infants with congenital heart defects –Also used in impotance (Muse)

80 Functions of eicosanoids PGF 2  – causes constriction of the uterus –Carboprost; “Hebamate” (15-Me-PGF 2  ) – induces abortions PGE 2 is applied locally to help induce labor at term

81 Examples of drugs derived from prostaglandins

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83 Lipid-linked proteins Lipid-linked proteins (different from lipoproteins) –lipoproteins that have lipids covalently attached to them –these proteins are peripheral membrane proteins

84 Lipid-linked proteins 3 types are most common: –Prenylated proteins Farnesylated proteins (C15 isoprene unit) Geranylgeranylated proteins (C20 isoprene unit) –Fatty acylated proteins Myristoylated proteins (C14) Palmitoylated proteins (C16)

85 Lipid-linked proteins glycosylphosphatidylinositol-linked proteins (GPI-linked proteins) –occur in all eukaryotes, but are particularly abundant in parasitic protozoa –located only on the exterior surface of the plasma membrane

86 Fatty acylated proteins

87 Prenylated proteins

88 GPI-linked proteins

89 Lipoproteins particles found in plasma that transport lipids including cholesterol lipoprotein classes chylomicrons: take lipids from small intestine through lymph cells very low density lipoproteins (VLDL) intermediate density lipoproteins (IDL) low density lipoproteins (LDL) high density lipoproteins (HDL) Terpenes

90 Lipoprotein class Density (g/mL) Diameter (nm) Protein % of dry wt Phosphol ipid % Triacylglycerol % of dry wt HDL1.063-1.215 – 1533298 LDL1.019 – 1.063 18 – 2825214 IDL1.006-1.01925 - 50182231 VLDL0.95 – 1.00630 - 80101850 chylomicrons< 0.95100 - 5001 - 2784 Composition and properties of human lipoproteins most proteins have densities of about 1.3 – 1.4 g/mL and lipid aggregates usually have densities of about 0.8 g/mL

91 Lipoprotein structure

92 LDL molecule

93 The apolipoproteins major components of lipoproteins often referred to as aproteins classified by alphabetical designation (A thru E) the use of roman numeral suffix describes the order in which the apolipoprotein emerge froma chromatographic column responsible for recognition of particle by receptors

94 HELICAL WHEEL PROJECTION OF A PORTION OF APOLIPOPROTEIN A-I

95 LIPOPROTEINS spherical particles with a hydrophobic core (TG and esterified cholesterol) apolipoproteins on the surface large: apoB (b-48 and B-100) atherogenic smaller: apoA-I, apoC-II, apoE classified on the basis of density and electrophoretic mobility (VLDL; LDL; IDL;HDL; Lp(a)

96 Apoproteins of human lipoproteins A-1 (28,300)- principal protein in HDL 90 –120 mg% in plasma A-2 (8,700) – occurs as dimer mainly in HDL 30 – 50 mg % B-48 (240,000) – found only in chylomicron <5 mg % B-100 (500,000) – principal protein in LDL 80 –100 mg %

97 C-1 (7,000) – found in chylomicron, VLDL, HDL 4 – 7 mg % C-2 (8,800) - found in chylomicron, VLDL, HDL 3 – 8 mg % C-3 (8,800) - found in chylomicron, VLDL, IDL, HDL 8 15 mg % D (32,500) - found in HDL 8 – 10 mg % E (34,100) - found in chylomicron, VLDL, IDL HDL 3 – 6 mg % Apoproteins of human lipoproteins

98 Major lipoprotein classes chylomicrons –density <<1.006 –diameter 80 - 500 nm –dietary triglycerides –apoB-48, apoA-I, apoA-II, apoA-IV, apoC- II/C-III, apoE –remains at origin in electrophoretic field

99 Major lipoprotein classes VLDL –density >1.006 –diameter 30 - 80nm –endogenous triglycerides –apoB-100, apoE, apoC-II/C-III –prebeta in electrophoresis

100 Major lipoprotein classes IDL (intermediate density lipoproteins) –density: 1.006 - 1.019 –diameter: 25 - 35nm –cholesteryl esters and triglycerides –apoB-100, apoE, apoC-II/C-III –slow pre-beta

101 Major lipoprotein classes HDL (high density lipoproteins) –density: 1.063-1.210 –diameter: 5-12nm –cholesteryl esters and phospholipids –apoA-I, apoA-II, apoC-II/C-III –alpha (electrophoresis)

102 Major lipoprotein classes LDL (low density lipoproteins) –density: 1.019 - 1.063 –diameter: 18-25nm –cholesteryl esters –apoB-100 –beta (electrophoresis) – 160 is high

103 Komposisi dan posisi asam lemak dalam molekul lemak

104 Interesterifikasi Reaksi anatara ester dan ester sehingga terjadi pertukaran guus asil Reaksi interesterifikasi terhadap lemak (triester) maka akan terjadi pertukaran posisi asam lemak dalam molekul TAG Ada dua interesterifikasi: a)Kimia (randomisasi) b) Enzimatik spesifik untuk mensintesa lemak tertentu.

105 Komposisi interesterifikasi kimiawi

106 Komposisi setelah interesterifikasi

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108 Interesterifikasi

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110 Interesterifikasi enzimatis

111 Pengaruh interesterifikasi LemakTL sebelum interesterifik asi TL sesudah IE Minyak kedelai -76 Lemak sapi49,547 Minyak biji kapas 1034 MK sawit39,547

112 Pengaruh IE thd aterogenisitas Jenis lemakPosisi palmitat Pd sn-2 Posisi palmitat Pd sn-2 Aterogenisit as Sesud.IE Babi25%8%menurun Sapimeningkat Biji kapas2 %10%Meningkat 2x

113 Kesimpulan Sifat kimia, fisika dan biokimia lemak ditentukan oleh komposisi asam lemak dan posisi/distribusi dalam molekul lemak Komposisi asam lemak yang sama dari dua lemak tidak berarti bahwa sifat keduanya sama Asam lemak pada posisi 1,3 akan dibebaskan dalam pencernaan Asam lemak bebas rantai pendek segera dapat diteruskan kehati dan dimetaboliser; asam lemak rantai panjang sedikit diabsorbsi sebagian akan keluar dengan feses

114 Kesimpulan (lanjutan) Asam lemak pada posisi sn-2 akan diserap secara effektif melalui kelenjar limpha dan menaikkan trigliserida darah Interesterifikasi lemak dapat mengubah posisi asam lemak dalam molekulnya sehingga dapat mengubah sifat biokimia dari lemak yang mengubah nilai nutrisinya. Diperlukan penelitian untuk mengetahui pengaruh interesterifikasi terhadap resiko penyaskit kardiovaskular