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Paper : 05 Metabolism of Module: 01 Prologue to Lipids

Principal Investigator Dr. Sunil Kumar Khare, Professor,

Department of Chemistry, IIT-Delhi

Paper Coordinator and Dr. Suaib Luqman, Scientist (CSIR-CIMAP) Content Writer & Assistant Professor (AcSIR)

CSIRDr. Vijaya-CIMAP, Khader Lucknow Dr. MC Varadaraj Content Reviewer Prof. Prashant Mishra, Professor, Department of Biochemical Engineering and Biotechnology, IIT-Delhi

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METABOLISM OF LIPIDS Biochemistry Prologue to Lipids

DESCRIPTION OF MODULE

Subject Name Biochemistry

Paper Name 05 Metabolism of Lipids

Module Name/Title 01 Prologue to Lipids

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METABOLISM OF LIPIDS Biochemistry Prologue to Lipids

1. Objectives

 To understand what is  Why they are important  How they occur in nature

2. Concept Map

LIPIDS

Fatty Acids

3. Description

3.1 Prologue to Lipids

In 1943, the term lipid was first used by BLOOR, a German biochemist.

Lipids are heterogeneous group of compounds present in plants and animal tissues related either actually or

potentially to the fatty acids. They are amphipathic molecules, hydrophobic in nature originated utterly or in part

by thioesters (carbanion-based condensations of fatty acids and/or polyketides etc) or by isoprene units

(carbocation-based condensations of prenols, sterols, etc). Lipids have the universal property of being:

i. Quite insoluble in water (polar solvent)

ii. Soluble in , chloroform, ether (non-polar solvent)

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METABOLISM OF LIPIDS Biochemistry Prologue to Lipids

Thus, lipids include oils, , waxes, steroids, vitamins (A, D, E and K) and related compounds, such as

phospholipids, , diglycerides, monoglycerides and others, which are allied more by their physical

properties than by their chemical assests.

They are vital constituents related to diet because of high energy value, essential fatty acids and soluble

vitamins present in the content of fat foods. Lipids serve as adept source of energy when stored in adipose tissue.

Fat also dole out as Thermal Insulators in the subcutaneous tissues and in the region of some organs and non-

polar lipids acts as Electrical Insulators permitting quick propagation of depolarization waves by the side of

myelinated nerves. Lipoproteins (combinations of lipid and protein) transport lipids in the blood and the

biochemical acquaintance of lipids is obligatory in understanding atherosclerosis, diabetes mellitus, obesity etc.

The function of diverse polyunsaturated fatty acids (PUFAs) in nutrition and health can also be best understood

by studying its biochemical profile.

Chemically, lipids are defined as of glycerol and fatty acids or else refer as the triglycerides of fatty acids.

They are the substances of natural origin, soluble in non-polar solvents and hence may be extorted by using

organic solvents such as . Lipids could be fractionated by either using adsorption chromatography (thin

layer chromatography) or reverse-phase chromatography.

Fatty acid

It may be defined as an organic acid that occurs in a natural and is a mono ranging

in chain length from C4-C24 carbon atoms. Fatty acids are obtained from the hydrolysis of fats. They are

naturally occurring straight chain derivatives containing carbon atoms with even numbers (4-28) as they

assemble from two carbon units. Typically derived from triglycerides or phospholipids, fatty acids are vital

sources of fuel yielding huge quantities of ATP. Fatty acids that contain C=C are recognized as unsaturated fatty 4

METABOLISM OF LIPIDS Biochemistry Prologue to Lipids

acid (UFAs) and those lacking double bonds are recognized as saturated (SFAs). They are named after

corresponding hydrocarbons and vary in length. UFAs end with suffix-enoic and SFAs ends with suffix-anoic.

Based on length as short to very long, they may be categorized as under:

 SCFA: Short Chain Fatty Acids with less than six carbons (e.g. ).

 MCFA: Medium Chain Fatty Acids with 6-12 carbons.

 LCFA: Long Chain Fatty Acids with 13-21 carbons.

 VLCFA: Very Long Chain Fatty Acids with more than 22 carbons.

The condensation of Acetyl Co-A, a coenzyme, results in the biosynthesis of fatty acids as it carries two carbon

units. That is why all FAs have even numbers of carbon atoms.

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METABOLISM OF LIPIDS Biochemistry Prologue to Lipids

Unsaturated Fatty Acid (UFA)

UFAs contain carbon units linked by double bonds, saturated with atoms that convert double bonds to

single bonds (one or more double bonds between carbon units). The carbon atoms occur either in a cis or a trans

configuration. When two hydrogen atoms nearby to the double bond fasten on the chain (same side), it is cis

configuration of fatty acid (, etc). When the neighboring two hydrogen atoms lie on the

chain (opposite side), it is trans configuration of fatty acid (, etc). Unsaturated fatty

acid may be of following types.

 Monounsaturated: Presence of one double bond

 Polyunsaturated: Presence of two or more double bond

 Eicosanoid: are signaling molecules made by the oxidation of 20-carbon fatty acids

 Prostanoid: It includes (a) Prostaglandins e.g. PGE1, (b) Prostacyclin e.g. PCI2, (c) Thromboxanes e.g.

TXA2

 Leukotriene: Containing three double bonds sequentially e.g. LTB4, LTE4

Table 1. Selected examples of Unsaturated Fatty Acids

n-x Name Structure & C:D Δx n-3 18:3 cis,cis,cis- α-Linolenic acid CH CH CH=CHCH CH=CHCH CH=CH(CH ) COOH 3 2 2 2 2 7 Δ9,Δ12,Δ15 20:5 cis,cis,cis,ci Eicosapentaenoic CH CH CH=CHCH CH=CHCH CH=CHCH CH=CHCH CH=CH(CH ) 3 2 2 2 2 2 2 3 s,cis-Δ5, Δ8, acid COOH Δ11, Δ14, Δ17 22:6 cis,cis,cis,ci 4 Docosahexaenoi CH3CH2CH=CHCH2CH=CHCH2CH=CHCH2CH=CHCH2CH=CHCH2C s,cis,cis-Δ , 7 10 13 c acid H=CH(CH2)2COOH Δ , Δ , Δ , Δ16, Δ19 9 n-5 CH3(CH2)3CH=CH(CH2)7COOH 14:1 cis-Δ n-6 18:2 cis,cis-Δ9, Linoleic acid CH (CH ) CH=CHCH CH=CH(CH ) COOH 3 2 4 2 2 7 Δ12 18:2 trans,trans- Linoelaidic acid CH (CH ) CH=CHCH CH=CH(CH ) COOH 3 2 4 2 2 7 Δ9, Δ12 6

METABOLISM OF LIPIDS Biochemistry Prologue to Lipids

20:4 cis,cis,cis,ci 5 8 11 CH3(CH2)4CH=CHCH2CH=CHCH2CH=CHCH2CH=CH(CH2)3COOH s-Δ Δ , Δ , Δ14 9 n-7 CH3(CH2)5CH=CH(CH2)7COOH 16:1 cis-Δ 11 Vaccenic acid CH3(CH2)5CH=CH(CH2)9COOH 18:1 trans-Δ 9 n-9 Oleic acid CH3(CH2)7CH=CH(CH2)7COOH 18:1 cis-Δ 9 Elaidic acid CH3(CH2)7CH=CH(CH2)7COOH 18:1 trans-Δ 13 CH3(CH2)7CH=CH(CH2)11COOH 22:1 cis-Δ 6 n-10 CH3(CH2)8CH=CH(CH2)4COOH 16:1 cis-Δ C:D = Number of carbon units and double bond ratio

Adapted and Modified from http://en.wikipedia.org/wiki/Fatty_acid

Table 2. List of Other Unstaurated Fatty Acids

C:D ω-n Name Structure & Chemical Formula Δn Configuration Source

16:1 Palmitoleic CH (CH ) CH=CH(CH ) COOH Δ9 cis Macadamia nut ω-7 3 2 5 2 7 acid 18:1 Vaccenic CH (CH ) CH=CH(CH ) COOH Δ11 Butter, Milk, ω-7 3 2 5 2 9 trans acid and Yogurt Δ9 Canola, Olive ω-9 Oleic acid CH (CH ) CH=CH(CH ) COOH cis 3 2 7 2 7 and Pecan oil Δ9 ω-9 Elaidic acid CH (CH ) CH=CH(CH ) COOH trans 3 2 7 2 7 (hydrogenated) 18:2 Δ9,12 Chicken fat, ω-6 Linoleic acid CH3(CH2)4CH=CHCH2CH=CH(CH2)7COOH cis Olive and Peanut oil 18:3 Δ9,12,1 Chiaseeds, α-Linolenic CH CH CH=CHCH CH=CHCH CH=CH(CH ω-3 3 2 2 2 5 cis Flaxseeds and acid ) COOH 2 7 Walnuts Δ6,9,12 Black currant oil, Borage oil, γ-Linolenic CH (CH ) CH=CHCH CH=CHCH CH=CH( ω-6 3 2 4 2 2 cis Evening acid CH ) COOH 2 4 primrose oil and safflower oil 18:4 Δ6,9,12, Blackcurrant, Stearidonic CH CH CH=CHCH CH=CHCH CH=CHCH 15 Corn gromwell ω-3 3 2 2 2 2 cis acid CH=CH(CH2)4COOH and Seed oils of hemp 20:1 Paullinic Δ13 ω-7 CH (CH ) CH=CH(CH ) COOH cis Guarana acid 3 2 5 2 11 Δ11 Jojoba oil (non- Gondoic ω-9 CH (CH ) CH=CH(CH ) COOH cis caloric and non- acid 3 2 7 2 9 digestible but 7

METABOLISM OF LIPIDS Biochemistry Prologue to Lipids

edible) 20:3 Dihomo-γ- Δ8,11,1 Trace amounts CH (CH ) CH=CHCH CH=CHCH CH=CH( ω-6 linolenic 3 2 4 2 2 4 cis (Animal CH ) COOH acid 2 6 products) CH (CH ) CH=CHCH CH=CHCH CH=CH( Δ5,8,11 ω-9 Mead acid 3 2 7 2 2 cis Cartilage CH2)3COOH 5,8,11, 20:4 Arachidonic CH3(CH2)4CH=CHCH2CH=CHCH2CH=CHC Δ Dairy, Eggs, ω-6 14 cis acid H2CH=CH(CH2)3COOH Meat 20:5 Δ5,8,11, Cod liver, 14,17 Herring, Eicosapenta CH CH CH=CHCH CH=CHCH CH=CHCH Menhaden, ω-3 3 2 2 2 2 cis enoic acid CH=CHCH2CH=CH(CH2)3COOH Mackerel, Salmon and Sardine 22:1 Δ13 Mustard oil, ω-9 Erucic acid CH (CH ) CH=CH(CH ) COOH cis 3 2 7 2 11 Wallflower seed 7,10,1 22:4 Docosatetrae CH3(CH2)4CH=CHCH2CH=CHCH2CH=CHC Δ ω-6 3,16 cis - noic acid H2CH=CH(CH2)5COOH 22:6 CH CH CH=CHCH CH=CHCH CH=CHCH Δ4,7,10, Docosahexa 3 2 2 2 2 Fish oil and ω-3 CH=CHCH CH=CHCH CH=CH(CH ) COO 13,16,19 cis enoic acid 2 2 2 2 Maternal milk H 24:1 Δ15 Flaxseed, King Salmon, Nervonic Macademia ω-9 CH (CH ) CH=CH(CH ) COOH cis acid 3 2 7 2 13 nuts, Sesame seed and Sockeye salmon

Saturated Fatty Acid (SFA)

They are long chain carboxylic acids without double bonds but with 12-24 carbon units. As its name indicates

they are saturated with hydrogen atoms having solitary bonds with each carbon units inside the chain has 2

hydrogen atoms (except 3 at the end for omega carbon). Examples of the SFAs are ,

Palmitic acid, etc.

Table 2. List and Examples of Saturated Fatty Acids

C:D Name Chemical Formula Nomenclature 3:0 CH3CH2COOH Propanoic acid 4:0 Butyric acid CH3(CH2)2COOH Butanoic acid 5:0 CH3(CH2)3COOH Pentanoic acid

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METABOLISM OF LIPIDS Biochemistry Prologue to Lipids

6:0 CH3(CH2)4COOH Hexanoic acid 7:0 CH3(CH2)5COOH Heptanoic acid 8:0 CH3(CH2)6COOH Octanoic acid 9:0 CH3(CH2)7COOH Nonanoic acid 10:0 Capric acid CH3(CH2)8COOH Decanoic acid 11:0 CH3(CH2)9COOH Undecanoic acid 12:0 CH3(CH2)10COOH Dodecanoic acid 13:0 CH3(CH2)11COOH Tridecanoic acid 14:0 CH3(CH2)12COOH Tetradecanoic acid 15:0 CH3(CH2)13COOH Pentadecanoic acid 16:0 CH3(CH2)14COOH Hexadecanoic acid 17:0 CH3(CH2)15COOH Heptadecanoic acid 18:0 Stearic acid CH3(CH2)16COOH Octadecanoic acid 19:0 CH3(CH2)17COOH Nonadecanoic acid 20:0 CH3(CH2)18COOH Eicosanoic acid 21:0 CH3(CH2)19COOH Heneicosanoic acid 22:0 CH3(CH2)20COOH Docosanoic acid 23:0 CH3(CH2)21COOH Tricosanoic acid 24:0 CH3(CH2)22COOH Tetracosanoic acid 25:0 CH3(CH2)23COOH Pentacosanoic acid 26:0 CH3(CH2)24COOH Hexacosanoic acid 27:0 Heptacosylic acid CH3(CH2)25COOH Heptacosanoic acid 28:0 CH3(CH2)26COOH Octacosanoic acid 29:0 Nonacosylic acid CH3(CH2)27COOH Nonacosanoic acid 30:0 CH3(CH2)28COOH Triacontanoic acid 31:0 Henatriacontylic acid CH3(CH2)29COOH Henatriacontanoic acid 32:0 CH3(CH2)30COOH Dotriacontanoic acid 33:0 Psyllic acid CH3(CH2)31COOH Tritriacontanoic acid 34:0 Geddic acid CH3(CH2)32COOH Tetratriacontanoic acid 35:0 Ceroplastic acid CH3(CH2)33COOH Pentatriacontanoic acid 36:0 Hexatriacontylic acid CH3(CH2)34COOH Hexatriacontanoic acid

Modified and Adapted from http://en.wikipedia.org/wiki/Fatty_acid

Essential Fatty Acid (EFA)

They are indispensable for the human body not produced in adequate amount from substrates, and consequently

ought to be obtained from diet (food). The idiom ‘EFA’ refers to fatty acids obligatory for biological processes

and excludes those fats that merely act as fuel. Two vital series of EFAs have been reported: (i) Three carbon

units with double bond removed from the methyl end and (ii) Six carbon units with double bond removed from 9

METABOLISM OF LIPIDS Biochemistry Prologue to Lipids

the methyl end. Omega 3-fatty acid (α-linolenic acid = ALA) and Omega 6-fatty acid (Linoleic acid = LA) are

the two EFAs widely distributed in plant oils. Humans lack the ability to synthesize these two EFAs due to

absence of desaturase enzymes required for their production. In 1923, these two EFAs were preferred as Vitamin

F but later (1929), studies on mice revealed that these two EFAs should be categorized under fats rather

vitamins. Omega-3 fatty acid () and Omega 6-fatty acid (γ- Linoleic acid) are occasionally

referred to as ‘Conditionally Essential’ as they happen to indispensable under disease or some developmental

circumstances. In the human body, EFAs dole out numerous functions such as:

 Customized to make

o Eicosanoids: Distressing several cellular functions including inflammation

o Endocannabinoids: Upsetting mood, behavior and inflammation

o Lipoxins: A faction of eicosanoid derivatives produced from ω-6 EFAs via the

lipoxygenase pathway and resolvins from ω-3 (down regulating

inflammation in the presence of acetylsalicylic acid)

o Epoxyeicosatrienoic acids (EETs), Hepoxilins, Isofurans, Isoprostanes, Neurofurans and

Neuroprotectin D

 EFAs affect cellular signaling by forming lipid rafts.

 They either activate or inhibit transcription factors such as NF-κB and act on DNA.

Examples of the food sources with EFAs are canola (rapeseed) oil, chia seeds, fish and shellfish, flaxseed

(linseed), hemp seed, leafy vegetables, pumpkin seeds, soya oil, sunflower seeds and walnuts. Nearly, all the

PUFAs in the human diet are EFAs that play a vital part in the existence and loss of cardiac cells. The deficiency

of EFAs results in depression, dermatitis and osteoporosis. 10

METABOLISM OF LIPIDS Biochemistry Prologue to Lipids

Free Fatty Acid

When fatty acids do not affixed to supplementary molecules, they are acknowledged as ‘Free Fatty Acids’

(FFAs) or ‘Uncombined Fatty Acids’ (UCFAs). The FFAs or UCFAs ensued from the triglyceride breakdown,

insoluble in water, circulated, solubilized and transported through albumin (a plasma protein). However, their

blood echelon is restricted by the accessibility of binding sites of albumin.

Table 3. Composition of dietary fats

Monounsaturated Polyunsaturated Saturated Cholesterol Vitamin E g per 100 g g per 100 g g per 100 g mg per 100 g mg per 100 g Vegetable Fats Canola (Rapeseed 5.3 64.3 24.8 0 22.21 Oil) Coconut oil 6.6 1.7 85.2 0 0.66 Corn oil 24.7 57.8 12.7 0 17.24 Cottonseed oil 21.3 48.1 25.5 0 42.77 Hemp oil 15 75 10 0 12.34 Olive oil 69.7 11.2 14.0 0 5.10 Palm kernel oil 11.4 1.6 81.5 0 3.80 Palm oil 41.6 8.3 45.3 0 33.12 Safflower oil 12.6 72.1 10.2 0 40.68 Soybean oil 23.2 56.5 14.5 0 16.29 Sunflower oil 20.2 63.0 11.9 0 49.00 Wheat germ oil 15.9 60.7 18.8 0 136.65 Animal Fats Butter 19.8 2.6 54.0 230 2.00 Duck fat 49.3 12.9 33.2 100 2.70 Lard 43.8 9.6 40.8 93 0.60

Modified and Adapted from http://en.wikipedia.org/wiki/Fatty_acid#Free_fatty_acids

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METABOLISM OF LIPIDS Biochemistry Prologue to Lipids

Triglycerides (TG)

Are most abundant form of lipids and constitute about 98% of total dietary lipids. TGs are esters of glycerol with

three fatty acid molecules. Glycerol (Alcohols) contains a hydroxyl (OH) moiety and Fatty acid (Organic acids)

encloses a carboxyl (-COOH) group. Both join together to form esters. During each esterification one molecule

of water is released. In TGs, the OH group of the glycerol connects the COOH group of the fatty acid to form

bonds. They may be fats and oils and are also known as Triacylglycerol (TAG) or Triacylglyceride. TGs

contain three moles of fatty acids which may be similar or dissimilar. Similar kind of FAs in all the three

positions are called simple TGs e.g. Tripalmitin, triolein etc. Most of the TGs contains different kinds of fatty

acids in position 1, 2 or 3 and are called mixed TGs e.g. Oleodipalmitin etc. There are a lot of triglycerides

obtainable from the oil source, a number of them are highly unsaturated and a few are unsaturated. Saturated are

those having single bonds between the carbon atoms (C-C) where hydrogen atoms bonds with carbon atoms

while unsaturated compounds bears double bonds between carbon units (C=C), plummeting the integer of places

wherever hydrogen atoms bonds with carbon atoms. Furthermore, at room temperature saturated have an

elevated and are solid while unsaturated have a lower melting point and are liquid.

TGs are the vital constituents of animal fats (saturated) including human skin oils and vegetable oil

(unsaturated). In naturally occurring TGs, the chain lengths of the FAs include even number (16, 18, 20) of

carbon units. However, in bacteria and ruminants fat odd number (15) carbon atoms are present. Majority of

natural fats include an intricate blend of individual TGs and due to this, they deliquesce over a wide array of

temperatures. In TGs form, lipids cannot be engrossed by the duodenum unless broke dowm into fatty acids,

monoglycerides and a few diglycerides. In the intestine, TGs ripped into FFAs and monoacylglycerol following

the secretion of bile and lipases in a process called lipolysis. TGs advances to the intestine through enterocyte

cells and reinstate it from their wreckage, wrap up with proteins and cholesterol to guise chylomicrons. An array 12

METABOLISM OF LIPIDS Biochemistry Prologue to Lipids

of tissues incarcerates the chylomicrons and releases the TGs to be worn as an energy source. TGs can pass

through cell membranes freely via the fatty acid transporter (FAT) only after its split into fatty acid and glycerol

by lipoprotein lipases. TGs being the foremost components of chylomicrons and VLDL (very low density

lipoprotein) perform an imperative role (energy source) in metabolism and transporters of dietary fat (38 kJ/g or

9 kcal/g compared to carbohydrates: 17 kJ/g or 4kcal/g). A high level of TGs in human body has been related to

atherosclerosis, stroke risk and heart disease.

In oil paints and coating, di and triunsaturated fatty acid components present in linseed and related oil are used

which apt to congeal in the presence of . Using trans-esterification phenomenon, TGs are also ripped into

their components in the biodiesel manufacturing. The ensuing esters of FA be able to be worn as a fuel in diesel

engines. The glycerin is used in the production of pharmaceuticals and food. Lysochromes (Fat soluble dye, Oil

Red O, Sudan Black B, Sudan IV) has been employed for staining fatty acids, triglycerides, lipoproteins, and

other lipids.

Lipids contain hydrocarbons which are the base for the structure and function of living cells. The biological

functions of the lipids are as distinct as their chemistry. Oils and fats are the primary stored arrangement of

energy in numerous organisms. Sterols and phospholipids are key structural essentials of biological membranes.

Other lipids, though present in reasonably small quantities, perform crucial roles as electron carriers, anchors for

proteins (hydrophobic), enzyme cofactors, light absorbing pigments, as intracellular messengers, as chaperones

in protein folding of membranes and as an emulsifying agents in the digestive tract.

Being largely hydrocarbon, lipids yield huge amounts of energy on oxidation and represent exceedingly reduced

forms of carbon. Based on biochemical subunits, lipids may be alienated into the following class: saccharolipids,

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METABOLISM OF LIPIDS Biochemistry Prologue to Lipids

sphingolipids, sterol lipids, polyketides (consequential of ketoacyl subunits condensation), prenol lipids

(resultant of isoprene subunits condensation), glycerophospholipids, glycerolipids and fatty acids.

The major functions of lipids include energy storage, integral part of cell membrane components and signaling.

Oils and fats are the main source of energy in innumerable organisms. Sterols and phospholipids are key

structural elements of membranes. Other present in comparatively diminutive quantities, perform essential roles

as electron carriers, enzyme cofactors, light absorbing pigments, hormones, as intracellular messenger, as an

anchor for hydrophobic proteins, as chaperones in membrane proteins folding, as an emulsifying agent in the

digestive tract. Lipids have a burly relevance in nanotechnology as well as in food and cosmetic industries.

In a nutshell, lipids:

 Acts as a fuel in the body

 Yields 9.0 kcal of energy per gram

 Exerts an insulating effect in the body

 Provide padding and protect the internal organs like kidney

 Supply EFAs for normal health, development and growth

 Vital for fat soluble vitamins

 Fundamental constituent of cell wall, cell membrane and cell organelle like mitochondria

The present prologue introduces lipids and their representative of every type with a prominence on their physical

properties and chemical structure.

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METABOLISM OF LIPIDS Biochemistry Prologue to Lipids

4. Summary

In this lecture we learnt about:

 The Definition of Lipids

 Their

 Chemical and Biological nature

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METABOLISM OF LIPIDS Biochemistry Prologue to Lipids