Paper 4: Biomolecules and their inte ractions

Module 21: Classification of Lipids: simple and compound lipids, phospholipids,

Cholesterol

OBJECTIVE

 The main aim of this module is to introduce the students to various

subtypes of lipids like simple lipids, compound lipids and derived lipids
AND
 To understand as to how these various lipids help in providing structural
integrity to cell me mbrane and function as storage and signaling
molecules in the cell

1. INTRODUCTION

Lipids can be divided into three classes:

a. Simple lipids
b. Compound lipids
c. Derived lipids

Figure 1

2. Simple lipids: Triacylglycerols and waxes are classified as simple lipids. The
characteristics of each are described in the sections below.

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2.1 Triacylglycerols (TAGs)/triglyderides/fats/neutral fats

TAGs are constructed from fatty acids and are classified as simple lipids. They consist of 3
fatty acids in ester linkage with a single glycerol molecule that serves as the backbone, as
illustrated in Fig. 2.
Figure 2

2.1.1. Characteristics of TAGs

 These are non-polar molecules because of the absence of any available free polar
group. The carboxylate groups of the fatty acids are in ester linkage with the hydroxyl
groups of the glycerol molecule.
 TAGs appear as oily droplets in aqueous cytosol, when observed under a microscope.
 The storage and synthesis of TAGs takes place in adipocytes and in the seeds of
plants, which are enriched in the oil droplets as opposed to a normal cell.
 TAGs are mobilized from their storage sites by lipases that catalyze their breakdown,
to provide energy.

2.1.1.1. TAGs as energy depots

There are two advantages of choosing TAGs as the stored source of energy
as opposed to carbohydrates:
a. The carbon atoms of the fatty acids are more reduced, compared to those
in sugars, which in turn leads to generation of twice as much energy upon
their oxidation versus oxidation of sugars.
b. TAGs are hydrophobic and hence unhydrated, due to which they do not
have to bear with the weight of water of hydration, unlike glycogen
(storage form of carbohydrates) molecule that would carry about 2g of
water for every gram of stored glycogen.

TAGs also serve as insulators in animals such as seals, penguins, polar bears
etc.
Additionally, TAGs also provide insulation and energy in hibernating
animals.

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 The low density of TAGs is advantageous in sperm whales, where these
lipids are stored in the spermaceti organ located in their large heads.
Spermaceti organ contains upto 3600 kg of spermaceti oil, which is a mixture
of TAGs and waxes with a large number of unsaturated fatty acids. At normal
body temperature of the whales, this mixture is a liquid, while it crystallizes
to turn into a solid mass when the temperature drops.
The sperm whales usually encounter a temperature drop, when they deep dive
into ocean for feeding on squids, their primary food source. For sperm whales
to remain still at such depths without much of swimming, they need to match
their buoyancy with that of the surrounding water, which is cold and dense at
these depths. The crystallization of the spermaceti oil at this low temperature
enables these whales to keep afloat during their deep dives. The spermaceti
oils turns into a liquid when the whale resurfaces at the surface of the ocean.
Sperm whales therefore are a very good example of biochemical and
anatomical adaptation. The TAGs and waxes in the spermaceti oil have the
right degree of unsaturation and chain length in their fatty acids.

2.2. Waxes

 Waxes are considered as simplest fatty acid esters in nature. Structurally, they are
considered as esters of long-chain (C14 -C36 ) saturated and unsaturated fatty acids with
long-chain (C16 -C30 ) alcohols (Fig. 3).

Figure 3

 They are the main source of energy in planktons.

 The melting point of waxes is higher than that of TAGs.
 Waxes are considered water-repellant due to which certain skin glands secrete them
to protect hair and skin by keeping them lubricated.
 The leaves of plants like rhododendrons, poison ivy and several tropical plants are
shiny in appearance due to wax coating on them. This prevents excess evaporation of
water and provides protection from the parasites.

3. Compound lipids/Conjugated lipids: Defined as esters that contain

chemical groups in addition to fatty acids and alcohols. Depending on their chemical
groups they are further subdivided into:
a. Glycerophospholipids
b. Sphingolipids (phosphor- or glycol-)
c. Glycolipids (cerebrosides and gangliosides)
d. Sulfolipids
e. Lipoproteins

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 3.1. Glycerophospholipids/Phospholipids

 are the major structural component of all biological membranes

 structurally they consist of a glycerol backbone with fatty acids at the C1 and C2
positions, while the C3 position is occupied by a phosphate group attached to a polar
moiety termed “x” as depicted in Fig. 4.
Figure 4

 these are amphiphilic molecules because they have the hydrophobic fatty acids as
well as the polar head groups.
 If ‘x’ is an –H, the phospholipid is referred to as phosphatidic acid, the simplest form
of phospholipid.
 As shown in Fig. 4 the ‘x’ can also be a choline moiety, in which case it is
referred to as phosphatidylcholine.
 ‘x’ can be a serine, ethanolamine also, generating phosphotidylserine and
phosphotidylethanolamine, respectively.
 The C1 position is occupied by a saturated fatty acid of length ranging between C 16 -
C18 .
 The C2 position is occupied by unsaturated C16 -C20 fatty acid.
 The phosphate group imparts a negative charge to the phospholipid molecule, while
the charge on the polar head group can vary. Thus,
Phosphatidyl 4,5 bisphosphate is a negatively charged phospholipid
Phosphotidylserine is neutral and
Phosphotidylcholine and –ethanolamine have a positive charge.

3.1.1. Glycerophospholipids with Ether-linked fatty acids

 In these phospholipids, one of the two fatty acid chain is in a ether linkage with the
glycerol backbone.
 In alkyl ether lipids, the fatty acyl chain may be saturated or may be unsaturated in
the case of plasmalogens.
 The human heart and the membranes of certain halophilic bacteria are enriched in
ether lipids.
 These lipids are resistant to the action by phospholipases, which may be the reason
why they are predominant in our heart tissue.
 The platelet-activating factor, released from the basophils, serves as a signaling
molecule to spur the clumping of platelets. A vasoconstrictor, serotonin is thus
released from platelets.

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  It also serves a role in inflammatory reactions and allergic responses.

3.1.1.1. Phospholipases hydrolyze phospholipids

Hydrolysis of phospholipids by phospholipases generates specific end products. The

chemical structure of a phospholipid can be predicted based on the type of end product
generated as depicted in Fig. 5.

Figure 5

As an example lysophosphatidic acid is the end product generated after the action of
phospholipase A2 (PLaseA2 ). The ability of lysophosphatidic acid to act as a detergent
is lethal for cell membranes. Bee and snake venoms are enriched in PLaseA2.

The end products most often are not subjected to further degradation in vivo. In such
situations, they function as intra- or extracellular signaling molecules.
Lysophosphatidic acid in vivo is generated by the hydrolysis of phospholipids within
the membrane of the platelets and damaged cells but since it has a very small head
group, its production does not lyse the cells. It instead activates cell growth, which is
necessary for the repair process of the damaged cells.

1, 2 diacylglycerol (DAG), another molecule which is derived from the phospholipids

by the action of PLaseC, serves as an intracellular messenger that activates the protein
kinase C cascade.

PLaseA2 or any other phospholipase should be able to gain access into the
hydrophobic environment of the plasma membrane, to act on phospholipids.
Therefore, solving the X-ray structures of these enzymes has been a fascinating area
for biochemists. Amongst the phospholipases, PLaseA 2 is considered the most well
characterized lipid-specific enzyme.
It is a very small protein of 14 kDa (125 amino acid residues).
The X-ray structure of PLaseA2 from cobra venom has been solved and it shows
that :
a. the active site of the enzyme is occupied by the polar head group,
while
b. the hydrophobic fatty acid tails, stretch out of the active site to
interact with the side chains of many aromatic amino acids.

3.1.2. Galactolipids and sulfolipids

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 Plant membranes are enriched in another class of lipids, namely galactolipids,
wherein,
The C3 of a 1,2 diacylglycerol molecule is linked to one or two galactose molecules by
a glycosidic linkage (Fig. 6).
Figure 6

 the thylakoid membranes of chloroplasts are enriched in galactolipids.

 phosphate can be a limiting nutrient for plants, due to which they have galactolipids
(phosphate-free) instead of phospholipids.
 they are also the most abundant lipids in the biosphere
 additionally, plant membranes also have sulfolipids wherein; a negatively charged
sulfonate group replaces the negatively charged phosphate (Fig. 7).

Figure 7

3.2. Sphingolipids

 Sphigolipids are also important for the structural integrity of plasma membrane
 They comprise of a polar head group and two nonpolar tails but no glycerol moiety
and are considered as the 4th largest class of membrane lipids.
 Sphingolipids contain the following:

One molecule of sphingosine/4-sphingenine, which is a long chain amino alcohol

or one of its derivatives
A polar head group that is linked to the sphingosine molecule by a glycosidic
linkage or is in a phosphodiester linkage AND
One molecule of a long-chain fatty acid

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 The general structure of sphingolipid is shown in Fig. 8, followed by Table 1
showing structures of various sphingolipids.

Figure 8.

As shown in Table 1, if the X is a –H, then the sphingolipid is referred to as ceramide, which
is the parent compound for all other sphingolipids.

The carbon atoms in sphingosine are numbered starting from the polar head group. These 3
carbons are considered to be analogous to the carbon atoms of glycerol in phospholipids.

The fatty acid at C2 position is in an amide linkage with the amino group of sphingosine and
can be saturated or unsaturated with a chain length of 16, 18, 22 or 24 carbon atoms.

If the X is replaced by a phosphocholine moiety, it is called sphingomyelin.

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 3.2.1. Subclasses of sphingolipids

Figure 9

The subclasses of sphingolipids differ in their head groups though ceramide

remains the backbone for all them.

Sphingomyelin (SM) contain phosphocholine or phosphoethanolamine as

their head group. As a consequence, they carry the same net charge and have general
properties similar to phosphatidylcholine (phospholipid)

It comprises of 10-20% of total plasma membrane lipids.

SM is abundant in the myelin sheath that surrounds the neurons.

Cerebrosides/glycosphingolipids contain one or more sugars as their head

group and are abundant in the outer face of the plasma membrane (Fig. 10).

Figure 10

The sugar groups are connected to ceramide directly through the –OH group at C1 of
ceramide.

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Cerebrosides contain a single sugar residue, which can be either galactose or glucose, linked
to ceramide (Table 1).

Globosides on the other hand contain two or more sugars, which are D-glucose, D-galactose
or N-acetyl-D-galactosamine.

Both cerebrosides and globosides do not carry any net charge at pH 7, hence are also referred
to as neutral glycolipids.

Gangliosides contain one or more residues of N-acetylneuraminic acid at their termini (also
referred to as sialic acid) and oligosaccharides as the polar head group.

The gangliosides carry a negative charge due to the presence of sialic acid.

Depending on the number of sialic acid residues the gangliosides are further subdivided into
the following categories (Fig. 11):
a. GM (M is for mono-) series, that contain one sialic acid at the termini
b. GD (D is for di-) series that contain two sialic acid residues
c. GT (t for tri-) and so on…

Figure 11

4. Derived lipids are defined as lipids obtained after the hydrolysis of simple and
compound lipids. Alcohols, fatty acids, aldehydes, ketones, bile acid and sterols are a few
examples of derived lipids.

4.1. Sterols

 Sterols are structural lipids present in the eukaryotic cell membranes.

 They contain
a. a steroid nucleus that has four fused rings AND
b. a hydroxyl group that makes sterols amphipathic
 the fused rings impart rigidity to the sterol molecule as it does not allow
free rotation around the C-C bond.

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  Cholesterol is the most abundant sterol in the eukaryotic plasma membrane
(Fig. 12), while the plant and fungal plasma membranes are enriched in
stigmasterol and ergosterol.

Figure 12

 Bacteria cannot synthesize sterol but have the ability to use exogenous
sterols, which they incorporate into their membranes.
 Five-isoprene subunits are the starting material for the synthesis of sterols.
 Sterols also serve as precursors of steroid hormones, bile acids etc.

4.1.1. Cholesterol is the precursor for steroid hormones and vitamin D

The classification of steroid hormones is based on the physiological response they are
involved in:

1. Glucorticoids have an effect on carbohydrate, protein and lipid metabolism and

also influence various other functions such as the inflammatory response. Cortisol
is an example of a glucocorticoid.
 They are synthesized by the cortex of the adrenal gland
 Impaired functioning of glucocorticoids leads to Addison’s disease

2. Mineralocorticoids like aldosterone control the kidney functions

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 3. Androgens and estrogens are involved in sexual development. Testosterone, an
androgen, is the male sex hormone while estradiol, an estrogen is a female sex
hormone.
4. Vitamin D is also a sterol derivative wherein the steroid B ring is disrupted
between C9 and C10 (Fig. 13).

Figure 13

 Vitamin D2 and D3 are generally in inactive forms and become active only
upon hydroxylation.
 Vitamin D increases calcium absorption, which in turn increases calcium
deposition in the bones and teeth.
 Deficiency of vitamin D causes rickets in children, while excess of it causes
vitamin D intoxication.

5. Summary

 Lipids are classified as simple, compound and derived which are further divided
into various subtypes.
 Triacylglycerols contain three fatty acids esterified to glycerol and are stored in
adipocytes.
 Glycerophospholipids are amphiphilic molecules with a polar head group and
two fatty acyl chains in an ester or ether linkage to glycerol.
 Sphingolipids, considered as compound lipids are classified into sphingomyelin,
gangliosides and cerebrosides.
 Glycerophospholipids and sphingolipids provide structural integrity to the
biological menbranes.
 Cholesterol is a derived lipid and has a fused four ring structure.
 Steroid hormones and vitamin D are all based on the four ring structure and
serve important biological roles.

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