Phospholipids and Related Complex Lipids

Let's first remind ourselves of what a simple triglyceride looks like.
We start with the simple 3 carbon glycerol molecule.

And onto this backbone of three carbons we attach 3 fatty acid chains, thereby making a triglyceride.

Now to construct a phospholipid, the cell simply removes one of the fatty acid tails
and replaces it with a phosphate group.

You hopefully remember that phospholipids are the molecules that make up the plasma membrane
and all of the membranes of a human cell (nuclear membrane, lysosomal membrane,
both mitochondrial membranes, endoplasmic reticulum, Golgi apparatus).
They have a polar, hydrophilic head and two non-polar, hydrophobic tails.

In the diagram, you will notice that phospholipids have a saturated fatty
acid (no double bonds between carbons) on C-1 and an unsaturated fatty acid (double
bonds between carbons) on C-2 of the glycerol backbone.

The Various Forms of Triglycerides and Phospholipids
Found in the Cell

(Most frequently found in membranes.)

I agree, the following different forms on the standard triglyceride and
phospholipid structure can be confusing. However we will not focus too much on the
chemical definitions, but more on the major structural similarities and
differences between these various triglyceride related membrane molecules.

Let's look at the following chart:

Look at the left, and you will see a cartoon of a triglyceride. And you recognize it well.
Next to it, to the right, is a cartoon of a phospholipid, which you also recognize.
It has two fatty acid tails and the third carbon of glycerol is bound to a phosphate group.
If you look to the right of the phospholipid, you will see what's called a Ether Glycerolipid.
It is an awkward name, but all we need to recognize is that it still has the three
carbon glycerol backbone, it has just been slightly modified with an ether group.
And this ether group has replaced the first fatty acid tail. Why we even go into detail
about such an awkward molecule is that two very important molecules in the body
fall into this catagory. They are Platelet Activating Factor, which turns
on your platelets to form plugs; and the Plasmalogens, which are the predominant
membrane lipid in neurons.

If you have the courage, look at the next two cartoons in the chart.
What the chart does not show you, but you would see if the chemical structure
was shown, the attachment of the first fatty acid tail to glycerol is modified slightly.
By modifying this portion of the molecule, it now has to have a different chemical name.
And so it does, it is now called a Sphingosine. Don't blame me, blame the chemists.
But if you will allow yourself to accept that, the remaining parts of these last
two cartoons make some sense. These last two cartoons to the right of the chart
are called Sphingolipids. The one sphingolipid has a phosphate group, and
so is called a Sphingophospholipid. A very important molecule in the body
that is a sphingophospholipid is Sphingomyelin.
The other sphingolipid cartoon has the phosphate group replaced with a sugar (carbohydrate group).
These are the Glycolipids. The two most common, and most related to diseases, are
the Cerebrosides and the Gangliosides.

The Most Prevalent Phospholipids in a Human Cell's Membranes

If you look back to the first chart, you will see the second cartoon from the left shows glycerol with two fatty acid tails and a phosphate group. This is a phospholipid. But there is one small chemical modification to it. The phosphate group has additional molecules attached to it (what the cartoon labels as the 'Head group'). There are different 'groups' that can be attached here. There can be a 'choline' group attached here, or a 'serine' group attached here, or an 'ethanolamine' group attached and so on. The following diagrams show these molecules. Before you allow yourself to be confused, you will recognize the three carbon glycerol backbone, the two fatty acid tails (although the diagram shows them pointing in opposite directions), the phosphate, and now notice the different 'Head groups' attached.


phosphatidylcholine (PC) or Lecithin, found in pulmonary surfactant


phosphatidylethanolamine (PE)


PhosphatidylSerine (PS) is a naturally occurring phospholipid, first isolated and characterized in 1942 by Jordi Folch. Structurally PS consists three different parts: a glycerol backbone, a polar head group, and two hydrophobic tails. The head group consists of the amino acid serine which is attached to the 3-carbon backbone via a phosphate group; the two other hydroxy groups of the glycerol are each esterified with a fatty acid. PS is amphiphilic, meaning that part of it is water-soluble and the other part fat-soluble. This unique property results from the negatively charged head group (water-soluble or hydrophilic/"water-loving") and the fat-soluble fatty acid tails (lipophilic or hydrophobic/"water-avoiding"). PhosphatidylSerine is present in all biological membranes of animals, higher plants and microorganisms. In humans, PS is most concentrated in the brain where it comprises 15% of the total phospholipid pool. In other human tissue the ratio of PS in the phospholipid pool varies: lungs (7.4%), testes (6.4%), kidneys (5.7%), liver (3.8%), skeletal muscle (3.3%), heart (3.2%) and blood plasma (0.2%).



phosphatidylserine (PS)


phosphatidylinositol (PI)


phosphatidylglycerol (PG), found in mitochondrial membranes and pulmonary surfactant


diphosphatidylglycerol (DPG) or Cardiolipin


Structures of Cardiolipin (A-top) and Plasmalogen (B-bottom).
Cardiolipin is a major lipid found in the inner mitochondrial membrane.
Plasmalogens make up to 10% of the phospholipids in muscle cells and neurons.

Just as a reminder, also keep in mind that each of the three bonds in a triglyceride and these various forms of lipids has it's own unique lipase to cleave it. Why do we need to be reminded of this? If our cells do not have a specific enzyme needed to break one of these bonds, the cell will not be able to tear that large lipid apart, and so those lipids will begin to accummulate in the cell (typically the lysosome), causing disease. Remember your cells are constantly remodeling, constantly making and breaking apart the same types of molecules.

Plasmalogens:
Plasmalogens are glycerol ether phospholipids. Three major classes of plasmalogens
have been identified: choline, ethanolamine and serine plasmalogens.
Ethanolamine plasmalogen is prevalent in myelin. Choline plasmalogen is abundant in cardiac tissue.
One particular choline plasmalogen has been identified as an extremely powerful biological mediator.
This molecule is called platelet activating factor, PAF.


PAF

PAF functions as a mediator of hypersensitivity, acute inflammatory reactions
and anaphylactic shock. The synthesis and release of PAF from cells leads to platelet aggregation.

Sphingolipids:
The sphingolipids, like the phospholipids, are composed of a polar head group and two nonpolar tails.
The core of sphingolipids is the sphingosine.


The sphingolipids include the sphingomyelins and glycosphingolipids (the cerebrosides,
sulfatides, globosides and gangliosides). Sphingomyelins are the only sphingolipid that are phospholipids.
Sphingolipids are a component of all membranes but are particularly abundant in the myelin sheath.

Sphingomyelins are sphingolipids that are also phospholipids. Sphingomyelins are important
structural lipid components of nerve cell membranes.


Defects in the enzyme acid sphingomyelinase result in the lysosomal storage disease known as Niemann-Pick disease.

You are required to click here and read about Niemann-Pick disease

You are also required to view this case report

Glycosphingolipids

Glycosphingolipids, or glycolipids, are composed of a ceramide backbone with a wide variety
of carbohydrate groups (mono- or oligosaccharides) attached to carbon 1 of sphingosine.
The four principal classes of glycosphingolipids are the cerebrosides, sulfatides, globosides and gangliosides.

Cerebrosides have a single sugar group linked to ceramide. The most common of these is
galactose (galactocerebrosides), with a minor level of glucose (glucocerebrosides).
Galactocerebrosides are found predominantly in neuronal cell membranes. By contrast
glucocerebrosides are not normally found in membranes, especially neuronal membranes;
instead, they represent intermediates in the synthesis or degradation of more complex glycosphingolipids.

Galactocerebrosides are synthesized from ceramide. Excess accumulation of glucocerebrosides
is observed in Gaucher's disease.


Galactocerebroside

Gangliosides: Gangliosides are very similar to globosides except that they also contain NANA
in varying amounts. The specific names for gangliosides are a key to their structure.

Deficiencies in lysosomal enzymes, which normally are responsible for the degradation
of the carbohydrate portions of various gangliosides, underlie the symptoms observed in rare
autosomally inherited diseases termed lipid storage diseases, many of which are listed below.

Clinical Significances of Sphingolipids

One of the most clinically important classes of sphingolipids are those that act as antigens
on the surfaces of cells, particularly the erythrocytes. The ABO blood group antigens are sphingolipids
with sugar groups attached. When present on the surface of cells the ABO carbohydrates are
linked to sphingolipid and are therefore of the glycosphingolipid class.
When the ABO carbohydrates are associated with protein in the form of glycoproteins
they are found in the serum and are referred to as the secreted forms. Some individuals
produce the glycoprotein forms of the ABO antigens while others do not. This property
distinguishes secretors from non-secretors, a property that has forensic importance such as in cases of rape.


R represents the linkage to protein in the secreted forms, sphingolipid in the cell-surface bound form

ABO Blood Group Carbohydrates