Introduction

Lipids is a broad category of organic compounds that vary greatly in their structure and properties. Phospholipids are one of these heterogeneous compounds included in this category of biological molecules. Phospholipids are characterized by having a phosphate group in their structure making them polar compounds. They are the most prominent lipids present in all types of membranes. 

Different phospholipids have different structures, properties, and importance in the human body. In this article, we will discuss the general structure and classification of phospholipids. Later, we will try to understand the structure, metabolism and functions of some important phospholipids present in the human body. 

General Structure

Phospholipids include a large variety of compounds that have different structures and properties. However, all the compounds included in this category follow one general structure or general formula. All the phospholipids have;

• A phosphate group
• An alcohol
• Fatty acids

The nature of alcohol and the fatty acids varies from compound to compound. However, it must for a phospholipid to have two fatty acids attached to alcohol via an ester bond, and a phosphate group attached to the same alcohol molecule via a phosphodiester bond. 

The presence of phosphate group in phospholipids makes them polar. However, the fatty acids impart the hydrophobic characteristics to these compounds. Thus, each phospholipid has both polar and non-polar ends. Phospholipids have,

• Polar head, made by a phosphate group
• Hydrophobic tails, made by two fatty acids present in them

 The hydrophobic tails are attached to the polar head of the compound. 

The structure of individual phospholipids will be discussed as we move on in this article. 

Classification

Phospholipids are divided into two broad categories based on the alcohol present in their backbone. These are:

• Glycerophospholipids
• Sphingophospholipids

Both of them are present in the cellular membranes and perform important functions, essential for the maintenance of life. 

Glycerophospholipids

These are the phospholipids that contain glycerol as an alcohol in their backbone. They are also called phosphoglycerides. They are the most abundant lipids in the membranes of living organisms. 

All glycerophospholipids either contain a molecule of phosphatidic acid or are its derivatives. 

Phosphatidic acid (PA)

A molecule of phosphatidic acid is made up of two components,

• Diacylglycerol (DAG)
• Phosphate group

Diacylglycerol contains glycerol alcohol along with two fatty acids attached to the first and second carbon of glycerol via ester bonds. The addition of a phosphate group to the third carbon of glycerol via phosphodiester bond converts DAG into phosphatidic acid (PA). 

Having understood the structure of phosphatidic acid, it will easier for us now to have a look at the structure of various glycerophospholipids. 

Phosphatidyl alcohol

Many glycerophospholipids simply contain an alcohol esterified to the phosphate group attached to the 3^rd carbon of glycerol. These phospholipids are given names by simply adding the name of alcohol after the prefix ‘phosphatidyl’. This prefix represents the presence of phosphatidic acid in the structure of the compound. 

Examples of such lipids are as follows.

• Phosphatidylserine: It contains serine alcohol attached to phosphatidic acid. 
• Phosphatidylethanolamine: It has ethanolamine attached to phosphatidic acid. 
• Phosphatidylcholine: In this phospholipid, the alcohol is choline. 
• Phosphatidylinositol: Inositol is the alcohol in this phospholipid. 
• Phosphatidylglycerol: It has a second molecule of glycerol attached to the phosphate group. 

Cardiolipin

Cardiolipin has two molecules of phosphatidic acid attached to an additional molecule of glycerol. The phosphate groups of two phosphatidic acid molecules make ester bonds with glycerol resulting in the formation of diphosphatidylglycerol, also called cardiolipin.

Plasmalogens

Instead of having a fatty acid, plasmalogens have an alkyl group attached to the first carbon of glycerol. The alkyl group is attached via an ether linkage to the glycerol. The rest of the structure plasmalogen is the same as phosphatidyl alcohols.

Plasmalogens are given names by adding the name of alcohol after the prefix ‘phosphatidal’ such as phosphatidalcholine.  

Don’t confuse phosphatidalcholine (a plasmalogen) with phosphatidylcholine (a phosphatidylcholine). 

Platelet-activating factor

It is another derivative of phosphatidic acid having a structure similar to that of plasmalogens. The first carbon of glycerol has an alkyl group while the second carbon has an acetyl group.  No fatty acid is present in these phospholipids. Both the alkyl and the acetyl group are linked via ether linkages. 

Because of the presence of ether linkages, plasmalogens and platelet-activating factors are collectively called ether glycerophospholipids.

Synthesis

The synthesis of glycerophospholipids can occur in two ways; either transfer of phosphatidic acid to an alcohol or transfer of phospho-monoester of alcohol to diacylglycerol. 

In both cases, the donor molecule is bound to a CDP derivative and it acts as an intermediate. A molecule of CMP is released as a result of this transfer. 

The synthesis of most of the phospholipids takes place inside the endoplasmic reticulum. After synthesis, phospholipids are transferred to the Golgi apparatus which packs them into vacuoles for transport to various cellular membranes. 

Synthesis of individual phospholipids is as follows.

Phosphatidic acid

It is the precursor of all glycerophospholipids. Phosphatidic acid is synthesized from glycerol-3-phosphate. Acetyl groups of fatty acids are transferred to the first and second carbon of glycerol-3-phosphate by acetyltransferase enzyme.

Phosphatidylcholine and Phosphatidylethanolamine

For the synthesis of these phospholipids, ethanolamine and choline obtained either from diet or from the turnover of other phospholipids are used. They are first phosphorylated by kinases and the phosphorylated forms are then converted to activated form CDP-choline and CDP-ethanolamine. 

The activated forms transfer the choline-phosphate or ethanolamine-phosphate to a molecule of DAG, forming phosphatidylcholine and phosphatidylethanolamine, respectively.

Phosphatidylserine

Phosphatidylserine is synthesized by base exchange reaction. In this reaction, free base serine is exchanged with the base of phosphatidylethanolamine. The result is the formation of phosphatidylserine and free ethanolamine.  

Phosphatidylinositol 

It is synthesized from inositol and CDP-diacylglycerol (CDP-DAG). The CDP-DAG molecule donates its phosphatidic acid to inositol and a molecule of CMP is released. The CMP molecule can be converted to CDP by kinases for use in other reactions. 

Phosphatidylglycerol and Cardiolipin

Both these phospholipids share the synthetic pathway. First of all, phosphatidylglycerol is made by the reaction between CDP-diacylglycerol and glycerol-3-phosphate. 

For the synthesis of cardiolipin, a molecule of DAG is transferred from CDP-diacylglycerol to already existing molecule of phosphatidylglycerol. 

Importance

The glycerophospholipids discussed above have profound importance in the human body. The following are some of the functions performed by them.

Phosphatidylcholine

Phosphatidylcholine having palmitic acid at carbon 1 and 2 of glycerol, called dipalmitoyl phosphatidylcholine (DPPC), is the main constituent of lung surfactant. It is synthesized and secreted by type 2 pneumocytes present in the lungs. Its main role is to decrease the surface tension in the lungs so that they can be inflated easily. Premature babies born with less surfactant in the lungs suffer from respiratory distress syndrome (RDS). In RDS, the infants are unable to inflate their lungs due to decreased surfactant. Their lungs collapse and most of them die as a result of respiratory insufficiency. 

Phosphatidylinositol 

It plays an important role in the cell signaling pathway. Phosphatidylinositol is present in the cell membrane as phosphatidylinositol 4-5 bisphosphate (PIP₂). It is involved  G_q protein signaling pathway. Activation of G_q by G-protein coupled receptor results in activation of phospholipase C that cleaves the PIP₂ into inositol-3-phosphate (IP₃) and diacylglycerol (DAG). Both these byproducts ultimately result in the activation of protein kinase C (PK_c) that produces cellular effects. 

Phosphatidylinositol is also involved in anchoring extracellular proteins to the cell membrane. These proteins attach to the PI present in the cell membrane via a carbohydrate bridge and are called glycosyl phosphatidyl (GPI) anchored proteins.

Alkaline phosphatase enzyme is an example of GPI-anchored proteins. 

Cardiolipin

It is an important structure in the mitochondrial membranes of eukaryotes. Cardiolipin is present in the inner mitochondrial membrane where it maintains the structure of some complexes involved in the respiratory chain.  

It has antigenic characteristics and can be recognized by antibodies raised against Treponema pallidum and is thus involved in the pathogenesis of cardiolipin. 

Plasmalogens

These phospholipids are abundantly present in the membranes of living cells. An important plasmalogen is phosphatidalcholine that is mainly present in the heart cells.

Platelet-activating factor (PAF)

It is an important signaling molecule that binds to cell surface receptors and triggers acute inflammatory and thrombogenic events. For example, it activates inflammatory cells involved in acute inflammatory, anaphylactic and thrombotic events.  It also causes platelet activation for thrombogenesis and activation of neutrophils and macrophages to kill bacteria. 

Sphingophospholipids

They are the phospholipids having sphingosine as an alcohol instead of glycerol. They are also called sphingolipids.
Sphingomyelin is the most important sphingolipid present in the human body. Its structure, synthesis, and importance will be discussed under this heading. 

Structure

Sphingomyelin has a backbone made up of amino alcohol sphingosine. 

The difference between sphingosine and glycerol in the presence of an amino group and an alkyl chain. Sphingosine has an amino group at its second carbon while two hydroxyl groups are present on first and third carbon. The third carbon of sphingosine is also linked to an unsaturated alkyl chain. On the other hand, in the case of glycerol, hydroxyl groups are present at all the three carbons with no alkyl chain. 

A saturated fatty acid attaches to the amino group of sphingosine through an amide linkage resulting in the formation of Ceramide. 

The hydroxyl group at the first carbon of ceramide form an ester linkage with the phosphorylated choline molecule to form sphingomyelin. 

Synthesis

The synthesis of sphingomyelin follows various steps as described below. 

In the first step, a molecule of palmitoyl CoA (an unsaturated fatty acid) condenses with serine (an amino acid) resulting in the formation of dihydrosphingosine. The carboxylic group of serine is lost in this process in the form of carbon dioxide. A coenzyme, pyridoxal phosphate, and NADPH as a reducing agent are essential for this reaction to occur. 

In the next step, dihydrosphingosine is acetylated with a long-chain fatty acid at its amino group in the presence of FAD. The product thus formed in desaturated to form ceramide. 

In the final step, choline is transferred from phosphatidylcholine to ceramide resulting in the formation of sphingomyelin along with releasing a molecule of diacylglycerol. 

Importance

Sphingomyelin is the most important phospholipid in the nervous system. It is the main lipid present in the myelin sheath that encloses the axonal fibers of neurons. It is necessary for the prompt conduction of nerve impulses that acquire a jumping pattern in myelinated axons.  

Sphingomyelin is also involved in signaling pathways responsible for planned cell death or apoptosis. In this case, it is cleaved into ceramide and choline. Ceramide may also be further hydrolyzed to form sphingosine. The ceramide and sphingosine serve to activate the protein kinase C that brings about cellular effects. 

Neiman-Pick diseases is a hereditary diseases associated with deficiency of sphingomyelinase enzyme. As a result, sphingomyelin cannot be degraded in such individuals. It gets deposited in the lipid stores of the body. This causes massive hepatosplenomegaly as the liver and spleen are the primary lipid storage organs in our body. 

Summary

Phospholipids are a broad category of organic compounds having both polar and non-polar characteristics. 

All phospholipids have;

• A polar head
• Two non-polar tails

They are the most abundant lipids in the plasma membrane. The ‘lipid-bilayer’ of cellular membranes is made by the phospholipids. 

Based on the nature of alcohol present in their backbone, they are divided into two groups;

• Glycerophospholipids
• Sphingophospholipids

Glycerophospholipids have glycerol alcohol backbone. 

• They are the most abundant phospholipids. 
• Most of them contain phosphatidic acid or are derivatives of phosphatidic acid.
• Some examples of glycerophospholipids include phosphatidylcholine, cardiolipin, phosphatidylinositol, and platelet-activating factor.
• Important functions performed by these phospholipids in human body are as follows;
• Phosphatidylcholine is a major component of a surfactant that decreases surface tension in the lungs. 
• Cardiolipin holds the respiratory complexes in the inner mitochondrial membrane.
• Phosphatidylinositol is involved in cell signaling and anchoring extracellular proteins. 
• Platelet-activating factor is involved in several inflammatory and thrombogenic events. 

Sphingophospholipids have a backbone made of sphingosine alcohol. 

• Sphingomyelin is the most important sphingophospholipid. 
• It has choline base at first carbon and a saturated fatty acid at the second carbon of sphingosine. 
• It is the most important component of the myelin sheath.
• Neiman-Pick disease is associated with an inability to degrade sphingosine, resulting in severe hepatosplenomegaly. 

Frequently Asked Questions

What are phospholipids?

Phospholipids are complex lipids that consist of two long chain fatty acids, a nitrogenous base, phosphoric acid and an alcohol. They are an important component of membranes found in living organisms.

What are the functions of phospholipids?

Phospholipids are an important component of cell membranes. They provide fluidity to the membranes. They are also involved in cell signalling and anchoring of proteins. 

What are four important phospholipids?

Four important phospholipids include phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, and sphingomyelin.

Which foods contain phospholipids?

Phospholipids are found in chicken, eggs, soya, milk, sunflower, etc. 

References

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3. ^ Ketoconazole Encapsulated Liposome and Ethosome: GUNJAN TIWARI
4. Prinz, William A.; Choudhary, Vineet; Liu, Li-Ka; Lahiri, Sujoy; Kannan, Muthukumar (2017-03-01). “Phosphatidylserine synthesis at membrane contact sites promotes its transport out of the ER”. Journal of Lipid Research. 58 (3): 553–562. doi:10.1194/jlr.M072959. ISSN 0022-2275. PMC 5335585. PMID 28119445
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