Phospholipids are prevalent in the cells of bacteria and eukaryotes. They are molecules made of a phosphate head and a lipid tail. The head is considered water-loving or hydrophilic, whereas the tail is hydrophobic, or repellent to water. Phospholipids are therefore called amphiphilic. Because of this dual nature of phospholipids, many types arrange themselves into two layers in a watery environment. This is called a phospholipid bilayer. Phospholipid synthesis occurs primarily in the endoplasmic reticulum. Other areas of biosynthesis include the Golgi apparatus and mitochondria. Phospholipids function in various ways inside cells.
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Phospholipids are molecules with hydrophilic phosphate heads and hydrophobic lipid tails. They comprise cellular membranes, regulate certain cellular processes, and possess both stabilizing and dynamic qualities that can aid in drug delivery.
Phospholipids Form Membranes
Phospholipids provide barriers in cellular membranes to protect the cell, and they make barriers for the organelles within those cells. Phospholipids work to provide pathways for various substances across membranes. Membrane proteins stud the phospholipid bilayer; these respond to cell signals or act as enzymes or transporting mechanisms for the cell membrane. The phospholipid bilayer readily allows essential molecules such as water, oxygen and carbon dioxide to cross the membrane, but very large molecules cannot enter the cell in this way or may not be able to at all. With this combination of phospholipids and proteins, the cell is said to be selectively permeable, allowing only certain substances in freely and others via more complex interactions.
Phospholipids provide structure to the cell’s membranes, which in turn keep organelles organized and divided to work more efficiently, but this structure also aids in the membranes' flexibility and fluidity. Some phospholipids will induce negative curvature of a membrane, while others induce a positive curvature, depending on their makeup. Proteins also contribute to the membrane curvature. Phospholipids can also translocate across membranes, often by special proteins such as flippases, floppases and scramblases. Phospholipids contribute to the surface charge of membranes as well. So while phospholipids contribute to stability, their fusion and their fission, they also aid in transportation of materials and signals. Phospholipids therefore make membranes highly dynamic, rather than simple bilayer barriers. And while phospholipids contribute more than originally thought to various processes, they remain the stabilizers of cellular membranes across species.
Other Functions of Phospholipids
With better technology, scientists are able to visualize some phospholipids within live cells via fluorescent probes. Other methods to elucidate phospholipid functionality include using knockout species (such as mice) that possess over-expressed lipid-modifying enzymes. This aids in understanding more functions for phospholipids.
Phospholipids take an active role aside from forming bilayers. Phospholipids maintain a gradient of chemical and electrical processes to ensure cell survival. They are also essential to regulate exocytosis, chemotaxis and cytokinesis. Some phospholipids play a role in phagocytosis, working to surround particles to form phagosomes. Phospholipids also contribute to endocytosis, which is the generation of vacuoles. The process entails binding of the membrane around particles, extension and finally scission. The resulting endosomes and phagosomes in turn posses their own lipid bilayers.
Phospholipids regulate cellular processes related to growth, synaptic transmission and immune surveillance.
Another function of phospholipids is that of assembling circulating lipoproteins. These proteins play the essential role of transport for lipophilic triglycerides and cholesterols in the blood.
Phospholipids also work as emulsifiers in the body, such as when they are mixed with cholesterols and bile acid in the gallbladder to make micelles for fatty-substance absorption. Phospholipids also play the role of wetting of surfaces for such things as joints, alveoli and other parts of the body requiring smooth motion.
Phospholipids in eukaryotes are made in the mitochondria, endosomes and endoplasmic reticulum (ER). Most phospholipids are made in the endoplasmic reticulum. In the ER, phospholipids are used in nonvesicular lipid transport between the ER and other organelles. In mitochondria, phospholipids play numerous roles for cellular homeostasis and mitochondrial functioning.
Phospholipids that do not form bilayers aid in membrane fusion and bending.
Types of Phospholipids
The most prevalent phospholipids in eukaryotes are the glycerophospholipids, which possess a glycerol backbone. They have a head group, hydrophobic side chains and aliphatic chains. The head group of these phospholipids can vary in chemical makeup, leading to diverse varieties of phospholipids. The structures of these phospholipids range from cylindrical to conical to inversely conical, and as such their functionality differs. They work with cholesterol and sphingolipids to aid in endocytosis, they make up lipoproteins, are used as surfactants and are the chief components of cellular membranes.
Phosphatidic acid (PA), also called phosphatidate, comprises only a small percentage of phospholipids in cells. It is the most basic phospholipid and serves as a precursor to other glycerophospholipids. It possesses a conical shape and can result in curving of membranes. PA promotes mitochondrial fusion and fission and is essential for lipid metabolism. It binds to the Rac protein, associated with chemotaxis. It is also thought to interact with many other proteins because of its anionic nature.
Phosphatidylcholine (PC) is the phospholipid in greatest abundance, making up as much as 55 percent of total lipids. PC is an ion known as a zwitterion, has a cylinder shape and is known for forming bilayers. PC serves as a component substrate for generation of acetylcholine, a crucial neurotransmitter. PC can be converted to other lipids such as sphingomyelins. PC also serves as surfactant in the lungs and is a component of bile. Its general role is that of membrane stabilization.
Phosphatidylethanolamine (PE) is also quite abundant but is somewhat conical and does not tend to form bilayers. It comprises as much as 25 percent of phospholipids. It is profuse in the inner membrane of mitochondria, and it can be made by the mitochondria. PE possesses a relatively smaller head group compared to PC. PE is known for macroautophagy and aids in membrane fusion.
Cardiolipin (CL) is a cone-shaped phospholipid dimer and is the chief non-bilayer phospholipid found in mitochondria, which are the only organelles to make CL. Cardiolipin is found primarily on the inner mitochondrial membrane and affects protein activity in the mitochondria. This fatty acid-rich phospholipid is necessary for the functionality of mitochondrial respiratory chain complexes. CL makes up a significant amount of cardiac tissues and is found in cells and tissues that require high energy. CL works to attract protons to an enzyme called ATP synthase. CL also aids in signaling cell death by apoptosis.
Phosphatidylinositol (PI) makes up as much as 15 percent of phospholipids found in cells. PI is found in numerous organelles, and its head group can undergo reversible changes. PI works as a precursor that aids in message transmission in the nervous system as well as membrane trafficking and protein targeting.
Phosphatidylserine (PS) comprises up to 10 percent of phospholipids in cells. PS plays a significant role in signaling inside and outside of cells. PS helps nerve cells to function and regulates nerve impulse conduction. PS features in apoptosis (spontaneous cell death). PS also comprises platelet membranes and therefore plays a role in clotting.
Phosphatidylglycerol (PG) is a precursor for bis(monoacylglycero)phosphate or BMP, which is present in many cells and potentially necessary for cholesterol transportation. BMP is found chiefly in the cells of mammals, where it makes up roughly 1 percent of phospholipids. BMP is made primarily in multivesicular bodies and is thought to induce inward membrane budding.
Sphingomyelin (SM) is another form of phospholipid. SMs are important to the makeup of animal cell membranes. Whereas the backbone of glycerophospholipids is glycerol, the backbone of sphingomyelins is sphingosine. Bilayers of SM phospholipids react differently to cholesterol, and are more highly compressed yet have decreased permeability to water. SM comprises lipid rafts, stable nanodomains in membranes that are important for membrane sorting, signal transduction and the transport of proteins.
Diseases Related to Phospholipid Metabolism
Phospholipid dysfunction leads to a number of disorders such as Charcot-Marie-Tooth peripheral neuropathy, Scott syndrome and abnormal lipid catabolism, which is associated with several tumors.
Genetic disorders caused by gene mutations can lead to dysfunctions in phospholipid biosynthesis and metabolism. These prove to be quite marked in disorders related to mitochondria.
An efficient lipid networking is needed in the mitochondria. The phospholipids cardiolipin, phosphatidic acid, phosphatidylglycerol and phosphatidylethanolamine all play a crucial role in maintaining the membrane of the mitochondria. Mutations of genes that affect these processes sometimes lead to genetic diseases.
In the mitochondrial X-linked disease Barth syndrome (BTHS), conditions include weakness of skeletal muscles, reduced growth, fatigue, motor delay, cardiomyopathy, neutropenia and 3-methylglutaconic aciduria, a potentially fatal disease. These patients exhibit defective mitochondria, which possess decreased amounts of the phospholipid CL.
Dilated cardiomyopathy with ataxia (DCMA) presents with early-onset dilated cardiomyopathy, ataxia of the cerebrum that is not progressive (but which results in motor delays), growth failure and other conditions. This disease results from functional issues with a gene that aids in regulation of CL remodeling and mitochondrial protein biogenesis.
MEGDEL syndrome presents as an autosomal recessive disorder with encephalopathy, a certain form of deafness, motor and developmental delays, and other conditions. In the affected gene, CL’s precursor phospholipid, PG, possesses a changed acyl chain, which in turn changes the CL. Additionally, the gene defects reduce levels of the phospholipid BMP. Since BMP regulates cholesterol regulation and trafficking, its being reduced leads to accumulating unesterified cholesterol.
As researchers learn more about the roles of phospholipids and their importance, it is hoped that new therapies can be made to treat diseases that result from their dysfunction.
Uses for Phospholipids in Medicine
The biocompatibility of phospholipids makes them ideal candidates for drug delivery systems. Their amphiphilic (containing both water-loving and water-hating components) construction aids with self-assembly and making larger structures. Phospholipids often form liposomes that can carry drugs. Phospholipids also serve as good emulsifiers. Pharmaceutical companies can choose phospholipids from eggs, soybeans or artificially constructed phospholipids to aid in drug delivery. Artificial phospholipids can be made from glycerophospholipids by altering head or tail groups or both. These synthetic phospholipids are more stable and more pure than natural phospholipids, but their cost tends to be higher. The amount of fatty acids in either natural or synthetic phospholipids will affect their encapsulation efficiency.
Phospholipids can make liposomes, special vesicles that can better match cell membrane structure. These liposomes then serve as drug carriers for either hydrophilic or lipophilic drugs, controlled-release drugs and other agents. Liposomes made of phospholipids are often used in cancer drugs, gene therapy and vaccines. Liposomes can be made to be highly specific for drug delivery, by making them resemble the cell membrane they need to cross. Phospholipid content of liposomes can be altered based on the site of the targeted disease.
The emulsifying properties of phospholipids make them ideal for intravenous injection emulsions. Egg yolk and soybean phospholipid emulsions are often used for this purpose.
If drugs have poor bioavailability, sometimes natural flavonoids can be used to form complexes with phospholipids, aiding drug absorption. These complexes tend to yield stable drugs with longer action.
As continued research yields more information about the increasingly useful phospholipids, science will benefit from the knowledge to better understand cellular processes and to make more highly targeted medicines.
- Molecular Biology of the Cell: Specific Requirements of Nonbilayer Phospholipids in Mitochondrial Respiratory Chain Function and Formation
- University of Utah Genetic Science Learning Center: Membranes Organize Cellular Complexity
- BBC Bitesize: Transport Across Membranes
- Frontiers in Genetics: Disorders of Phospholipid Metabolism: an Emerging Class of Mitochondrial Disease Due to Defects in Nuclear Genes
- Asian Journal of Pharmaceutical Sciences: A Review on Phospholipids and Their Main Applications in Drug Delivery Systems
- American Physiological Society Physiological Reviews: Role of Phospholipids in Endocytosis, Phagocytosis, and Macropinocytosis