Signalling Lipids PDF

# Signaling Lipids ## Introduction Lipids serve many roles in living organisms, including: * energy storage molecules * the primary structural component of membranes * signaling molecules * regulatory molecules * coenzymes This lesson will provide a brief introduction to some of these additiona...

# Signaling Lipids ## Introduction Lipids serve many roles in living organisms, including: * energy storage molecules * the primary structural component of membranes * signaling molecules * regulatory molecules * coenzymes This lesson will provide a brief introduction to some of these additional roles of lipids. ## Signaling Lipids Derived from Hydrolyzable Membrane Lipids ### Signaling Lipids Derived from Glycerophospholipids * Membrane lipids surround every cell and organelle, serving as an important reservoir of signaling molecules. * Lipid bilayer membranes are asymmetric; certain lipids are more common in one leaflet than the other. **Phosphatidylserine (PS)** is an example of a glycerophospholipid that is found only on the inner (cytosolic) leaflet of the plasma membrane of healthy cells. * However, in **apoptotic cells**, this asymmetry is disrupted, and PS moves to the outer leaflet. * Outer leaflet PS is a recognition signal for macrophages to phagocytose apoptotic bodies. **Figure 9.41**: Phosphatidylserine (PS) is an example of a phospholipid that acts as a signal when localized to a certain region. ### Phosphatidylinositol (PI) * Phosphatidylinositol (PI) and its derivatives are another example of glycerophospholipids that can serve as both structural lipids and signaling lipids. * For example, **phosphatidylinositol 4,5-bisphosphate (PIP2)** can be phosphorylated by **phosphatidylinositol 3-kinase (PI3K)** to make **phosphatidylinositol 3,4,5-trisphosphate (PIP3)**. * Membrane PIP3 can then allosterically activate downstream effector molecules in various pathways, such as cell growth or neuronal plasticity. **Figure 9.42**: Phosphatidylinositol (PI) is an example of a membrane lipid that can act in a signaling role based on its phosphorylation status. ### PIP2 Hydrolysis * Alternatively, PIP2 can be hydrolyzed to form two different molecules that both have signaling properties. * The enzyme **phospholipase C (PLC)** hydrolyzes the phosphoester bond between the glycerol backbone and the polar head group to yield **inositol 1,4,5-trisphosphate (IP3)** and **diacylglycerol (DAG)**. * IP3 is a second messenger that activates the IP3 receptor to release calcium into the cytosol. * DAG is an allosteric activator of the enzyme **protein kinase C (PKC)**. **Figure 9.43**: PIP2 is an example of a membrane lipid that is hydrolyzed to release products involved in signaling pathways. ### Phospholipase A (PLA) * Whereas PLC hydrolyzes a phospholipid's polar head group from the rest of the phospholipid molecule, the **phospholipase A (PLA) enzymes hydrolyze a fatty acid group from the rest of the molecule**. * In this way, hydrolyzable membrane lipids serve as a reservoir of fatty acids, which can also serve as signaling molecules. **Figure 9.44**: Arachidonic acid is an example of a fatty acid that is released via phospholipid hydrolysis and converted into a signaling molecule. ### Arachidonic Acid * Arachidonic acid is a 20-carbon polyunsaturated fatty acid that serves as a precursor molecule to the various eicosanoid signaling molecules. * Eicosanoids include the prostaglandins, the leukotrienes, and the thromboxanes. * Eicosanoids tend to act as paracrine or autocrine signals. * They often function in local processes such as injury response or inflammation. **Prostaglandins** are eicosanoids that contain a cyclic five-membered ring as well as several oxidized functional groups. * Many **nonsteroidal anti-inflammatory drugs (NSAIDs)** decrease prostaglandin synthesis by targeting the cyclooxygenase (COX) enzymes that produce them. **Figure 9.45**: Arachidonate and examples of eicosanoids. ### Post-Translational Modification * Fatty acids can also serve as signaling molecules by acting as lipid modifications of other molecules. * For example, **palmitic acid** is commonly used to post-translationally lipidate a protein and anchor it to the membrane. * The 16-carbon saturated fatty acid palmitic acid (palmitate in its deprotonated form) is commonly used to post-translationally lipidate a protein and anchor it to the membrane. * Palmitoylation of a protein can traffic that protein toward the membrane or toward lipid rafts within a membrane. **Figure 9.46**: Palmitoylation is an example of a post-translational addition of a fatty acid to a protein and of fatty acids acting as regulatory signals. ## Sphingolipids as Signaling Molecules * Like the glycerophospholipids, **sphingolipids** are important membrane components and serve as an easily accessible reservoir of signaling molecules. * Membrane sphingolipids can be hydrolyzed to form signaling molecules (eg, ceramide, sphingosine 1-phosphate), or they can serve as signals in their intact form. * **Glycosphingolipids** are the most common type of glycolipid in mammals. * Glycosphingolipids are commonly found in the outer leaflet of the plasma membrane, where their carbohydrate moiety is exposed to the external environment. * This allows other cells and proteins to recognize the exposed carbohydrate group of the glycosphingolipid. **Figure 9.47**: ABO blood types are an example of glycolipids that can send a signal (eg, native versus foreign body) based on recognition of the attached carbohydrate. ## Terpenoids as Signaling Molecules ### Steroid Hormones * **Terpenoids**, also called isoprenoids, are molecules derived from the combination of two or more isoprene units. * Cholesterol is an example of a triterpene and serves as the precursor of several steroid hormones. **Steroid hormones** can be used to coordinate a large variety of processes in a multicellular organism. * For example, the **sex steroid hormones** (eg, estrogen, testosterone) affect a variety of cells and tissues to regulate development of secondary sex characteristics and other metabolic processes. **Figure 9.48**: Examples of sex steroids produced by the gonads (ie, ovaries, testes). #### Glucocorticoids and Mineralocorticoids * **Glucocorticoids** such as cortisol are especially important in the stress response and consequently have effects on energy metabolism, inflammation, the immune response, and other processes. * **Mineralocorticoids** such as aldosterone regulate mineral excretion and reabsorption in the kidney and thereby regulate blood volume and blood pressure. **Figure 9.49**: Corticosteroids produced by the adrenal cortex. * **Vitamin D** is another steroid hormone that can be made in limited quantities in the skin through an ultraviolet light-catalyzed reaction. * Vitamin D is involved in calcium homeostasis. **Figure 9.50**: Example of a form of vitamin D, a signaling lipid. ### Other Terpenoid Signaling Lipids * **Retinal** is a terpenoid that acts as a signaling lipid in the visual system, covalently binding as a ligand to a G protein-coupled receptor known as rhodopsin. * Retinal has a long, conjugated hydrocarbon tail, which allows it to absorb specific wavelengths of light. * The absorbed light energy can then induce *cis-trans* isomerization of one of its double bonds, allowing it to act as an activating agonist for rhodopsin. **Figure 9.53**: Retinal is an example of a lipid ligand that can activate a receptor based on its *cis-trans* configuration. * **Retinoic acid** is another form of vitamin A, acts like a steroid hormone in that it binds a nuclear receptor to induce expression of genes related to growth and development. * **Ubiquinone**, also called coenzyme Q (CoQ), acts as a redox cofactor in the electron transport chain (ETC). * Ubiquinone (Q) receives a pair of electrons (and two H+) at either Complex I or Complex II of the ETC, which reduces the lipid to ubiquinol (QH2). * QH2 then diffuses through the inner mitochondrial membrane to Complex III, where it deposits its electrons one at a time. **Figure 9.54**: Ubiquinone and ubiquinol are examples of lipids acting as redox coenzymes. ### Vitamins A, D, E and K * **Vitamins E and K** are also lipids with redox capability and with terpenoid tails. * Vitamin E acts as a general antioxidant, whereas vitamin K functions as a redox coenzyme in the clotting pathway. **Collectively, vitamins A, D, E, and K are known as the lipid-soluble vitamins.** * Lipid-soluble vitamins (also called fat-soluble vitamins) are nonhydrolyzable lipids that can be stored in adipose tissue (ie, fat tissue). **Table 9.1**: The lipid-soluble vitamins. ## Concept Check: 9.4 Which of the following describe a role of lipids? Select all that apply. * An intracellular signaling molecule * A barrier around cells and organelles * A specific recognition signal for other cells or antibodies * An extracellular signaling molecule * A fuel that can be broken down for energy * A waterproof coating of hair and skin * A means of storing excess energy * An allosteric regulator * A redox coenzyme **Solution:** All are roles of various types of lipids.