LIPIDS Biochemistry (BMS 233) L.Noha Soliman

OBJECTIVES Define simple and complex lipids and identify the lipid classes in each group. Indicate the structure of saturated and unsaturated fatty acids, explain how the chain length and degree of unsaturation influence their melting point. Understand the difference between cis and trans carbon-carbon double bonds. Describe how eicosanoids are formed by modification of the structure of unsaturated fatty acids; identify the various eicosanoid classes and indicate their functions. Outline the general structure of triacylglycerols and indicate their function.

OBJECTIVES Outline the general structure of phospholipids and glycosphingolipids and indicate the functions of the different classes. Describe the importance of cholesterol as the precursor of many biologically important steroids. Understand that many lipid molecules are amphipathic and explain how this influences their behavior in an aqueous environment and enables certain classes to form the basic structure of biologic membranes.

BIOMEDICAL IMPORTANCE The lipids are a heterogeneous group of compounds. They have the common property of being relatively insoluble in water and soluble in nonpolar solvents such as ether and chloroform. They are important dietary constituents not only because of the high energy value of fats, but also because essential fatty acids and fat-soluble vitamins and other lipophilic micronutrients are contained in the fat of natural foods. Dietary supplementation with long chain omega 3 Fatty acids is believed to have beneficial effects in a number of chronic diseases, including cardiovascular disease, rheumatoid arthritis and dementia.

BIOMEDICAL IMPORTANCE Fat is stored in adipose tissue, where it also serves as a thermal insulator in the subcutaneous tissues and around certain organs. Nonpolar lipids act as electrical insulators, allowing rapid propagation of depolarization waves along myelinated nerves. Lipids are transported in the blood combined with proteins in lipoprotein particles. Lipids have essential roles in nutrition and health and knowledge of lipid biochemistry is necessary for the understanding of many important biomedical conditions, including obesity, diabetes mellitus, and atherosclerosis.

Functions of lipids Energy source. Serves as an energy reserve. Cell Membrane Structural components. Thermal Insulator: Subcutaneous layer of fat reduces heat loss in cold weather (helps maintain body temperature). Carry Lipid-soluble vitamins (A,D,E, and K) & essential fatty acids.

Classification of lipids 3.Precursor & Derived Lipids 1. Simple Lipids 2. Complex Lipids 3.Precursor & Derived Lipids

Simple lipids 1. Simple lipids include fats and waxes which are esters of fatty acids with various alcohols: a. Fats: Esters of fatty acids with glycerol. Oils are fats in the liquid state. b. Waxes: Esters of fatty acids with higher molecular weight monohydric alcohols.

Complex lipids 2. Complex lipids are esters of fatty acids containing groups in addition to an alcohol and one or more fatty acids. They can be divided into three groups: a. Phospholipids: Lipids containing, in addition to fatty acids and an alcohol , a phosphoric acid residue. They frequently have nitrogen-containing bases (eg,choline) and other substituents. In many phospholipids the alcohol is glycerol (glycerophospholipids), but in sphingophospholipids it is sphingosine, which contains an amino group.

Complex lipids b. Glycolipids (glycosphingolipids): Lipids containing a fatty acid, sphingosine, and carbohydrate. c. Other complex lipids: Lipids such as sulfolipids and amino lipids. Lipoproteins may also be placed in this category.

Precursor and derived lipids 3. Precursor and derived lipids: These include fatty acids, glycerol, steroids, other alcohols, fatty aldehydes, ketone bodies, hydrocarbons, lipid-soluble vitamins and micronutrients, and hormones. Fatty acids Glycerol Steroids hormones Vitamins (A,D,E,K)

Fatty acids Fatty acids are aliphatic carboxylic acids: Fatty acids occur in the body mainly as esters in natural fats and oils, but are found in the unesterified form as free fatty acids, a transport form in the plasma. Fatty acids that occur in natural fats usually contain an even number of carbon atoms.

Fatty acids Fatty acids are aliphatic carboxylic acids: The chain may be saturated (containing no double bonds) or unsaturated (containing one or more double bonds).

Saturated fatty acids Saturated fatty acids contain no double bonds: Saturated fatty acids may be envisaged as based on acetic acid (CH3—COOH) as the first member of the series in which— CH2— is progressively added between the terminal CH3— and —COOH groups.

Properties of saturated fatty acids General Formula: CH3 (CH2)n COOH. Each C being “saturated” with H. Contain only single C–C bonds. long, straight chain.

Closely packed. Strong attractions between chains. High melting points. Solids at room temperature.

unsaturated fatty acids Unsaturated Fatty Acids Contain One or More Double Bonds: Unsaturated fatty acids may be further subdivided as follows: Monounsaturated acids: containing one double bond. 2. Polyunsaturated acids: containing two or more double bonds.

unsaturated fatty acids 3. Eicosanoids: These compounds, derived from 20-carbon polyunsaturated fatty acids, comprise the prostanoids , leukotrienes (LTs), and lipoxins (LXs). Prostanoids include prostaglandins (PGs), prostacyclins (PGIs), and thromboxanes (TXs).

unsaturated fatty acids Properties of unsaturated fatty acids Contain one or more double C=C bonds. The kinks made by double bonded C prevent the molecules from packing tightly together. Few interactions between chains.

unsaturated fatty acids Properties of unsaturated fatty acids Low melting points Liquids at room temperature Plant & fish fats Vegetable oils

Most Naturally Occurring Unsaturated Fatty Acids Have cis Double Bonds Cis-Fatty Acid H’s on same side of the double bond; fold into a U-like formation; naturally occurring Trans-Fatty Acid H’s on the opposite side of the double bond; occur in partially hydrogenated food

Cis - Fatty acids

Trans - Fatty acids

Physical and physiologic properties of fatty acids reflect chain length and degree of unsaturation The melting points of even-numbered carbon fatty acids increase with chain length and decrease according to unsaturation. A triacylglycerol containing three saturated fatty acids of 12 carbons or more is solid at body temperature, whereas if the fatty acid residues are polyunsaturated, it is liquid to below 0°C. In practice, natural acylglycerols contain a mixture of fatty acids tailored to suit their functional roles. For example, membrane lipids, which must be fluid at all environmental temperatures, are more unsaturated than storage lipids.

ω3 Fatty acids are anti-inflammatory and have health benefits Long chain ω3 fatty acids such as α-linolenic (ALA) (found in plant oils), eicosapentaenoic (EPA) (found in fish oil) and docosahexaenoic (DHA) (found in fish and algal oils) have anti-inflammatory effects, perhaps due to their effects in promoting the synthesis of less inflammatory prostaglandins and leukotrienes as compared to ω6 fatty acids. In view of this, their potential use as a therapy in severe chronic disease where inflammation is a contributory cause is under intensive investigation. Current evidence suggests that diets rich in ω3 fatty acids are beneficial, particularly for cardiovascular disease, but also for other chronic degenerative diseases such as cancer, rheumatoid arthritis, and Alzheimer disease.

Triacylglycerols (triglycerides) are the main storage forms of fatty acids The triacylglycerols are esters of the trihydric alcohol glycerol and fatty acids. Mono- and diacylglycerols, wherein one or two fatty acids are esterified with glycerol, are also found in the tissues.

Triacyleglycerols

Phospholipids are the main lipid constituents of membranes Many phospholipids are derivatives of phosphatidic acid , in which the phosphate is esterified with one OH group of glycerol and the other two OH groups are esterified to two long chain fatty acids. Phosphatidic acid is important as an intermediate in the synthesis of triacylglycerols as well as phosphoglycerols but is not found in any great quantity in tissues.

Glycerophospholipids Structure: Glycerol + 2 Fatty acids + PO4 + polar molecule ( x).

Glycerophospholipids Structure: Glycerol + 2 Fatty acids + PO4 + polar molecule (x).

Sphingolipids Sphingolipids such as sphingomyelin, in which the phosphate is esterified to sphingosine, a complex amino alcohol , are also important membrane components.

Phospholipids are the main lipid constituents of membranes Both glycerophospholipids and sphingolipids have two long chain hydrocarbon tails which are important for their function in forming the lipid bilayer in cell membranes.

Glycolipids Glycolipids are lipids with an attached carbohydrate or carbohydrate chain. They are important constituents of nervous tissue such as brain and the outer leaflet of the cell membrane, where they contribute to the carbohydrates on the cell surface. The major glycolipids found in animal tissues are glycosphingolipids.

Glycolipids Galactosylceramide is a major glycosphingolipid of brain and other nervous tissue.

Steroids play many physiologically important roles All steroids have a similar cyclic nucleus resembling phenanthrene (rings A, B, and C) to which a cyclopentane ring (D) is attached.

Steroids play many physiologically important roles Although cholesterol is probably best known for its association with atherosclerosis and heart disease, it has a number of essential roles in the body. It is the precursor of a large number of equally important steroids that include the bile acids, adrenocortical hormones, sex hormones, vitamin D, and cardiac glycosides.

Cholesterol is a significant constituent of many tissues Cholesterol is widely distributed in all cells of the body but particularly in nervous tissue. It is a major constituent of the plasma membrane and of plasma lipoproteins. It is often found as cholesteryl ester, where the hydroxyl group on position 3 is esterified with a long-chain fatty acid. It occurs in animals but not in plants or bacteria.

Amphipathic lipids self-orient at oil: Water interfaces In general, lipids are insoluble in water since they contain a predominance of nonpolar (hydrocarbon) groups. However, fatty acids, phospholipids, sphingolipids, bile salts, and, to a lesser extent, cholesterol contain polar groups. Therefore, a part of the molecule is hydrophobic, or water insoluble; and a part is hydrophilic, or water soluble. Such molecules are described as amphipathic. They become oriented at oil-water interfaces with the polar group in the water phase and the nonpolar group in the oil phase.

Amphipathic lipids self-orient at oil: Water interfaces A bilayer of such amphipathic lipids is the basic structure in biologic membranes. When a critical concentration of these lipids is present in an aqueous medium, they form micelles.

Amphipathic lipids self-orient at oil: Water interfaces Liposomes may be formed by sonicating an amphipathic lipid in an aqueous medium. They consist of spheres of lipid bilayers that enclose part of the aqueous medium. Aggregation of bile salts into micelles and liposomes and the formation of mixed micelles with the products of fat digestion are important in facilitating absorption of lipids from the intestine. Liposomes are of potential clinical use—particularly when combined with tissue-specific antibodies—as carriers of drugs in the circulation, targeted to specific organs, for example, in cancer therapy. In addition, they are used for gene transfer into vascular cells and as carriers for topical and transdermal delivery of drugs and cosmetics.

Amphipathic lipids self-orient at oil: Water interfaces Emulsions are much larger particles, formed usually by nonpolar lipids in an aqueous medium. These are stabilized by emulsifying agents such as amphipathic lipids (eg, phosphatidylcholine), which form a surface layer separating the main bulk of the nonpolar material from the aqueous phase.

Summary Lipids have the common property of being relatively insoluble in water (hydrophobic) but soluble in nonpolar solvents. Amphipathic lipids also contain one or more polar groups, making them suitable as constituents of membranes at lipid water interfaces. The lipids of major physiologic significance are fatty acids and their esters, together with cholesterol and other steroids. Long-chain fatty acids may be saturated, monounsaturated, or polyunsaturated, according to the number of double bonds present. Their fluidity decreases with chain length and increases according to degree of unsaturation. Eicosanoids are formed from 20-carbon polyunsaturated fatty acids and make up an important group of physiologically and pharmacologically active compounds known as prostaglandins, thromboxanes, leukotrienes, and lipoxins.

Summary The esters of glycerol are quantitatively the most significant lipids, represented by triacylglycerol (“fat”), a major constituent of some lipoprotein classes and the storage form of lipid in adipose tissue. Glycerophospholipids and sphingolipids are amphipathic lipids and have important roles—as major constituents of membranes and the outer layer of lipoproteins, and as constituents of nervous tissue. Glycolipids are also important constituents of nervous tissue such as brain and the outer leaflet of the cell membrane, where they contribute to the carbohydrates on the cell surface. Cholesterol, an amphipathic lipid, is an important component of membranes. It is the parent molecule from which all other steroids in the body, including major hormones such as the adrenocortical and sex hormones, D vitamins, and bile acids, are synthesized.