Lipids Course: Medicinal Chemistry-1 Course Code: 301 By Mahabob Mazumder

Lipids are naturally occurring substances grouped together on the basis of a common property—they are more soluble in nonpolar solvents than in water. Some of the most important of them—the ones in this chapter—are related in that they have acetic acid (acetate) as their biosynthetic origin. In many biosynthetic pathways a substance called acetyl coenzyme A serves as the source of acetate. Lipids

Definition  Insoluble in water but soluble in non-polar organic solvents like hydrocarbon or diethy ether.  Lipids are organic compounds formed mainly from alcohol and fatty acids combined together by ester linkage.

Example: Triglyceride

Properties of Lipid  Lipids are insoluble in water, but soluble in fat or organic solvents (ether, chloroform, benzene, acetone).  Lipids include fats, oils, waxes and related compounds.  They are widely distributed in nature both in plants and in animals.

Biological Importance of Lipids 1. They are more palatable and can be stored more easily than carbohydrates. 2. They have high energy value (25% of body needs) and they provide more energy per gram than carbohydrates and proteins but carbohydrates are the preferable source of energy. 3. Supply the essential fatty acids that cannot be synthesized by the body. 4. Supply the body with fat-soluble vitamins (A, D, E and K). 5. They are important constituents of the nervous system. 6. Tissue fat is an essential constituent of cell membrane and nervous system. It is mainly phospholipids in nature that are not affected by starvation.

At room temp.

Fatty Acid Structure H - C - ( C ) n - C - OH - H = O Carboxyl group Carbon group(s) Methyl group

Fatty Acids and Lipids Key building blocks for lipids Chains of carbon atoms with a carboxyl group at one end, and a methyl group at the other May be “free” or attached to another compound Determine the characteristics of the fat

Fatty Acid Chain Length  Short chain: 2 to 6 C (volatile fatty acids)  Medium chain: 8 – 12 C  Long chain: 14 – 24 C  As chain length increases, melting point increases  Fatty acids synthesized by plants and animals have an even number of carbons  Mostly long chain  16C to 18C fatty acids are most prevalent

Fatty Acid Saturation  Saturated - no double bonds  Unsaturated – contain double bonds  Monounsaturated – one double bond  Polyunsaturated - >1 double bond  The double bond is a point of unsaturation  As number of double bonds increases, melting point decreases

Saturated Fats  All the chemical bonds between the carbon are single bondsC-C-C-  No double bonds  No space for more H atoms; fully “saturated”  Solid at room temperature  Butter, lard, coconut oil, palm oil, and fully hydrogenated vegetable oils

Mono-Unsaturated Fatty Acids  Only one double bond  Therefore, two H atoms can be added  Liquid at room temperature  Olive oil, peanut oil  Other sources: almonds, cashews and sesame seeds

Poly-Unsaturated Fatty Acids  Two or more double bonds  Include omega-3 and omega-6 fatty acids (essential fatty acids)  Linolenic acid: omega 3 fatty acid  Linoleic acid: omega 6 fatty acid  Richest sources of poly-unsaturated fatty acids include:  Vegetable oils  Corn, sunflower, cotton seed oils

Omega System and Essential Fatty Acids C-C-C=C-C-C=C-C-C=C-C-C-C-C-C-C-C-COOH  Animals can synthesize a fatty acid with a double bond in the omega 9 position but not at either 3 or 6 positions  Omega-3 and omega-6 fatty acids must be derived from diet  Cold water fish accumulate high levels of omega 3 fatty acids from their diet Ω-3Ω-6Ω-9

Omega System and Essential Fatty Acids  Linolenic acid is an omega-3 fatty acid  Linoleic and arachidonic acids are omega-6 fatty acids  Linoleic and linolenic acids are essential fatty acids  Arachidonic acid can be synthesized from linoleic acid, so not essential

Arachedonic Acid Linoleic Acid

Acids CarbonsDouble bonds AbbreviationSource Acetic 202:0bacterial metabolism Propionic 303:0bacterial metabolism Butyric 404:0butterfat Caproic 606:0butterfat Caprylic 808:0coconut oil Capric 10010:0coconut oil Lauric 12012:0coconut oil Myristic 14014:0palm kernel oil Palmitic 16016:0palm oil Palmitoleic 16116:1animal fats Stearic 18018:0animal fats Oleic 18118:1olive oil Linoleic 18218:2grape seed oil Linolenic 18318:3flaxseed (linseed) oil Arachidonic 20420:4peanut oil, fish oil

Types of Fatty Acid Fatty Acids are two types according to the function  Essential Fatty Acids  Non-essential fatty acids

Essential fatty acids  They can not be synthesized in the human body and must be taken in adequate amounts from the diet.  They are required for normal growth and metabolism

 Sources:  Vegetable oils such as corn oil, linseed oil, peanut oil, olive oil, cottonseed oil, soybean oil and many other plant oils, cod liver oil and animal fats.  Deficiency:  Their deficiency in the diet leads to nutrition deficiency disease.  Symptoms :  Poor growth and health with susceptibility to infections, dermatitis, decreased capacity to reproduce, impaired transport of lipids, fatty liver, and lowered resistance to stress.

Linoleic Acid  C18:2  9, 12.  It is the most important one since other essential fatty acids can be synthesized from it in the body. CH 3 -(CH 2 ) 4 -CH = CH-CH 2 -CH=CH-(CH 2 ) 7 -COOH Linolenic Acid C18:3  9, 12, 15 in corn, linseed, peanut, olive, cottonseed and soybean oils. CH 3 -CH 2 -CH=CH-CH 2 -CH=CH-CH 2 -CH=CH-(CH 2 ) 7 - COOH

Arachidonic acid:  C20:4  5, 8, 11, 14.  It is an important component of phospholipids in animals  Prostaglandins are synthesized from Arachidonic acid. CH 3 -(CH 2 ) 4 -CH=CH-CH 2 -CH=CH-CH 2 -CH=CH-CH 2 - CH=CH-(CH 2 ) 3 -COOH

Functions of Essential Fatty Acids 1. They are useful in the treatment of atherosclerosis by transporting blood cholesterol and lowering its levels (they also transport triglycerides). 2. The hormones are synthesized from them. 3. They enter into the structure of all cellular and subcellular membranes and the transporting plasma phospholipids. 4. They are essential for skin integrity, normal growth and reproduction. 5. They have an important role in blood clotting (intrinsic factor). 6. Important in preventing and treating fatty liver. 7. Important role in the health of the retina and vision. 8. They can be oxidized for energy production.

Fatty alcohols Glycerol:  It is a trihydric alcohol (i.e., containing three OH groups) and has the popular name glycerin.  It is synthesized in the body from glucose.

Properties of Glycerol 1. Colorless viscous oily liquid with sweet taste. 2. On heating with sulfuric acid or KHSO 4 (dehydration) it gives acrolein that has a bad odor. This reaction is used for detection of free glycerol or any compound containing glycerol.

3-It combines with three molecules of nitric acid to form trinitroglycerin (TNG) which is used as vasodilator. 4-On esterification with fatty acids it gives:  Monoglyceride or monoacyl-glycerol: one fatty acid + glycerol.  Diglyceride or diacyl-glycerol: two fatty acid + glycerol.  Triglyceride or triacyl-glycerol: three fatty acids + glycerol. 5-It has nutritional value due to it potential for conversion into glucose

Uses of Glycerol 1. Glycerol is used extensively in pharmaceutical and cosmetic preparations. 2. Reduces brain edema in cerebrovascular disease. 3. Nitroglycerin is used as vasodilator especially for the coronary arteries, thus it is used in treatment of angina pectoris. 4. Also, enters in explosives manufacturing. 5. Glycerol is used in treatment of glaucoma (increased intraocular pressure)due to its ability to dehydrate the tissue from its water content.

Sphingosine:  It is the alcohol(monohydric) present in sphingolipids.  It is synthesized in the body from serine and palmitic acid.  It is not positive with acrolein test.

Classification of Lipids 1. Simple lipids (Fats & Waxes) 2. Compound or conjugated lipids 3. Derived Lipids

Simple Lipids  Neutral fats and oils  Monoacyl glycerols (monoglycerides)  Diglycerides (diglycerides) found in plant leaves  Triacyl glycerols (triglycerides)  Lipid storage form  Most lipids consumed are triglycerides  Triglycerides found in seeds and animal adipose tissue

Triglycerides  Most common structure in dietary lipids  Composed of one glycerol molecule and three fatty acids connected by an ester bond (bond between an alcohol and and organic acid)  Fatty acids may be same or mixed Glycerol Fatty Acid

Triglyceride Structure  Fatty acid composition of triglyceride varies according to function  Membrane lipids must be fluid at all temperatures  Contain more unsaturated fatty acids  Lipids in tissues subjected to cooling (e.g., hibernators or tissues in extremities)  Contain more unsaturated FAs

Most Common Fatty Acids in Di- and Triglycerides Fatty acidCarbon:Double bondsDouble bonds Myristic14:0 Palmitic16:0 Palmitoleic16:1 Cis-9 Stearic18:0 Oleic18:1 Cis-9 Linoleic18:2 Cis-9,12 Linolenic18:3 Cis-9,12,15 Arachidonic20:4 Cis-5,8,11,14 Eicosapentaenoic20:5 Cis-5,8,11,14,17 Docosahexaenoic22:6 Cis-4,7,10,13,16,19 CH 3 (CH 2 ) n COOH

Compound Lipids  They are lipids that contain additional substances, e.g., sulfur, phosphorus, amino group, carbohydrate, or proteins beside fatty acid and alcohol.  Compound or conjugated lipids are classified into the following types according to the nature of the additional group: 1. Phospholipids 2. Glycolipids. 3. Lipoproteins 4. Sulfolipids and amino lipids.

Phospholipids Definition: Phospholipids or phosphatides are compound lipids, which contain phosphoric acid group in their structure. Importance: 1. They are present in large amounts in the liver and brain as well as blood. Every animal and plant cell contains phospholipids. 2. The membranes bounding cells and subcellular organelles are composed mainly of phospholipids. Thus, the transfer of substances through these membranes is controlled by properties of phospholipids.

Phospholipids Importance: 1. They are important components of the lipoprotein coat, essential for secretion and transport of plasma lipoprotein complexes. 2. Myelin sheath of nerves is rich with phospholipids.

 Two primary types:  Glycerophosphatides  Core structure is glycerol  Part of cell membranes, chylomicrons, lipoproteins  Sphingophosphatides  Core structure is sphingosine  Part of sphingomyelin

 Glycerophosphatides resemble triglyceride in structure except one of the fatty acids is replaced by a compound containing a phosphate group, or occasionally, nitrogen  Most prevalent is lecithin lecithin

Phospholipid  Significant use in food industry as emulsifiers  Lipids form emulsion in water  Phospholipid sources:  Liver, egg yolk,  Soybeans, wheat germ  Peanuts

Lipoproteins  Definition: Lipoproteins are lipids combined with proteins in the tissues. The lipid component is phospholipid, cholesterol or triglycerides. The holding bonds are secondary bonds. They include:  Structural lipoproteins: These are widely distributed in tissues being present in cellular and subcellular membranes. In lung tissues acting as a surfactant in a complex of a protein and lecithin. In the eye, rhodopsin of rods is a lipoprotein complex.

Lipoproteins  Transport lipoproteins:  These are the forms present in blood plasma. They are composed of a protein called apolipoprotein and different types of lipids. (Cholesterol, cholesterol esters, phospholipids and triglycerides). As the lipid content increases, the density of plasma lipoproteins decreases

a) Chylomicrons : They have the largest diameter and the least density. They contain 1-2% protein only and % fat. The main lipid fraction is triglycerides absorbed from the intestine and they contain small amounts of the absorbed cholesterol and phospholipids.

b) Very low-density lipoproteins (VLDL) or pre-  - lipoproteins : Their diameter is smaller than chylomicrons. They contain about 7-10% protein and 90-93% lipid. The lipid content is mainly triglycerides formed in the liver. They contain phospholipid and cholesterol more than chylomicrons.

c ) Low-density lipoproteins (LDL) or  -lipoproteins : They contain 10-20% proteins in the form of apolipoprotein B. Their lipid content varies from 80-90%. They contain about 60% of total blood cholesterol and 40% of total blood phospholipids. As their percentage increases, the liability to atherosclerosis increases.

d) High-density lipoproteins (HDL) or  -Lipoproteins: They contain 35-55% proteins in the form of apolipoprotein A. They contain 45-65% lipids formed of cholesterol (40% of total blood content) and phospholipids (60% of total blood content). They act as cholesterol scavengers, as their percentage increases, the liability to atherosclerosis decreases. They are higher in females than in males. Due to their high protein content they possess the highest density.

Derived Lipids  Prostaglandins  Synthesized from arachidonic acid  Several metabolic functions  Steroids  Cholesterol, ergosterol, bile acids  Terpenes  Made by plants  Carotenoids, xanthophylls

Sterols  Compounds with multi-ring structure  Insoluble in water  Present both in plant and animal foods  Major sterol is cholesterol  However, cholesterol is found only in animal products (manufactured in liver)  High content in organ meats and egg yolk

Common Sterol Compounds Stigmasterol (a phytosterol) Cholesterol (a sterol) Vitamin D3 (cholecalciferol) Testosterone (a steroid hormone)

Cholesterol  Source: -  It is synthesized in the body from acetyl-CoA (1gm/day, cholesterol does not exist in plants) and is also taken in the diet (0.3 gm/day as in, butter, milk, egg yolk, brain, meat and animal fat). Importance: -  It is the most important sterol in animal tissues as free alcohol or in an esterified form (with linoleic, oleic, palmitic acids or other fatty acids).  Steroid hormones, bile salts and vitamin D are derivatives from it.  Tissues contain different amounts of it that serve a structural and metabolic role, e.g., adrenal cortex content is 10%, whereas, brain is 2%, others %.

 Cholesterol life cycle  Biosynthesis in liver  Transport by carrier lipoproteins in the blood: LDL and HDL  Return to liver to serve as biosynthetic precursor to other steroids  “Bad Cholesterol”  LDL: carry cholesterol from liver  “Good Chlesterol”  HDL: return cholesterol to liver  High LDL/HDL ratio  Cholesterol buildup on artery walls  Atherosclerosis Cholesterol Lifecycle: Who are the good guys? Who are the bad guys?

Interventions to Reduce Cholesterol 1. Eat heart-healthy foods  Reduce saturated fat intake: Less than 7% of daily calories from saturated fat  Eliminate trans fats  Increase intake of omega-3 fatty acids  Eat more soluble fiber  Increase whey protein

Interventions to Reduce Cholesterol 2. Exercise more at least 30 minutes of exercise everyday 3. Quit smoking 4. Lose weight 5. Use medication Statins

Cholesterol-lowering Drug: Statins Atorvastatin

 Statins inhibit the enzyme 3-hydroxy-3- methylglutaryl coenzyme A reductase.  This enzyme is required for mevalonic acid biosynthesis.  Since mevalonic acid is an obligatory precursor to cholesterol, inhibition of mevalonic acid biosynthesis leads to reduced cholesterol production. How do statins lower cholesterol?