Chapter 27. Biomolecules: Lipids Based on McMurry’s Organic Chemistry, 6th edition ©2003 Ronald Kluger Department of Chemistry University of Toronto

Based on McMurry, Organic Chemistry, Chapter 27, 6th edition, (c) 2003 About Lipids Naturally materials that preferentially extract into nonpolar organic solvents Includes fats, oils, waxes, some vitamins and hormones, some components of membrane General types: esters (“saponifiable”) and those that can’t be hydrolyzed Based on McMurry, Organic Chemistry, Chapter 27, 6th edition, (c) 2003

Based on McMurry, Organic Chemistry, Chapter 27, 6th edition, (c) 2003 27.1 Waxes, Fats, and Oils Waxes - contain esters formed from long-chain (C16-C36) carboxylic acids and long-chain alcohols (C24-C36) Triacontyl hexadecanoate is in beeswax Based on McMurry, Organic Chemistry, Chapter 27, 6th edition, (c) 2003

Based on McMurry, Organic Chemistry, Chapter 27, 6th edition, (c) 2003 Fats and Oils Animal fats and vegetable are triacylglycerols oil Triesters of glycerol with three long-chain carboxylic acids Saponification of a fat or oil with (reaction with aqueous NaOH) yields glycerol and three fatty acids Based on McMurry, Organic Chemistry, Chapter 27, 6th edition, (c) 2003

Fatty Acids (from Fats and Oils) Straight-chain (C12 - C20) carboxylic acids Double bonds are cis-substituted but trans-fatty acid also occur A fat or oil in nature occurs as a mixture of many different triacylglycerols The most abundant saturated fatty acids are palmitic (C16) and stearic (C18) Based on McMurry, Organic Chemistry, Chapter 27, 6th edition, (c) 2003

Unsaturated and Polyunsaturated Fatty Acids Oleic (C18 with one C=C) and linolenic (C18 with 3 C=C) are the most abundant unsaturated Based on McMurry, Organic Chemistry, Chapter 27, 6th edition, (c) 2003

Based on McMurry, Organic Chemistry, Chapter 27, 6th edition, (c) 2003 27.2 Soap A mixture of sodium or potassium salts of long-chain fatty acids produced by alkaline hydrolysis (saponification) of animal fat with alkali Based on McMurry, Organic Chemistry, Chapter 27, 6th edition, (c) 2003

Cleansing Action of Soap The carboxylate end of the long-chain molecule is ionic and therefore is preferentially dissolved in water The hydrocarbon tail is nonpolar and dissolves in grease and oil Soaps enable grease to be dissolved into water Based on McMurry, Organic Chemistry, Chapter 27, 6th edition, (c) 2003

Based on McMurry, Organic Chemistry, Chapter 27, 6th edition, (c) 2003 Detergents “Hard” water contains Mg+2 and Ca+2 that form insoluble salts with soaps Synthetic detergents are alkylbenzene sulfonates that dissolve dirt like soaps but do not form scums with Mg+2 and Ca+2 . Based on McMurry, Organic Chemistry, Chapter 27, 6th edition, (c) 2003

Based on McMurry, Organic Chemistry, Chapter 27, 6th edition, (c) 2003 27.3 Phospholipids Phospholipids are diesters of H3PO4, phosphoric acid Phosphoric acid can form monoesters, diesters and triesters In general these are known as “phosphates” Based on McMurry, Organic Chemistry, Chapter 27, 6th edition, (c) 2003

Based on McMurry, Organic Chemistry, Chapter 27, 6th edition, (c) 2003 Phosphoglycerides Contain a glycerol backbone linked by ester bonds to two fatty acids and phosphoric acid Fatty acid residues with C12–C20 The phosphate group at C3 has an ester link to an amino alcohol Based on McMurry, Organic Chemistry, Chapter 27, 6th edition, (c) 2003

Phosphoglyceride Membranes Phosphoglycerides comprise the major lipid component of cell membranes Nonpolar tails aggregate in the center of a bilayer Ionic head is exposed to solvent Based on McMurry, Organic Chemistry, Chapter 27, 6th edition, (c) 2003

Based on McMurry, Organic Chemistry, Chapter 27, 6th edition, (c) 2003 Sphingolipids The other major group of phospholipids Sphingosine or a dihydroxyamine backbone Constituents of plant and animal cell membranes Abundant in brain and nerve tissue, as coating around nerve fibers. Based on McMurry, Organic Chemistry, Chapter 27, 6th edition, (c) 2003

Based on McMurry, Organic Chemistry, Chapter 27, 6th edition, (c) 2003 27.4 Prostaglandins C20 lipids that contain a five-membered ring with two long side chains Present in small amounts in all body tissues and fluids Many physiological effects Based on McMurry, Organic Chemistry, Chapter 27, 6th edition, (c) 2003

Prostaglandin Sources Biosynthesized from arachidonic acid (C20 unsaturated fatty acid) Catalyzed by cyclooxygenase (COX) Based on McMurry, Organic Chemistry, Chapter 27, 6th edition, (c) 2003

Based on McMurry, Organic Chemistry, Chapter 27, 6th edition, (c) 2003 27.5 Terpenoids Steam distillation of plant extracts produces “essential oils” Chemically related to compounds in turpentine (from pine sap) called terpenes and thus called terpenoids Mostly hydrocarbons (some oxygens) that do not contain esters (stable to hydrolysis) Based on McMurry, Organic Chemistry, Chapter 27, 6th edition, (c) 2003

Terpenoids Are Isoprenoids Terpenoid structures are derived from isoprene (2-methyl-1,3-butadiene) units connected head-to-tail (Isoprene Rule) The term “head-to-tail” means that dissimilar ends are connected (you can choose which is a “head” and which is a “tail”) Based on McMurry, Organic Chemistry, Chapter 27, 6th edition, (c) 2003

Classification of Terpenoids Classified according to the number of di-isoprenoid (C10) units they contain Monoterpenes have 10-carbons, sesquiterpenes (sesqui = 1 1/2) have 15-carbons from three isoprene units, and so on Based on McMurry, Organic Chemistry, Chapter 27, 6th edition, (c) 2003

Some Important Terpenoids The triterpene lanosterol is the precursor of steroid hormones The tetraterpene b-carotene is a source of vitamin A Based on McMurry, Organic Chemistry, Chapter 27, 6th edition, (c) 2003

27.6 Biosynthesis of Terpenoids Isopentenyl pyrophosphate (IPP) forms higher isoprenoids in reactions catalyzed by prenyl transferase Monoterpenoids, diterpenoids, and tetraterpoids arise from 1-deoxyxylulose 5-phosphate. Based on McMurry, Organic Chemistry, Chapter 27, 6th edition, (c) 2003

Mevalonate Pathway to Isopentenyl Diphosphate Begins with the conversion of acetate to acetyl CoA followed by Claisen condensation to yield acetoacetyl CoA Catalyzed by acetoacetyl-CoA acetyltransferase Based on McMurry, Organic Chemistry, Chapter 27, 6th edition, (c) 2003

Aldol Condensation Produces HMG-CoA Carbonyl condensation reaction of acetoacetyl CoA with acetyl CoA Produces 3-hydroxy-3-methylglutaryl CoA (HMG-CoA) Based on McMurry, Organic Chemistry, Chapter 27, 6th edition, (c) 2003

Reduction Forms Mevalonate HMG CoA is reduced to mevalonate Catalyzed by HMG CoA reductase utilizing NADPH Based on McMurry, Organic Chemistry, Chapter 27, 6th edition, (c) 2003

Conversion of Mevalonate to IPP Pyrophosphorylation gives mevalonyl-PP Addition of phosphate from ATP followed by loss of CO2 and phosphate Based on McMurry, Organic Chemistry, Chapter 27, 6th edition, (c) 2003

Conversion of Isopentenyl Diphosphate to Terpenoids For triterpenes and larger, head-to-head coupling of farnesyl diphosphates gives squalene Based on McMurry, Organic Chemistry, Chapter 27, 6th edition, (c) 2003

Mechanism of Isomerization Isomerization of IPP to DMAPP is catalyzed by IPP isomerase through a carbocation pathway Based on McMurry, Organic Chemistry, Chapter 27, 6th edition, (c) 2003

Based on McMurry, Organic Chemistry, Chapter 27, 6th edition, (c) 2003 Coupling Mechanism Nucleophilic substitution reaction in which the double bond of IPP behaves as a nucleophile in displacing diphosphate ion leaving group (PPO) Based on McMurry, Organic Chemistry, Chapter 27, 6th edition, (c) 2003

Conversions of Monoterpenoids Typically involves carbocation intermediates and multistep reaction pathways catalyzed by a terpene cyclase Based on McMurry, Organic Chemistry, Chapter 27, 6th edition, (c) 2003

Based on McMurry, Organic Chemistry, Chapter 27, 6th edition, (c) 2003 27.7 Steroids Steroids,are another class of nonsaponifiable lipid, defined by structure Has four fused rings A, B, C, and D, beginning at the lower left Carbon atoms are numbered beginning in the A ring The six-membered rings are in fixed chair conformations Based on McMurry, Organic Chemistry, Chapter 27, 6th edition, (c) 2003

Based on McMurry, Organic Chemistry, Chapter 27, 6th edition, (c) 2003 Functions of Steroids In humans as hormones, steroids are chemical messengers secreted by glands and carried through the bloodstream to target tissues Also widely distributed as cholesterol Based on McMurry, Organic Chemistry, Chapter 27, 6th edition, (c) 2003

Based on McMurry, Organic Chemistry, Chapter 27, 6th edition, (c) 2003 Male Sex Hormones Testosterone and androsterone are the two most important male sex hormones, or androgens Androstanedione is a precursor Based on McMurry, Organic Chemistry, Chapter 27, 6th edition, (c) 2003

Based on McMurry, Organic Chemistry, Chapter 27, 6th edition, (c) 2003 Female Sex Hormones Estrone and estradiol are the two most important female sex hormones, or estrogens Progesterone is the most important progestin, steroids that function in pregnancy Based on McMurry, Organic Chemistry, Chapter 27, 6th edition, (c) 2003

Adrenocortical Hormones Adrenocortical steroids: secreted by the adrenal glands near the upper end of each kidney Mineralocorticoids: control tissue swelling by regulating cellular salt balance Glucocorticoids: regulation of glucose metabolism and in the control of inflammation Based on McMurry, Organic Chemistry, Chapter 27, 6th edition, (c) 2003

Based on McMurry, Organic Chemistry, Chapter 27, 6th edition, (c) 2003 Synthetic Steroids Made in pharmaceutical laboratories as new drugs Includes oral contraceptives and anabolic agents Methandrostenolone is an anabolic steroid used for tissue-building Based on McMurry, Organic Chemistry, Chapter 27, 6th edition, (c) 2003

27.8 Stereochemistry of Steroids Two cyclohexane rings can be joined in either a cis or a trans manner In cis-decalin, both groups at the ring-junction positions are on the same side of the two rings In trans-decalin, the groups at the ring junctions are on opposite sides Based on McMurry, Organic Chemistry, Chapter 27, 6th edition, (c) 2003

A/B Junction in Steroids Steroids can have either a cis or a trans fusion of the A and B ring (B–C and C–D) are usually trans Based on McMurry, Organic Chemistry, Chapter 27, 6th edition, (c) 2003

Based on McMurry, Organic Chemistry, Chapter 27, 6th edition, (c) 2003 27.9 Steroid Biosynthesis Enzyme-catalyzed addition of oxygen atom to squalene Stereospecific formation of an oxirane from an alkene Based on McMurry, Organic Chemistry, Chapter 27, 6th edition, (c) 2003

Cyclization to Steroid Stork-Eschenmoser mechanism Enzyme-catalyzed See Figure 27.6 Based on McMurry, Organic Chemistry, Chapter 27, 6th edition, (c) 2003