Ch.28 Lipids - Lecture notes 28 PDF

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Chapter 28: Lipids. Dr. Halaweish...

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Cholesterol is the most prominent member of the steroid family, a group of organic lipids that contains a tetracyclic structure. Cholesterol is synthesized in the liver and is found in almost all body tissues. ○ serves as the starting material for the synthesis of all other steroid

Intro ● ●

soluble in organic solvents. their identity is defined on physical property and not by a particular functional group.

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large number of carbon–carbon and carbon–hydrogen σ bonds make them very soluble in organic solvents and insoluble in water. Lipids can be categorized as hydrolyzable or nonhydrolyzable. ○ Hydrolyzable lipids can be cleaved into smaller molecules by hydrolysis with water. Most hydrolyzable lipids contain an ester unit. Three subgroups: waxes, triacylglycerols, and phospholipids.

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Nonhydrolyzable lipids cannot be cleaved into smaller units by aqueous hydrolysis. Nonhydrolyzable lipids tend to be more varied in structure there are four different types: fat-soluble vitamins, eicosanoids, terpenes, and steroids

Waxes ●

Waxes are the simplest hydrolyzable lipids. Waxes are esters (RCOOR') formed from a high molecular weight alcohol (R'OH) and a fatty acid (RCOOH). ○ Lanolin, a wax of a complex mixture of high molecular weight esters, coats the wool fibers of sheep.

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Spermaceti wax, isolated from the heads of sperm whales, is largely CH3(CH2)14COO(CH2)15CH3.

Triacylglycerols ● ●

Triacylglycerols, or triglycerides, are the most abundant lipids, Triacylglycerols are triesters that produce glycerol and three molecules of fatty acid upon hydrolysis.

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Simple triacylglycerols are made of three identical fatty acid side chains, mixed triacylglycerols have two or three different fatty acids

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All fatty acid chains are unbranched, they may be saturated or unsaturated. Naturally occurring fatty acids have an even number of carbon atoms. ○ Double bonds in naturally occurring fatty acids generally have the Z configuration. The melting point depends on the degree of unsaturation. The most common saturated fatty acids are palmitic and stearic acids. The most common unsaturated fatty acid is oleic acid. Linoleic and linolenic acids are called essential fatty acids because we cannot synthesize them and must acquire them in our diets. Fats have higher melting points, making them solids at room temperature. Oils have lower melting points, making them liquids at room temperature. As the number of double bonds increases, the melting point decreases, as it does for the constituent fatty acids as well.

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Allylic C H bonds are weaker than other C H bonds and are thus susceptible to oxidation by a radical process. The hydroperoxide formed is unstable, and it undergoes further oxidation to products that have a disagreeable odor. Example: oil oxidized and turns rancid

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triacylglycerols, store ~38 kJ/g, whereas carbohydrates and proteins store only ~16 kJ/g.

Phospholipids ●

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Phospholipids are hydrolyzable lipids that contain a phosphorus atom. There are two common types of phospholipids: p  hosphoacylglycerols and sphingomyelins Phospholipids are organic derivatives of phosphoric acid, formed by replacing two of the H atoms by R groups. This is called a p  hosphodiester, or a phosphoric acid diester

Phosphoacylglycerols ○ second most abundant type of lipid. They are the principal lipid component of most cell membranes. ○ In phosphoacylglycerols, only two of the hydroxy groups of glycerol are esterified with fatty acids. The third OH group is part of a phosphodiester, which bonds to a low molecular weight alcohol.

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When R'' = CH2CH2NH3+, the phosphoacylglycerol is called a phosphatidylethanolamine or cephalin. When R'' = CH2CH2N(CH3)3+, the phosphoacylglycerol is called a phosphatidylcholine or lecithin.

The middle carbon of the glycerol backbone of the compounds is a stereogenic center (labeled in blue), usually with the R configuration.

○ when mixed with water, they assemble a lipid bilayer. Sphingomyelins

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the second major class of phospholipids, are derivatives of the amino alcohol sphingosine

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sphingomyelins are also a component of the lipid bilayer of cell membranes. surrounds and insulates nerve cells, the myelin sheath,

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Fat Soluable Vitamins ● ● ●

required in small quantities for normal metabolism they must be obtained in the diet. Vitamins can be categorized as fat soluble or water soluble. The fat-soluble vitamins are lipids. The four fat-soluble vitamins—A, D, E, and K—are found in fruits and vegetables, fish, liver, and dairy products.

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obtained from fish liver oils and dairy products, and is synthesized from β-carotene, the orange pigment in carrots. converted to 11-cis- retinal, the light-sensitive compound responsible for vision in all vertebrates It is also needed for healthy mucous membranes.

Strictly speaking, it is not a vitamin because it can be synthesized in the body from cholesterol. Nevertheless, it is classified as such, and many foods (particularly milk) are fortified with vitamin D3 so that we get enough of this vital nutrient. ○ Vitamin D helps regulate both calcium and phosphorus metabolism. deficiency of vitamin D causes rickets, a bone disease characterized by knock-knees, spinal curvature, and other deformities ○

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is an antioxidant, so it protects unsaturated side chains in fatty acids from oxidation. deficiency of vitamin E causes numerous neurologic problems.

regulates the synthesis of prothrombin and other proteins needed for blood to clot. ○ deficiency of vitamin K leads to excessive and sometimes fatal bleeding because of inadequate blood clotting. electron density is virtually uniform in these compounds. The large regions of nonpolar ○

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C C and C H bonds tend to obscure small dipoles that occur in the one or two polar bonds, making these vitamins nonpolar and hydrophobic.

Eicosanoids

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The e icosanoids are a group of biologically active compounds containing 20 carbon atoms derived from arachidonic acid The p  rostaglandins, leukotrienes, thromboxanes, and prostacyclins are types of eicosanoids.

All eicosanoids are very potent compounds present in low concentration in cells. They are local mediators, meaning they perform their function in the environment in which they are synthesized. ○ This distinguishes them from hormones, which are first synthesized and then transported in the bloodstream to their site of action. Eicosanoids are not stored in cells; rather, they are synthesized from arachidonic acid in response to an external stimulus. begins with the oxidation of arachidonic acid with O2 by a cyclooxygenase enzyme, which forms an unstable cyclic intermediate, PGG2. PGG2 is then converted with different pathways to these three classes of compounds. Leukotrienes are formed an enzyme called a lipoxygenase

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dinoprostone, the generic name for PGE2, is administered to relax the smooth muscles of the uterus when labor is induced, and to terminate pregnancies in the early stages.

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Misoprostol is a prostaglandin analogue administered to prevent gastric ulcers in patients who are at high risk of developing them, and unoprostone isopropyl is used to decrease eye pressure in glaucoma patients.

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It has been discovered that two different cyclooxygenase enzymes, called COX-1 and COX-2, are responsible for prostaglandin synthesis. COX-1 is involved with the usual production of prostaglandins, but COX-2 is responsible for the synthesis of additional prostaglandins in inflammatory diseases like arthritis. NSAIDs like aspirin and ibuprofen inactivate both the COX-1 and COX-2 enzymes. These drugs—rofecoxib, valdecoxib, and celecoxib—do not cause an increase in gastric secretions, and thus were touted as especially effective NSAIDs for patients with arthritis, who need daily doses of these medications.

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Terpenes ●

Are lipids composed of repeating five-carbon units called isoprene units. An isoprene unit has five carbons: four in a row, with a one-carbon branch on a middle carbon

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Terpenes are hydrocarbons that may be acyclic or have one or more ring terpenoid is used for compounds that contain isoprene units as well as an oxygen heteroatom Locating Isoprene Units ○ look for a four-carbon chain with a one-carbon branch. This forms one isoprene unit. Continue along the chain or around the ring until all the carbons are part of an isoprene unit

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An isoprene unit may be composed of C C σ bonds only, or there may be π   bonds at any position. Isoprene units are always connected by one or more carbon–carbon bonds. Each carbon atom is part of one isoprene unit only. Every isoprene unit has five carbon atoms. Heteroatoms may be present but their presence is ignored in locating isoprene units.

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Terpenes and terpenoids are classified by the number of isoprene units they contain.

The biosynthesis of Terpenes and Terpenoids ○ The same reaction is used over and over again to prepare progressively more complex compounds. ○ Key intermediates along the way serve as the starting materials for a wide variety of other compounds. ○ All terpenes and terpenoids are synthesized from dimethylallyl diphosphate and isopentenyl diphosphate. Both of these five-carbon compounds are organic diphosphates with a good leaving group (diphosphate, P2O74–, PPi).

1. The two C5 diphosphates are converted to geranyl diphosphate, a C10 monoterpenoid. Geranyl diphosphate is the starting material for all other monoterpenes and monoterpenoids. 2. Geranyl diphosphate is converted to farnesyl diphosphate, a C15 sesquiterpenoid, by addition of a five-carbon unit. Farnesyl diphosphate is the starting material for all sesquiterpenes, diterpenes, and related terpenoids. 3. Two molecules of farnesyl diphosphate are converted to squalene, a C30 triterpene. Squalene is the starting material for all triterpenes and steroids.

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All other terpenes and terpenoids are biologically derived from geranyl and farnesyl diphosphates by a series of reactions. Cyclic compounds are formed by intramolecular reactions involving nucleophilic attack of π bonds on intermediate carbocations. ■ To form some cyclic compounds, the E double bond in geranyl diphosphate must first isomerize to an isomeric diphosphate with a Z double bond, neryl diphosphate,

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Isomerization forms a substrate with a leaving group and nucleophilic double bond in close proximity, so that an intramolecular reaction can occur.

Steriods ● ●

a group of tetracyclic lipids, many of which are biologically active. Steriod Stucture ○ Steroids are composed of three six-membered rings and one five-membered ring, ○ Many steroids also contain two methyl groups, called angular methyl groups

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two rings are fused together, the substituents at the ring fusion can be arranged cis or trans. Consider d  ecalin, which consists of two six-membered rings fused together. trans-Decalin has the two hydrogen atoms at the ring fusion on opposite sides, cis-decalin has them on the same side.

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The two rings of trans- decalin lie roughly in the same plane, whereas the two rings of cis- decalin are almost perpendicular to each other. The trans arrangement is lower in energy and therefore more stable.

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most common arrangement is trans. Because of this, all four rings of the steroid skeleton lie in the same plane These methyl groups make one side of the steroid skeleton significantly more hindered than the other,

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Cholesterol ○ It also has eight stereogenic carbons so there are 2^8 = 256 possible stereoisomers. In nature, however, only the following stereoisomer exists:

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Cholesterol is synthesized in the body from squalene, a C30 triterpene that is itself prepared from smaller terpenes Because the biosynthesis of all terpenes begins with acetyl CoA, every one of the 27 carbon atoms of cholesterol comes from the same two-carbon precursor.

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Epoxidation of squalene with squalene epoxidase, gives squalene oxide, which contains a single epoxide on one of the six double bonds. 2. Cyclization of squalene oxide yields a carbocation, called the protosterol

cation. This reaction results in the formation of four new C C bonds and the tetracyclic ring system. 3. The protosterol carbocation rearranges by a series of 1,2-shifts of either a hydrogen or methyl group to form another 3° carbocation. 4. Loss of a proton gives an alkene called lanosterol. Although lanosterol has seven stereogenic centers, a single stereoisomer is formed. 5. Lanosterol is then converted to cholesterol by a multistep process that results in removal of three methyl groups.

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Other Steriods ○ other important steroids are hormones secreted by the endocrine glands. Two classes are the sex hormonesand the adrenal cortical steroids. ○ There are two types of female sex hormones, estrogens and progestins. The male sex hormones are called androgens

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Synthetic androgen analogues, called anabolic steroids, promote muscle growth. They were first developed to help individuals whose muscles had atrophied from lack of use following surgery. Anabolic steroids, such as stanozolol, nandrolone, and tetrahydrogestrinone, have the same effect on the body as testosterone, but they are more stable, so they are not metabolized as quickly.

A second group of steroid hormones includes the adrenal cortical steroids.

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Cortisone and cortisol serve as anti-inflammatory agents, and they also regulate carbohydrate metabolism. Aldosterone regulates blood pressure and volume by controlling the concentration of Na+ and K+ in body fluids....