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    Lipids 3

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    Lipids 3

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    Lipids 3

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    Gerald Angelo Deguinio

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    Chapter 9 Lipids Figure 19.19 The kinks asto- ated with cis double bonds in fatsy acid chains prevent tight packing ofthe ipid molecules in 2 lipid bilayer ( i carbohydrate-protein and carbohydrate-lipid combinations are called, respectively, Chatetert lycoproteins and glycolipids (Section 18.20). Functionally, the carbohydrate por. Figure 19.20 Cholesterol tions of these glycoproteins and glycolipids are markers, substances that play key molecules between lay acc) roles inthe process by which different calls recognize each other. The red-blood-tel chains apis layer marker system previously discussed in Chemical Connections 18-D on page 633 Figure 19.21 Proteins are Important structural components abhydrate marker membrane protein of ell membranes, involves glycoproteins. Transport Across Cell Membranes In order for cellular processes to be maintained, molecules of various types must be able to cross cell membranes. Three common transport mechanisms exist by which molecules can enter and leave cells. They are passive transport, facilicated transport, and active transport. Protein with Peripheral Protein with carbohydrate tmarker Outside of col, Lipid ayer 1291 membrane ip layer Integral membrane protein that extends Inside of cel feoss then layer Choleterot 19.11 Emulsifcaton Lipids: Bite Acids a 7 Figure 19.22 Three processes f S. "| by which substances can cose as . zt | piasna membranes. Concentration gradient: Concentration gradient: ‘movement withthe gradient; | | movemeat wit th gradient; fom high tole concentration | | fom ighto ow convention | | Tom low thigh concentration CCatlar energy expenditure: | | Cellular energy expenditare: | | Cellular energy expenditure: ‘be gues none required enery np eg Protein lp: none required | | Protein el: proteins serve |_| Protein help: proteins serve spate spams Passive vansport Facilitated transport. Active transport Passive transport is she transport process in which a substance moves across 4 cell membrane by diffusion from a region of higher concentration to a region of lower concentration without the expenditure of any cellular energy. Only a few types of molecules, including O;, N;. HO. urea, and cthanol, can cross membranes in this manner. Passive transport is closely related to the process of osmosis (Section 8.9). Facilitated transport is che transport process in which a substance moves across 4a cell membrane, with the aid of membrane proteins, from a region of higher con- ‘centration to a region of lower concentration without the expenditure of cellular energy. The specific protein molecules involved in the process are called carriers fr transporters. A caztier protein forms a complex with a specific molecule at one surface of the membrane, Formation of the complex induces a conformational change in the protein that allows the molecule to move through a “gate” to the other side of the membrane. Once the molecule is released, the protein returns to its original conformation, Glucose, chloride ion, and bicarbonate ion eross mem- branes in this manner Active transport is the transport process in which a substance moves across a cell ‘membrane, with the aid of membrane proteins, against a concentration gradient with the expenditure of cellular energy. Proteins involved in active transport are called “pumps,” because they require energy much as a water pump requires enerey in order to function. The needed energy is supplied by molecules such as ATP (Section 23.3). The need for energy expenditure is related to the molecules moving against a concentration gradient —from lower to higher concentration. It is es- sential to life processes to have some solutes “permanently” at different concentra tions on the two sides of a membrane, a situation contrary to the natural tendency (osmosis) to establish equal concentrations on both sides of a membrane. Hence the need for active transport. Sodium, potassium, and hydronium ions cross mem- branes through active transport. Figure 19.22 contrasts the processes of passive transport, facilitated transport, and active transport. 19.11 Emulsification Lipids: Bile Acids An emulsifier isa substance that can disperse and stabilize water-insoluble substances as colloidal particles in an aqueous solution. Cholesterol derivatives called bile acids function as emulsifying agents that facilitate the absorption of dietary lipids in the intestine. Their mode of action is much like that of soap during washing (see Chemical Connections 19-C on page 672). A bile acid is a cholesteral derivative that functions as a lipid-emulsifving agent in the aqueous environment of the digestive tract. From one-third to one-half of the daily production of cholesterol by the liver is used to replenish bile acid stores Chapter 9 Lipids Figure 19.23 Stucturl formulas forcholesteral, cholic acd, and two eorychoii acids ‘The average bile acid composition in normal homan adult oe 38% cholic acid derivatives, 24% T-deoxycholic acid derivatives, and 289% 12-deonycholie acid deriva Glycine containing derivatives predominate over taurne-contining erative by a 3:1 to 4:1 rato, Uncomplened free) bile acids ore fat present in bile, Figure 19.24 The structures of alycocnalic acid and taurocholie acid. Cholesterol (Cz) Chole acid (C3) 12-Deoxycholic acid (C,) ‘-Deoxycholic acid (C,,) Obtained by oxidation of cholesterol, bile avids differ structurally from cholesterol in three respects: 1. They are tri- or dihydroxy cholesterol derivatives. 2. The carbon 17 side chain of cholesterol has been oxidized to a carboxylic acid. 3. The oxidized acid side chain is bonded to an amino acid (either glycine or taurine) through an amide linkage. Figure 19,23 gives structural formulas for the three major types of bile acids produced from cholesterol by biochemical oxidation: cholic acid, 7-deoxycholic acid, and 12-deoxycholic acid. The structural formulas are those for these bile acids prior to the attachment of the amino acid to the carbon 17 side chain, Bile acids always carry an amino acid (ether glycine or taurine) attached to the side-chain carboxyl group via an amide linkage. The presence of this amino acid attachment increases both the polarity of the bile acid and its water solubility Figure 19.24 shows the structures of glycocholic acid (glycine is the amino acid) and taurocholie acid (taurine is the amino acid). ‘The medium through which bile acids are supplied to the small intestine is bile. Bile is a fluid containing emulsifying agents that is seereted by the liver, stored in the gallbladder, and released into the small intestine during digestion. Besides Cone Seman sor aa Tne a 5 ; é é cor ES ra ee ‘Taurocholic acd Glycocholic acid 19.12 Messenger Lipids: Steroid Hormones bile avids, bile also contains bile pigments (breakdown products of hemoglobin; Section 26.7), cholesterol itself, and electrolytes such as bicarbonate ion. The bile acids that are present increase the solubility ofthe cholesterol in the bile uid. ‘A oumber of factors, including increased secretion of cholesterol and a decrease in the size of the bile pool, can upset the balance between the chales- terol present in bile and the bile acid derivatives needed to maintain cholesterol’s solubility in the bile. The result is the precipitation of crystallized cholesterol from the bile and the resulting formation of gallstones in the gallbladder. In Western countries, approximately 80% of gallstones are almost pure cholesterol (Figure 19.25). 19.12 Messenger Lipids: Steroid Hormones Figure 19.25 A large percentage of galletones, the causative agent for many “galloladder attack," are almost pure crystalizad cholestrol ‘thashas precipitated fom bile solution Previously considered were lipids that function as energy-storage molecules (triacyl- glycerols: Section 19.4) as components of cell membranes (phospholipids, sphingo- alycolipids, and cholesterol; Sections 19.7 through 19.9), and as emulsifying agents (bile acids: Section 19.11). An additional role played by lipids is that of “chemical messenger.” Steroid hormones and eicosanoids are (wo large families of lipids that hhave messenger functions. In this section, steroid hormones, which are cholesterol derivatives, will be considered, In Section 19.13, eicosanoids, which are fatty aci derivatives, will be considered, A hormone is a biochemical substance, produced by a ductless gland, that has a ‘messenger function. Hormones serve as a means of communication between vari- ous tissues. Some hormones, though not all, are lipids. A steroid hormone is a hormone that isa cholesterol derivative. There are (wo ‘major classes of steroid hormones: (I) sex hormones, which control reproduction and secondary sex characteristics and (2) adrenocorticoid hormones, which regu- late numerous biochemical processes in the body, Sex Hormones TThe sex hormones can be classified into three major groups: 1, Estrogens—the female sex hormones 2, Androgens—the male sex hormones 3. Progestins—the pregnancy hormones utrogens ae syshesied in the ovaries and adrenal cortex and are responsible Exrogen es cs of olsen for the development of female secondary sex characteristics at the onset of puberty rather than # single molecule an for regulation ofthe menstrual ele. They aso stimulate the development of ‘men he “he etogyn lvl the manamary glands during pregnancy and induc estrus (heat in ania Ishak she repay “Androgens ae synthesized inthe testes and adrenal cortex and promote the development of male secondary ex characteristics Tey ako promote muscle growth, Progestins are synthesized in the ovaries and the placenta and prepa the lining of the uterus for implantation ofthe fertilized ovum. They also suppress ovation Figure 19.260 gives the stueture of the primary hormone in each of the three sbelasis of sex hormones, Other members ofthese hormone families are motabolized forms of the primary hormone. Note in Figute 19.26 how similar the structures at for these principal hor rmones, and yet how diferent their functions ate The fact that seemingly minor Changes in structure effect great changes in biofunction points out agin, the extrene specifiy (Sesion 215) of the enzymes that contol biochemical eactions Thereused knowledge of the strictures and functions of sex hormones bas led to the development ofa number of synthe steroids whose actions often mimic those of the natural steroid hormones The beat known types of symtheti steroids are oral contraceptives and anabolic steroids Chapter 9 Lipids Figure 19.26 Smuctres of selected sex hormones and synthetic eompounds that have Similar actions. ‘The C=C functional group, which ‘ceurs in both norethynodrel (Erovid) ond RU=t86, rarely found in Biomolacu Estradiol (the primary esirogen; responsible for secondary Temale characteristics) “Testosterone (ehe primary androgen; responsible for seeondary male characteristics) Progesterone (the primary progestin: prepares the uterus for ' pregnancy) : ©) Natural hormones: Norethynodrel RU-86 Methandrostenotone ‘a synthetic progestin) (oifepsistone; a synthetic «a symthetic abortion drug) lissue-building steroid) Sythetc steroids Oral contraceptives are used to suppress ovulation as a method of birth con- trol. Generally, a mixture of a synthetic estrogen and a synthetic progestin is used. The synthetic estrogen regulates the menstrual eycle, and the synthetic progestin prevents ovulation, thus ereating a false state of pregnancy, The structure of nor- ethynodrel (Enovid). a synthetic progestin, is given in Figure 19.26b. Compare its structure (o that of progesterone (the real hormone); the structures are very similar, Interestingly, the controversial “morning after” pill developed in France and known as RU-486, is also similar in structure (o progesterone. RU-486 interferes with gestation of a fertilized egg and terminates a pregnancy within the first nine weeks of gestation more effectively and safely than surgical methods. The structure of RU-486 appears next to that of norethynodrel in Figure 19,26. Anabolic steroids include the illegal steroid drugs used by some athletes to build up muscle strength and enhance endurance. Such steroids are now known to hhave serious side effects in the user. The structure of one of the more commonly used anabolic steroids, methandrostenolone, is given in Figure 19.26b, Note the similarities between its structure and that of the naturally occurring testosterone. ‘The focus on relevancy feature Chemical Connections 19-E on the next page fur- ther explores the use, usually illegal, of anabolic steroids by athletes, Adrenocorticoid Hormones The second major group of steroid hormones consists of the adrenocorticoid hormones. Produced by the adrenal glands, small organs located on top of each kidney, at least 28 different hormones have been isolated from the adrenal cortex (the outer part of the glands). “There are two types of adrenocorticoid hormones. 1, Mineralocorticoids control the balance of Na* and K* ions in cells and body ids 2. Glucocorticoids control glucose metabolism and counteract inflammation, ‘The major mineralocorticoid is aldosterone, and the major glucocorticoid is cor- tisol (hydrocortisone). Cortisol is the hormone synthesized in the largest amount by the adrenal glands. Cortisol and its synthetic ketone derivative cortisone exert powerful antiinflammatory effects in the body. Both cortisone and prednisolone, a CHEMICAL CONNECTIONS Anabolic Steroid Use in Competitive Sports ‘The steroid hormone testosterone is the principal male sex hormone. It has masculinizing (androgenic) effects and ‘muscle-building (anabolic) effects. Masculinizing effects of testosterone include the growth of facial and body hair, deep ening of the voice, and maturation of the male sex organs. Testosterone’ anabolic effects are responsible for the muscle development that boys experience at puberty. Many synthetic derivatives of testosterone are now known, Some of these exert primarily androgenic eects, whereas others exert primarily anabolic effects. Androgenic steroids can be used {o correct hormonal imbalances in the body. Anabolic steroids can be used to prevent the withering of muscle in persons recovering from major surgery or serious injuries. ‘Anabolic steroids have also been “discovered” by athletes, who have found that these compounds can be used to help build muscle mass and reduce the healing time for muscle injuries. Often the net result of anabolic hormone use by an athlete is enhanced athletic performance. Anabolic steroid use by athletes in competitive sports is now referred to as “doping” and is banned by all major sport- ing organizations, including the International Olympic Com= mittee (IOC), National Football League (NFL), National Basketball Association (NBA), and Major League Baseball (MLB). To enforce the ban on anabolic steroid use, athletes are subjected to random drug screening. In major events, such, as the Olympics, testing is no longer random but mandatory forall competitors. One major athletic event that has been plagued with allegations of doping in recent years is the Tour de France This annual bicycle race, which is held in France and nearby countries, is one of the most physically grueling tests of en- durance available to athletes (see accompanying photo). Lasting three weeks, the race covers 2200 miles, includ- ing major “mountain climbs.” Numerous riders have been disqualified for testing positive for banned performance: enbancing drugs. Major League Baseball is another sport that has encoun- tered anabolic steroid problems, During the 1990s and the carly part of the next decade, many players, including some of the League's most prominent ones, were involved in ana- bolic steroid use In response to the growing problem of illegal use of ana~ bolic steroids, legislation was passed in the United States that supplemented (amended) the Controlled Substance Act. Called the Anabolic Steroid Control Act, which went into effect in 2005, this legislation makes possession of a banned ‘anabolic steroid a federal crime. Still, some athletes continue to use these substances illegally on © on ony Hy cme Ton —cHy cu, cu, o o o tate ‘A TH Anditeetone “erpogestcone 19.12 Messenger Lipids: Steroid Hormones EJ} 19: “Tour de France partcipants face one ofthe most physically grueling endurance tess inal of competitive athletes, ‘Two major reasons exist for prohibiting steroid use in ath- lees: (1) their use is considered a form of cheating because it ‘confers an unfair advantage and (2) their “beneficial effects” are far outweighed by serious negative side effects, Regarding the latter of these two reasons, medical evi- ‘dence now indicates that anabolic steroid use has many side effects that range from some that are physically unattractive, such as acne and breast development in men, to others that are life-threatening, such as heat attacks and liver problems, Most of these alarming effects are reversible if the abuser stops taking the drugs, but some are permanent. Steroid abuse disrupts the normal production of hormones in the body. causing both reversible and irreversible change. The male reproductive system is altered, causing testicular shrink- tage and decreased sperm production. Both of these effects are ‘reversible, but breast development is an ireversible change. In the female body, steroid abuse causes masculinization, Breast size and body fat decrease, the skin becomes coarse, tnd the voice deepens. Some women may experience exces- sive growth of body hair but lose hair from the scalp. ‘The structures of synthetic anabolic steroids closely resemble that of the naturally occuring male sex hormone testosterone. Chemically. most anabolic steroids are testoster- cone derivatives. Testosterone can be viewed as the “template” structure from which many synthetic variations (analogs) hhave been “designed.” Several of these testosterone deriva- tives inerease the body's ability to metabolize ingested protein and facilitate the synthesis of new skeletal muscle proteins. “Two of the most publicized anabolic steroids that athletes have used illegally are “andro” and “THG.” The structures of| ‘these two compounds, as well as that of testosterone for com parison purposes, are shown in the accompanying diagram, Gontinued) Chapter 9 Lipids “Andro,” which is short for androstenedione, was the steroid used during the 1990s and early part of the fol- owing decade in Major League Baseball. It was initially developed for use as a dietary supplement. At the time of its use in MLB, it was a legal supplement that could be purchased over the counter. Now, its possession without a proscription is illegal THG, short for tetrahydrogestrinone, is a “designer” steroid. Its molecular structure was designed so that drug testing procedures of the time could not detect the drug. For several years, it went undetected in drug testing. In 2003, the illegal use of this drug was discovered only after a spent syringe was sent anonymously to a testing agency with the comment that the syringe might con- tain a new performance-enhancing drug. Once the drug, was identified, tests were rapidly developed for its detec tion. Some Olympic sprinters have been disqualified for using THG. Eicosancids exert ther effects at very low concentrations, sometimes iss than one par ina bilion (107 Figure 19.27 Stuctures of selected adrwnocoricoid hormones and related symthatc compounds similar synthetic derivative, are used as prescription drugs to control inflammatory diseases such as rheumatoid arthritis. Figure 19.27 gives the structures of these adrenocorticoid hormones. 19.13 Messenger Lipids: Eicosanoids An cleosanoid is an oxygenated Cy fatty acid derivative that functions as a messen- ger lipid. The term eicosanoid is derived from the Greek word eikos, which means “twenty.” The metabolic precursor for most eicosanoids is arachidonic acid, the 20:4 fatty acid. Almost all cells, except red blood cells, produce eicosanoids, These substances. like hormones, have profound physiological effects at extremely low concentrations. Eicosanoids are hormonelike molecules rather than true hormones because they are not transported in the bloodstream to their site of action as true hormones are. Instead, they exert their effects in the tissues where they are synthesized. Bicos- aanoids usually have a very short “life.” being broken down, often within seconds of their synthesis, to inactive residues (which are eliminated in urine). For this reason, they are difficult to study and monitor within cells. The physiological effects of eicosanoids include mediation of ‘The inflammatory response, a normal response to tissue damage ‘The production of pain and fever The regulation of blood pressure The induction of blood clotting ‘The control of reproductive functions, such as induction of labor The regulation of the sleep/wake eycle ‘Aldosterone Cortisat (aminerelocorticoit) taplococorioid) Natural hormones por | oA Ghent. o o Cortione | Prednisone (Go antcinlammatory drug) (an antiinflammatory dug) 1D syrthetic serids 1913 Messenger Lipids icosanoids OER Figure 19.28 Relatonshio lof the structures of various ‘eicosanoids to their precursor, srachidonie ai. ‘The capital letter-numericl subscript designations for ind ‘idl eicosanoids is based on eiectod structural characteristics ofthe molecules, The numerical subscript indieates the number of carbon-carbon double bonds present. The letters denote sub Sroups of molecules. The prosto slandin group, for example, has 3 carbonyl group on carbon 9 © Thromboxane 82 TD veckoviene 84 ‘There are three principal types of eicosanoids: prostaglandins, thromboxanes, and leukotrienes Prostaglandins A prostaglandin isa messenger lipid that is a Cy-fatty-acid derivative that contains 4 eyelopentane ring and oxygen-containing functional groups. Twenty-carbon fatty acids are converted into a prostaglandin structure when the eighth and twelfth carbon atoms of the fatty acid become connected to form a five-membered ring Figure 19.280), Prostaglandins are named after the prostate gland, which was fist thought to be thei only source. Today, more than 20 prostaglandins have been discovered ina variety of tissues in both males and females Within the human body, prostaglandins are involved in many regulatory func- tions, including raising body temperature, inhibiting the secretion of gastric juices, increasing the secretion of a protective mucus layer into the stomach, relaxing and contracting smooth muscle, directing water and electrolyte balance. intensifying pain, and enhancing inflammation responses, Aspirin reduces inflammation and fever because it inactivates enzymes needed for prostaglandin synthesis. The focus on relevancy feature Chemical Connections 19-F on the next page considers further the relationship between prostaglandin synthesis and inflamma tiom in terms of how anti-infammatory drugs exert their effects in the human body. Thromboxanes Natural oceuing fatty acids are normally found in tho form ofaty A thromboxane isa messenger lipid that is a Cy-fatty-acld derivative that contains Sect resduos in such molocies 2» 4 cyclic ether ring and oxygen-contaning fnctional groups. As with prostaglandins, viacjlayceos, phospropds ara the eyclic structure involves a bond between carbons 8 and 12 (Figure 19,28c), An sphingolipid, suostances provi important function of thromboxanes is to promote the formation of blood clots, ps

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