Marks’ Basic Medical Biochemistry: A Clinical Approach - Chapter 5
Marks’ Basic Medical Biochemistry: A Clinical Approach - Chapter 5 BMS 9265
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Chapter 5 Structures of the Major Compounds of the Body The body contains compounds of great structural diversity: ranging from relatively simple sugars and amino acids to enormously complex polymers such as proteins and nucleic acids. Many of these compounds: have common structural features related to their names, their solubility in water, the pathways in which they participate, or their physiologic function. Thus, learning the terminology used to describe individual compounds and classes of compounds can greatly facilitate learning biochemistry. In this chapter: we describe the major classes of carbohydrates and lipids and some of the classes of nitrogencontaining compounds. The structures of amino acids, proteins, nucleic acids, and vitamins are covered in more detail in subsequent chapters. Functional Groups of Molecules. Organic molecules are composed principally of carbon and hydrogen. However, their unique characteristics are related to structures termed functional groups that involve oxygen, nitrogen, phosphorus, or sulfur. Carbohydrates. Carbohydrates commonly known as sugars, can be classified by their carbonyl group (aldo or keto sugars), the number of carbons they contain (e.g., pentoses, hexoses), or the positions of the hydroxyl groups on their asymmetric carbon atoms (D or Lsugars, stereoisomers, or epimers). They can also be categorized according to their substituents (e.g., amino sugars), or the number of monosaccharides (such as glucose) joined through glycosidic bonds (disaccharides, oligosaccharides, and polysaccharides). Glycoproteins and proteoglycans have sugars attached to their protein components. Lipids. Lipids are a group of structurally diverse compounds defined by their hydrophobicity; they are not very soluble in water The major lipids of the human body are the fatty acids, which are esterified to glycerol to form triacylglycerols (triglycerides) or phosphoacylglycerols (phosphoglycerides). In the sphingolipids, a fatty acid is attached to sphingosine, which is derived from serine and another fatty acid. Glycolipids contain sugars attached to a lipid hydroxyl group. Specific polyunsaturated fatty acids are precursors of eicosanoids. The lipid cholesterol is a component of membranes, and the precursor of other compounds that contain the steroid nucleus, such as the bile salts and steroid hormones. Cholesterol is one of the compounds synthesized from a fivecarbon precursor called the isoprene unit. NitrogenContaining Compounds. Nitrogen in amino groups or heterocyclic ring structures often carries a positive charge at neutral pH. Amino acids Amino acids contain a carboxyl group, an amino group, and one or more additional carbons. Purines, pyrimidines, and pyridines have heterocyclic nitrogencontaining ring structures. Nucleosides comprise one of these ring structures attached to a sugar. The addition of a phosphate produces a nucleotide. I. FUNCTIONAL GROUPS ON BIOLOGIC COMPOUNDS A. Biologic Compounds The organic molecules of the body consist principally of carbon, hydrogen, oxygen, nitrogen, sulfur, and phosphorus joined by covalent bonds. The key element is carbon, which forms four covalent bonds with other atoms. Carbon atoms are joined through double or single bonds to form the carbon backbone for structures of varying size and complexity (Fig. 5.1). Groups containing one, two, three, four, and five carbons plus hydrogen are referred to as methyl, ethyl, propionyl, butyl, and pentanyl groups, respectively. If the carbon chain is branched, the prefix “iso” is used If the compound contains a double bond, “ene” is sometimes incorporated into the name Carbon structures that are straight or branched with single or double bonds, but do not contain a ring, are called aliphatic. Carboncontaining rings are found in several biologic compounds. One of the most common is the sixmembered carboncontaining benzene ring, sometimes called a phenyl group (see Fig. 5.1B) This ring has three double bonds, but the electrons are shared equally by all six carbons and delocalized in planes above and below the ring. Compounds containing the benzene ring, or a similar ring structure with benzenelike properties, are called aromatic. B. Functional Groups Biochemical molecules are defined both by their carbon skeleton and by structures called functional groups that usually involve bonds between carbon and oxygen, carbon and nitrogen, carbon and sulfur, or carbon and phosphate groups (Fig. 5.2). In carbon–carbon and carbon–hydrogen bonds, the electrons are shared equally between atoms, and the bonds are nonpolar and relatively unreactive. In carbon–oxygen and carbon–nitrogen bonds, the electrons are shared unequally, and the bonds are polar and more reactive. Thus, the properties of the functional groups usually determine the types of reactions that occur and the physiologic role of the molecule. Functional group names are often incorporated into the common name of a compound. For example, a ketone might have a name that ends in “one,” such as acetone, and the name of a compound that contains a hydroxyl (alcohol or OH group) might end in “ol” (e.g., ethanol). The acyl group is the portion of the molecule that provides the carbonyl (MCFO) group in an ester or amide linkage. It is denoted in a name by an “yl” ending. For example, the fat stores of the body are triacylglycerols. Three acyl (fatty acid) groups are esterified to glycerol, a compound that contains three alcohol groups. In the remainder of this chapter, we will set in bold the portions of names of compounds that refer to a class of compounds or a structural feature. 1. OXIDIZED AND REDUCED GROUPS The carbon–carbon and carbon–oxygen groups are described as “oxidized” or “reduced” according to the number of electrons around the carbon atom. Oxidation is the loss of electrons and results in the loss of hydrogen atoms together with one or two electrons, or the gain of an oxygen atom or hydroxyl group. Reduction is the gain of electrons and results in the gain of hydrogen atoms or loss of an oxygen atom. Thus, the carbon becomes progressively more oxidized (and less reduced) as we go from an alcohol to an aldehyde or a ketone to a carboxyl group (see Fig. 5.2). Carbon–carbon double bonds are more oxidized (and less reduced) than carbon– carbon single bonds. 2. GROUPS THAT CARRY A CHARGE Acidic groups contain a proton that can dissociate, usually leaving the remainder of the molecule as an anion with a negative charge (see Chapter 4). In biomolecules, the major anionic substituents are carboxylate groups, phosphate groups, or sulfate groups (the “ate” suffix denotes a negative charge) (Fig. 5.3). Phosphate groups attached to metabolites are often abbreviated as P with a circle around it, or just as “P,” as in glucose 6P. Compounds that contain nitrogen: are usually basic and can acquire a positive charge (Fig. 5.4). Nitrogen has five electrons in its valence shell. If only three of these electrons form covalent bonds with other atoms, the nitrogen has no charge. If the remaining two electrons form a bond with a hydrogen ion or a carbon atom, the nitrogen carries a positive charge. Amines consist of nitrogen attached through single bonds to hydrogen atoms and to one or more carbon atoms. Primary amines, such as dopamine, have one carbon–nitrogen bond. These amines are weak acids with a pKa of approximately 9, so that at pH 7.4 they carry a positive charge. Secondary, tertiary, and quarternary amines have two, three, and four nitrogen–carbon bonds, respectively (see Fig. 5.4). C. Polarity of Bonds and Partial Charges Polar bonds are covalent bonds in which the electron cloud is more dense around one atom (the atom with the greater electronegativity) than the other. Oxygen is more electronegative than carbon, and a carbon–oxygen bond is therefore polar, with the oxygen atom carrying a partial negative charge and the carbon atom carrying a partial positive charge (Fig. 5.5). In nonpolar carbon–carbon bonds and carbon–hydrogen bonds, the two electrons in the covalent bond are shared almost equally. Nitrogen when it has only three covalent bonds, also carries a partial negative charge relative to carbon, and the carbon–nitrogen bond is polarized. Sulfur can carry a slight partial negative charge. 1. SOLUBILITY Water is a dipolar molecule in which the oxygen atom carries a partial negative charge and the hydrogen atoms carry partial positive charges (see Chapter 4). For molecules to be soluble in water, they must contain charged or polar groups that can associate with the partial positive and negative charges of water. Thus, the solubility of organic molecules in water is determined by both the proportion of polar to nonpolar groups attached to the carbon–hydrogen skeleton and to their relative positions in the molecule. Polar groups or molecules are called hydrophilic (water loving) Nonpolar groups or molecules are hydrophobic (water fearing) Sugars such as glucose 6phosphate, for example, contain so many polar groups that they are very hydrophilic and almost infinitely watersoluble (Fig. 5.6). The water molecules interacting with a polar or ionic compound form a hydration shell around the compound, which includes hydrogen bonds and/or ionic interactions between water and the compound. Compounds that have large nonpolar regions are relatively waterinsoluble. They tend to cluster together in an aqueous environment and form weak associations through van der Waals interactions and hydrophobic interactions. Hydrophobic compounds are essentially pushed together (the hydrophobic effect) as the water molecules maximize the number of energetically favorable hydrogen bonds they can form with each other in the water lattice. Thus, lipids form droplets or separate layers in an aqueous environment (e.g., vegetable oils in a salad dressing). 2. REACTIVITY Another consequence of bond polarity is that atoms that carry a partial (or full) negative charge are attracted to atoms that carry a partial (or full) positive charge and vice versa. These partial or full charges dictate the course of biochemical reactions, which follow the same principles of electrophilic and nucleophilic attack that are characteristic of organic reactions in general. The partial positive charge on the carboxyl carbon attracts more negatively charged groups and accounts for many of the reactions of carboxylic acids. An ester is formed when a carboxylic acid and an alcohol combine, splitting out water (Fig. 5.7). Similarly, a thioester is formed when an acid combines with a sulfhydryl group, and an amide is formed when an acid combines with an amine. Similar reactions result in the formation of a phosphoester from phosphoric acid and an alcohol and in the formation of an anhydride from two acids. D. Nomenclature Biochemists use two systems for the identification of the carbons in a chain. In the first system, the carbons in a compound are numbered, starting with the carbon in the most oxidized group (e.g., the carboxyl group). In the second system, the carbons are given Greek letters, starting with the carbon next to the most oxidized group. Hence, the compound shown in Figure 5.8 is known as 3hydroxybutyrate or βhydroxybutyrate. II. CARBOHYDRATES A. Monosaccharides Simple monosaccharides consist of a linear chain of three or more carbon atoms, one of which forms a carbonyl group through a double bond with oxygen (Fig. 5.9). The other carbons of an unmodified monosaccharide contain hydroxyl groups, resulting in the general formula for an unmodified sugar of CnH2nOn. The suffix “ose” is used in the names of sugars. If the carbonyl group is an aldehyde, the sugar is an aldose; if the carbonyl group is a ketone, the sugar is a ketose. Monosaccharides are also classified according to their number of carbons: Sugars containing three, four, five, six, and seven carbons are called trioses, tetroses, pentoses, hexoses, and heptoses, respectively. Fructose is therefore a ketohexose (see Fig. 5.9), and glucose is an aldohexose (see Fig. 5.6). 1. D- AND L-SUGARS A carbon atom that contains four different chemical groups forms an asymmetric (or chiral) center (Fig. 5.10A). The groups attached to the asymmetric carbon atom can be arranged to form two different isomers that are mirror images of each other and not superimposable. Monosaccharide stereoisomers are designated D or L based on whether the position of the hydroxyl group farthest from the carbonyl carbon matches D or Lglyceraldehyde (see Fig. 5.10B). Such mirror image compounds are known as enantiomers. Although a more sophisticated system of nomenclature using the designations (R) and (S) is generally used to describe the positions of groups on complex molecules such as drugs, the D and L designations are still used in medicine for describing sugars and amino acids. Because glucose (the major sugar in human blood) and most other sugars in human tissues belong to the D series, sugars are assumed to be D unless L is specifically added to the name. 2. STEREOISOMERS AND EPIMERS Stereoisomers have the same chemical formula but differ in the position of the hydroxyl group on one or more of their asymmetric carbons (Fig. 5.11). A sugar with n asymmetric centers has 2n stereoisomers unless it has a plane of symmetry. Epimers are stereoisomers that differ in the position of the hydroxyl group at only one of their asymmetric carbons. Dglucose and Dgalactose are epimers of each other, differing only at position 4, and can be interconverted in human cells by enzymes called epimerases. Dmannose and Dglucose are also epimers of each other, differing only at position 2. 3. RING STRUCTURES Monosaccharides exist in solution mainly as ring structures in which the carbonyl (aldehyde or ketone) group has reacted with a hydroxyl group in the same molecule to form a five or sixmembered ring (Fig. 5.12). The oxygen that was on the hydroxyl group is now part of the ring, and the original carbonyl carbon, which now contains an MOH group, has become the anomeric carbon atom. A hydroxyl group on the anomeric carbon drawn down below the ring is in the _ position; drawn up above the ring, it is in the β position. In the actual threedimensional structure, the ring is not planar but usually takes a “chair” conformation in which the hydroxyl groups are located at a maximal distance from each other. In solution, the hydroxyl group on the anomeric carbon spontaneously (nonenzymatically) changes from the α to the β position through a process called mutarotation. When the ring opens, the straightchain aldehyde or ketone is formed. When the ring closes, the hydroxyl group may be in either the α or the β position (Fig. 5.13). This process occurs more rapidly in the presence of cellular enzymes called mutarotases. However, if the anomeric carbon forms a bond with another molecule, that bond is fixed in the α or β position, and the sugar cannot mutarotate. Enzymes are specific for α or β bonds between sugars and other molecules and react with only one type. 4. SUBSTITUTED SUGARS Sugars frequently contain phosphate groups, amino groups, sulfate groups, or Nacetyl groups. Most of the free monosaccharides within cells are phosphorylated at their terminal carbons, which prevents their transport out of the cell (see glucose 6phosphate in Fig. 5.6). Amino sugars such as galactosamine and glucosamine contain an amino group instead of a hydroxyl group on one of the carbon atoms, usually carbon 2 (Fig. 5.14). Frequently, this amino group has been acetylated to form an Nacetylated sugar. In complex molecules termed proteoglycans, many of the Nacetylated sugars also contain negatively charged sulfate groups attached to a hydroxyl group on the sugar. 5. OXIDIZED AND REDUCED SUGARS Sugars can be oxidized at the aldehyde carbon to form an acid. Technically, the compound is no longer a sugar, and the ending on its name is changed from “ose” to “ onic acid” or “onate” (e.g., gluconic acid, Fig. 5.15). If the carbon containing the terminal hydroxyl group is oxidized, the sugar is called a uronic acid (e.g., glucuronic acid). If the aldehyde of a sugar is reduced, all of the carbon atoms contain alcohol (hydroxyl) groups, and the sugar is a polyol (e.g., sorbitol) (see Fig. 5.15). If one of the hydroxyl groups of a sugar is reduced so that the carbon contains only hydrogen, the sugar is a deoxysugar, such as the deoxyribose in DNA. Proteoglycans contain many long unbranched polysaccharide chains attached to a core protein. The polysaccharide chains, called glycosaminoglycans, are composed of repeating disaccharide units containing oxidized acid sugars (such as glucuronic acid), sulfated sugars, and Nacetylated amino sugars. The large number of negative charges causes the glycosaminoglycan chains to radiate out from the protein so that the overall structure resembles a bottle brush. The proteoglycans are essential parts of the extracellular matrix, aqueous humor of the eye, secretions of mucusproducing cells, and cartilage and are described in further detail in Chapter 49. B. Glycosides 1. N- AND O-GLYCOSIDIC BONDS The hydroxyl group on the anomeric carbon of a monosaccharide can react with an MOH or an MNH group of another compound to form a glycosidic bond. The linkage may be either _ or _, depending on the position of the atom attached to the anomeric carbon of the sugar. Nglycosidic bonds are found in nucleosides and nucleotides. For example, in the adenosine moiety of adenosine triphosphate (ATP), the nitrogenous base adenine is linked to the sugar ribose through a _Nglycosidic bond (Fig. 5.16). In contrast, Oglycosidic bonds, such as those found in lactose, join sugars to each other or attach sugars to the hydroxyl group of an amino acid on a protein. 2. DISACCHARIDES, OLIGOSACCHARIDES, AND POLYSACCHARIDES A disaccharide contains two monosaccharides joined by an Oglycosidic bond. Lactose, which is the sugar in milk, consists of galactose and glucose linked through a _(14) bond formed between the _–OH group of the anomeric carbon of galactose and the hydroxyl group on carbon 4 of glucose (see Fig. 5.16). Oligosaccharides contain from 3 to roughly 12 monosaccharides linked together. They are often found attached through N or Oglycosidic bonds to proteins to form glycoproteins (see Chapter 6). Polysaccharides contain tens to thousands of monosaccharides joined by glycosidic bonds to form linear chains or branched structures. Amylopectin (a form of starch) and glycogen (the storage form of glucose in human cells) are branched polymers of glucosyl residues linked through _(14) and _(16) bonds. III. LIPIDS A. Fatty Acids Fatty acids are usually straight aliphatic chains with a methyl group at one end (called the _carbon) and a carboxyl group at the other end (Fig. 5.17A). Most fatty acids in the human have an even number of carbon atoms, usually between 16 and 20. Saturated fatty acids have single bonds between the carbons in the chain, and unsaturated fatty acids contain one or more double bonds. The most common saturated fatty acids present in the cell are palmitic acid (C16) and stearic acid (C18). Although these two fatty acids are generally called by their common names, shorter fatty acids are often called by the Latin word for the number of carbons, such as octanoic acid (8 carbons) and decanoic acid (10 carbons). The melting point of a fatty acid increases with chain length and decreases with the degree of unsaturation. Thus, fatty acids with many double bonds, such as those in vegetable oils, are liquid at room temperature; and saturated fatty acids, such as those in butterfat, are solids. Lipids with lower melting points are more fluid at body temperature and contribute to the fluidity of our cellular membranes. Monounsaturated fatty acids contain one double bond, and polyunsaturated fatty acids contain two or more double bonds (see Fig. 5.17). The position of a double bond is designated by the number of the carbon in the double bond that is closest to the carboxyl group. For example, oleic acid, which contains 18 carbons and a double bond between positions 9 and 10, is designated 18:1, _9. The number 18 denotes the number of carbon atoms, 1 (one) denotes the number of double bonds, and _9 denotes the position of the double bond between the 9th and 10th carbon atoms. Oleic acid can also be designated 18:1(9), without the _. Fatty acids are also classified by the distance of the double bond closest to the _ end (the methyl group at the end farthest from the carboxyl group). Thus, oleic acid is an _9 fatty acid, and linolenic acid is an _3 fatty acid. Arachidonic acid, a polyunsaturated fatty acid with 20 carbons and 4 double bonds, is an _6 fatty acid that is completely described as 20:4, _5,8,11,14. The eicosanoids are a group of hormonelike compounds produced by many cells in the body. They are derived from polyunsaturated fatty acids such as arachidonic acid that contain 20 carbons (eicosa) and have 3, 4, or 5 double bonds. The prostaglandins, thromboxanes, and leukotrienes belong to this group of compounds. The double bonds in most naturally occurring fatty acids are in the cis configuration (Fig. 5.17B). The designation cis means that the hydrogens are on the same side of the double bond and the acyl chains are on the other side. In transfatty acids, the acyl chains are on opposite sides of the double bond. Margarine and the fat used in preparing French fries are probably the major sources of transfatty acids found in humans. Transfatty acids are produced by the chemical hydrogenation of polyunsaturated fatty acids in vegetable oils and are not a natural food product. B. Acylglycerols An acylglycerol comprises glycerol with one or more fatty acids (the acyl group) attached through ester linkages (Fig. 5.18). Monoacylglycerols, diacylglycerols, and triacylglycerols contain one, two, or three fatty acids esterified to glycerol, respectively. Triacylglycerols rarely contain the same fatty acid at all three positions and are therefore called mixed triacylglycerols. Unsaturated fatty acids, when present, are most often esterified to carbon 2. In the threedimensional configuration of glycerol, carbons 1 and 3 are not identical, and enzymes are specific for one or the other carbon. C. Phosphoacylglycerols Phosphoacylglycerols contain fatty acids esterified to positions 1 and 2 of glycerol and a phosphate (alone or with a substituent) attached to carbon 3. If only a phosphate group is attached to carbon 3, the compound is phosphatidic acid (Fig. 5.19). Phosphatidic acid is a precursor for the synthesis of the other phosphoacylglycerols. Phosphatidylcholine is one of the major phosphoacylglycerols found in membranes (see Fig. 5.19). The amine is positively charged at neutral pH, and the phosphate is negatively charged. Thus, the molecule is amphipathic; it contains large polar and nonpolar regions. Phosphatidylcholine is also called lecithin. Removal of a fatty acyl group from a phosphoacylglycerol leads to a lysolipid; for example, removing the fatty acyl group from lecithin forms lysolecithin. D. Sphingolipids Sphingolipids do not have a glycerol backbone; they are formed from sphingosine (Fig. 5.20) Sphingosine is derived from serine and a specific fatty acid, palmitate. Various sphingolipids are then formed by attaching different groups to the hydroxyl group on ceramide. As reflected in the names for cerebrosides and gangliosides, these sphingolipids contain sugars attached to the hydroxyl group of ceramide through glycosidic bonds. They are glycolipids (more specifically, glycosphingolipids). Sphingomyelin, which contains a phosphorylcholine group attached to ceramide, is a component of cell membranes and the myelin sheath around neurons. Ceramides are amides formed from sphingosine by attaching a fatty acid to the amino group. E. Steroids Steroids contain a fourring structure called the steroid nucleus (Fig. 5.21). Cholesterol is the steroid precursor in human cells from which all of the steroid hormones are synthesized by modifications to the ring or C20 side chain. Although cholesterol is not very watersoluble, it is converted to amphipathic watersoluble bile salts such as cholic acid. Bile salts line the surfaces of lipid droplets called micelles in the lumen of the intestine, where they keep the droplets emulsified in the aqueous environment. Cholesterol is one of the compounds synthesized in the human from branched fivecarbon units with one double bond called an isoprenyl unit (see Fig. 5.1A). Isoprenyl units are combined in long chains to form other structures, such as the side chains of coenzyme Q in humans and vitamin A in plants. Isoprene units form polymers to generate gerenyl groups (10 carbons) and farnesyl groups (15 carbons) (see Chapter 34). The gerenyl and farnesyl groups, due to their highly hydrophobic nature, are often covalently attached to proteins to allow the proteins to associate with cellular membranes. IV. NITROGEN-CONTAINING COMPOUNDS Nitrogen, as described in Section I.B.2, is an electronegative atom with two unshared electrons in its outer valence shell. At neutral pH, the nitrogen in amino groups is usually bonded to four other atoms and carries a positive charge. However, the presence of a nitrogen atom in an organic compound will increase its solubility in water, whether the nitrogen is charged or uncharged. A. Amino Acids Amino acids are compounds that contain an amino group and a carboxylic acid group. In proteins, the amino acids are always L_amino acids (the amino group is attached to the _ carbon in the Lconfiguration) (Fig. 5.22). These same amino acids also serve as precursors of nitrogencontaining compounds in the body, such as phosphatidylcholine (see Fig. 5.19) and are the basis of most human amino acid metabolism. However, our metabolic reactions occasionally produce an amino acid that has a _ or _amino group, such as the neurotransmitter _aminobutyric acid (see Fig. 5.22). Nevertheless, only L_amino acids are incorporated into proteins. Although Damino acids are not usually incorporated into proteins in living organisms, they serve many other functions in bacteria, such as synthesis of crosslinks in cell walls. B. NitrogenContaining Ring Structures 1. PURINES, PYRIMIDINES, AND PYRIDINES Nitrogen is also a component of ring structures referred to as heterocyclic rings or nitrogenous bases. The three most common types of nitrogencontaining rings in the body are: purines (e.g., adenine) pyrimidines (e.g., thymine) pyridines (e.g., the vitamins nicotinic acid, also called niacin, and pyridoxine, also called vitamin B6) (Fig. 5.23). The suffix “ine” denotes the presence of nitrogen (amine) in the ring. The pyrimidine uracil is an exception to this general type of nomenclature. The utility of these nitrogencontaining ring structures lies in the ability of the nitrogen to form hydrogen bonds and to accept and donate electrons while still part of the ring. In contrast, the unsubstituted aromatic benzene ring, in which electrons are distributed equally among all six carbons (see Fig. 5.1), is nonpolar, hydrophobic, and relatively unreactive. 2. NUCLEOSIDES AND NUCLEOTIDES Nitrogenous bases form nucleosides and nucleotides. Nucleoside consists of a nitrogenous base joined to a sugar, usually ribose or deoxyribose, through an Nglycosidic bond (see Fig. 5.16). If phosphate groups are attached to the sugar, the compound becomes a nucleotide. In the name of the nucleotide ATP, the addition of the ribose is indicated by the name change from adenine to adenosine (for the glycosidic bond). Monophosphate, diphosphate, or triphosphate is added to the name to indicate the presence of one, two, or three phosphate groups in the nucleotide. The structures of the nucleotides that serve as precursors of DNA and RNA are discussed in more detail in Section 3 of Chapter 12. 3. TAUTOMERS In many of the nitrogencontaining rings, the hydrogen can shift to produce a tautomer, a compound in which the hydrogen and double bonds have changed position (i.e., –N=C–OH → –NH–C=O) (Fig. 5.24). Tautomers are considered the same compound, and the structure may be represented either way. Generally, one tautomeric form is more reactive than the other. For example, in the two tautomeric forms of uric acid, a proton can dissociate from the enol form to produce urate. V. FREE RADICALS Radicals are compounds that have a single electron, usually in an outer orbital. Free radicals are radicals that exist independently in solution or in a lipid environment. Although many enzymes generate radicals as intermediates in reactions, these are not usually released into the cell to become free radicals. Many of the compounds in the body are capable of being converted to free radicals by natural events that remove one of their electrons, or by radiation. Radiation, for example, dissociates water into the hydrogen atom and the hydroxyl radical: Water normally dissociates into a proton and the negatively charged hydroxyl ion. The hydroxyl radical forms organic radicals by taking one electron (as H•) from a compound such as an unsaturated membrane lipid, which then has a single unpaired electron and is a new radical. Compounds that are radicals may be written with, or without, the radical showing. For example, nitrogen dioxide—a potent, reactive, toxic radical present in smog and cigarette smoke— may be designated in medical and lay literature as NO2 rather than NO 2. Superoxide, a radical produ–ed in the cell and that is the source of much destruction, is correctly written as the superoxide anion, O2. However, to emphasize its free radical nature, the same compound is sometimes written as O •2 If a compound is designated as a radical in the medical literature, you can be certain that it is a reactive radical, and that its radical nature is important for the pathophysiology under discussion. Reactive oxygen and nitrogencontaining free radicals are discussed in more detail in Chapter 24. BIOCHEMICAL COMMENTS Chlorinated Aromatic Hydrocarbon Environmental Toxins. As a result of human endeavor, toxic compounds containing chlorinated benzene rings have been widely distributed in the environment. The pesticide DDT (dichlorodiphenyltrichloroethane) and the class of chemicals called dioxins provide examples of chlorinated aromatic hydrocarbons and structurally related compounds that are very hydrophobic and poorly biodegraded (Fig. 5.25). As a consequence of their persistence and lipophilicity, these chemicals are concentrated in the adipose tissue of fish, fisheating birds, and carnivorous mammals, including humans. DDT, a chlorinated biphenyl, was widely used in the United States as an herbicide between the 1940s and 1960s (see Fig. 5.25). Although it has not been used in this country since 1972, the chlorinated benzene rings are resistant to biodegradation, and US soil and water are still contaminated with small amounts. DDT is still used in other parts of the world. Because this highly lipophilic molecule is stored in the fat of animals, organisms accumulate progressively greater amounts of DDT at each successive stage of the food chain. Fisheating birds, one of the organisms at the top of the food chain, have declined in population because of the effect of DDT on the thickness of their eggshells. DDT is not nearly as toxic in the human, although longterm exposure or exposure to high doses may cause reversible neurologic symptoms, hepatotoxic effects, or cancer. Dioxins, specifically chlorodibenzopdioxins (CDDs), constitute another class of environmental toxins that are currently of great concern (see Fig. 5.25). They have been measured at what is termed background levels in the blood, adipose tissue, and breast milk of all humans tested. CDDs are formed as a byproduct during the production of other chlorinated compounds and herbicides, and from the chlorine bleaching process used by pulp and paper mills. They are released during the incineration of industrial, municipal, and domestic waste and during the combustion of fossil fuels and are found in cigarette smoke and the exhaust from engines, which burn gasoline and diesel fuels. They can also be formed from the combustion of organic matter during forest fires. They enter the atmosphere as particulate matter, are vaporized, and can spread large distances to enter soil and water. As humans at the top of the food chain, we have acquired our background levels of dioxins principally through the consumption of food, primarily meat, dairy products, and fish. Once in the human body, dioxins are stored in human fat and adipose tissue and have an average halflife of approximately 5 to 15 years. They are unreactive, poorly degraded, and not readily converted to more watersoluble compounds that can be excreted in the urine. They are slowly excreted in the bile and feces, and together with lipids enter the breast milk of nursing mothers. Key Concepts Carbohydrates, commonly known as sugars, can be classified by several criteria: Type of carbonyl group (aldo or keto sugars) Number of carbons (pentoses [five carbons], hexoses [six carbons]) Positions of hydroxyl groups on asymmetric carbon atoms (D or Lconfiguration, stereoisomers, epimers) Substituents (amino sugars) Number of monosaccharides joined through glycosidic bonds (disaccharides, oligosaccharides, polysaccharides) Lipids are structurally diverse compounds that are not very soluble in water (i.e., they are hydrophobic). The major lipids are fatty acids. Triacylglycerol (triglycerides) consist of three fatty acids esterified to the carbohydrate glycerol. Phosphoacylglycerols (phosphoglycerides or phospholipids) are similar to triacylglycerol but contain a phosphate in place of a fatty acid. Sphingolipids are built on sphingosine. Cholesterol is a component of membranes and a precursor for molecules that contain the steroid nucleus, such as bile salts and steroid hormones. Nitrogen is found in various compounds in addition to amino sugars. Amino acids and heterocyclic rings contain nitrogens, which carry a positive charge at neutral pH. Amino acids contain a carboxyl group, an amino group, and a side chain attached to a central carbon. Proteins consist of a linear chain of amino acids. Purines, pyrimidines, and pyridines have heterocyclic nitrogencontaining ring structures. Nucleosides consist of a heterocyclic ring attached to a sugar. A nucleoside plus phosphate is a nucleotide. Glycoproteins and proteoglycans have sugars attached to protein components.
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