Our 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 functions. 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 nitrogen-containing compounds. The structures of amino acids, proteins, nucleic acids, and vitamins are covered in more detail in subsequent chapters.
Functional Groups on 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 L-sugars, 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 the amino acid serine and another fatty acid. Glycolipids contain lipids attached to a sugar 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 five-carbon precursor called the isoprene unit.
Nitrogen-Containing Compounds. Nitrogen in amino groups or heterocyclic ring structures often carries a positive charge at neutral pH. Amino acids contain a carboxyl group, an amino group, and one or more additional carbons. Purines, pyrimidines, and pyridines have heterocyclic nitrogen-containing ring structures. Nucleosides comprise one of these ring structures attached to a sugar. The addition of a phosphate to a nucleoside produces a nucleotide.
Dianne A. recovered from her bout of diabetic ketoacidosis (DKA) and was discharged from the hospital (see Chapter 4). She has returned for a follow-up visit as an outpatient. She reports that she has been compliant with her recommended diet and that she faithfully gives herself insulin by subcutaneous injection several times daily. She self-monitors her blood glucose levels at least 4 times a day and reports the results to her physician.
Lotta T. is a 54-year-old woman who came to her physician’s office complaining of severe throbbing pain in the right great toe that began 8 hours earlier. The toe has suffered no trauma but appears red and swollen. It is warmer than the surrounding tissue and is exquisitely tender to even light pressure. She is unable to voluntarily flex or extend the joints of the digit, and passive motion of the joints causes great pain.
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.
Carbon-containing rings are found in a number of biologic compounds. One of the most common is the six-membered carbon-containing 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 benzene-like 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 (–C=O) 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 bold the portions of names of compounds that refer to a class of compounds or a structural feature.
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 the 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 6-P.
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 quaternary amines have two, three, and four nitrogen–carbon bonds, respectively (see Fig. 5.4).
Polar bonds are covalent bonds in which the electron cloud is denser 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.
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), and nonpolar groups or molecules are hydrophobic (water-fearing). Sugars such as glucose 6-phosphate, for example, contain so many polar groups (many hydroxyl and one phosphate) that they are very hydrophilic and almost infinitely water-soluble (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 water-insoluble. 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).
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 attacks 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, releasing 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.
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 3-hydroxybutyrate or β-hydroxybutyrate.
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 containing 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 L-glyceraldehyde (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. D-Glucose and D-galactose are epimers of each other, differing only at position 4, and can be interconverted in human cells by enzymes called epimerases. D-Mannose and D-glucose are also epimers of each other, differing only at position 2.
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 six-membered 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 –OH group, has become the anomeric carbon atom. A hydroxyl group on the anomeric carbon drawn down below the ring is in the α position; drawn up above the ring, it is in the β position. In the actual three-dimensional 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 straight-chain 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.