《生物化学》课程教学资源（书籍文献）英文生化教材 Lippincott’s Illustrated Reviews Biochemistry, 5th 2010, Richard A. Harvey, PhD, Denise R. Ferrier, PhD

UNIT I: Protein Structure and Function Chapter 1: Amino Acids Chapter 2: Structure of Proteins Chapter 3: Globular Proteins Chapter 4: Fibrous Proteins Chapter 5: Enzymes UNIT II: Intermediary Metabolism Chapter 6: Bioenergetics and Oxidative Phosphorylation Chapter 7: Introduction to Carbohydrates Chapter 8: Glycolysis Chapter 9: Tricarboxylic Acid Cycle Chapter 10: Gluconeogenesis Chapter 11: Glycogen Metabolism Chapter 12: Metabolism of Monosaccharides and Disaccharides Chapter 13: Pentose Phosphate Pathway and NADPH Chapter 14: Glycosaminoglycans, Proteoglycans, and Glycoproteins UNIT III: Lipid Metabolism Chapter 15: Metabolism of Dietary Lipids Chapter 16: Fatty Acid and Triacylglycerol Metabolism Chapter 17: Complex Lipid Metabolism Chapter 18: Cholesterol and Steroid Metabolism UNIT IV: Nitrogen Metabolism Chapter 19: Amino Acids: Disposal of Nitrogen Chapter 20: Amino Acid Degradation and Synthesis Chapter 21: Conversion of Amino Acids to Specialized Products Chapter 22: Nucle

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Harvey Ferrier Lippincott’s Illustrated Reviews LWW.com 5th edition Lippincott’s Illustrated Reviews Richard Harvey Denise Ferrier Series Editor: Richard A. Harvey 5th edition Biochemistry—USMLE Review Figure 3.20 Molecular and cellular events leading to sickle cell crisis. Biochemistry 5th edition Richard A. Harvey Denise R. Ferrier Lippincott’s Illustrated Reviews Lippincott’s Illustrated Reviews: Biochemistry is the long-established, fi rst-and-best resource for the essentials of biochemistry. Students rely on this text to help them quickly review, assimilate, and integrate large amounts of critical and complex information. For more than two decades, faculty and students have praised LIR Biochemistry’s matchless illustrations that make concepts come to life. Get fully prepared for coursework and board exams with these hallmark features from Lippincott’s Illustrated Reviews: ✓ Outline format – perfect for both concise review and foundational learning. ✓ Annotated, full-color illustrations – visually explain complex biochemical processes. ✓ Chapter overviews and summaries – reinforce your study time! ✓ Clinical boxes – take students quickly from the classroom to the patient, associating key concepts with real-world scenarios. ✓ Cross-references within this book, and to other disciplines in the series. ✓ More than 100 review questions included in the book! ✓ Free With Purchase!!! A comprehensive online exam featuring an additional 450 practice questions, plus fully searchable online text! Additional FREE!! Online resources available on , where Teaching, Learning, and Technology “click.” Don’t miss these other titles in the Lippincott’s Illustrated Reviews series: LIR: Immunology • LIR: Microbiology LIR: Pharmacology • LIR: Cell and Molecular Biology Don’t miss these other titles in the Lippincott’s Illustrated Reviews series: LIR: Immunology • LIR: Microbiology LIR: Pharmacology • LIR: Cell and Molecular Biology Lippincott’s Illustrated Reviews—Seeing is Understanding

Amino Acids 1 I. OVERVIEW Proteins are the most abundant and functionally diverse molecules in living systems. Virtually every life process depends on this class of molecules. For example, enzymes and polypeptide hormones direct and regulate metabolism in the body, whereas contractile proteins in muscle permit movement. In bone, the protein collagen forms a framework for the deposition of calcium phosphate crystals, acting like the steel cables in reinforced concrete. In the bloodstream, proteins, such as hemoglobin and plasma albumin, shuttle molecules essential to life, whereas immuno globulins fight infectious bacteria and viruses. In short, proteins display an incredible diversity of functions, yet all share the common structural feature of being linear polymers of amino acids. This chapter describes the properties of amino acids. Chapter 2 explores how these simple building blocks are joined to form proteins that have unique three-dimensional structures, making them capable of performing specific biologic functions. II. STRUCTURE OF THE AMINO ACIDS Although more than 300 different amino acids have been described in nature, only 20 are commonly found as constituents of mammalian proteins. [Note: These are the only amino acids that are coded for by DNA, the genetic material in the cell (see p. 395).] Each amino acid (except for proline, which has a secondary amino group) has a carboxyl group, a primary amino group, and a distinctive side chain (“R-group”) bonded to the α-carbon atom (Figure 1.1A). At physiologic pH (approximately pH 7.4), the carboxyl group is dissociated, forming the negatively charged carboxylate ion (–COO– ), and the amino group is protonated (–NH3 +). In proteins, almost all of these carboxyl and amino groups are combined through peptide linkage and, in general, are not available for chemical reaction except for hydrogen bond formation (Figure 1.1B). Thus, it is the nature of the side chains that ultimately dictates the role Figure 1.1 Structural features of amino acids (shown in their fully protonated form). C +H3N NH-CH-COCOOH C H +H3N COOH H Common to all α-amino acids of proteins Free amino acid Amino acids combined through peptide linkages R R NH-CH-CO R Amino group Carboxyl group Cα H Carboxyl group α Amino R group R Side chain is distinctive for each amino acid. α-Carbon is between the carboxyl and the amino groups. R R Side chains determine properties of proteins. A B 1 UNIT I: Protein Structure and Function 168397_P001-012.qxd7.0:02 Protein structure 5-20-04 2010.4.4 9:45 AM Page 1

effect, is the result of the hydro phobicity of the nonpolar R-groups, which act much like droplets of oil that coalesce in an aqueous environment. The nonpolar R-groups thus fill up the interior of the folded protein and help give it its three-dimensional shape. However, for proteins that are located in a hydrophobic environment, such as a membrane, the nonpolar R-groups are found on the outside surface of the protein, interacting with the lipid environment (see Figure 1.4). The importance of these hydrophobic interactions in stabilizing protein structure is discussed on p. 19. Sickle cell anemia, a sickling disease of red blood cells, results from the substitution of polar glutamate by nonpolar valine at the sixth position in the β subunit of hemoglobin (see p. 36). 2. Proline: Proline differs from other amino acids in that proline’s side chain and α-amino N form a rigid, five-membered ring structure (Figure 1.5). Proline, then, has a secondary (rather than a primary) amino group. It is frequently referred to as an imino acid. The unique geometry of proline contributes to the formation of the fibrous structure of collagen (see p. 45), and often interrupts the α-helices found in globular proteins (see p. 26). B. Amino acids with uncharged polar side chains These amino acids have zero net charge at neutral pH, although the side chains of cysteine and tyrosine can lose a proton at an alkaline pH (see Figure 1.3). Serine, threonine, and tyrosine each contain a polar hydroxyl group that can participate in hydrogen bond formation (Figure 1.6). The side chains of asparagine and glutamine each contain a carbonyl group and an amide group, both of which can also participate in hydrogen bonds. 1. Disulfide bond: The side chain of cysteine contains a sulf hydryl group (–SH), which is an important component of the active site of many enzymes. In proteins, the –SH groups of two cysteines can become oxidized to form a dimer, cystine, which contains a covalent cross-link called a disulfide bond (–S–S–). (See p. 19 for a further discussion of disulfide bond formation.) Many extracellular proteins are stabilized by disulfide bonds. Albumin, a blood protein that functions as a transporter for a variety of molecules, is an example. 2. Side chains as sites of attachment for other compounds: The polar hydroxyl group of serine, threonine, and, rarely, tyrosine, can serve as a site of attachment for structures such as a phosphate group. In addition, the amide group of asparagine, as well as the hydroxyl group of serine or threonine, can serve as a site of attachment for oligosaccharide chains in glycoproteins (see p. 165). Figure 1.6 Hydrogen bond between the phenolic hydroxyl group of tyrosine and another molecule containing a carbonyl group. C +H3N COOH CH2 Tyrosine Hydrogen bond O C O H H Carbonyl group 4 1. Amino Acids Figure 1.4 Location of nonpolar amino acids in soluble and membrane proteins. Cell membrane Polar amino acids ( ) cluster on the surface of soluble proteins. Cell Nonpolar amino acids ( ) cluster on the surface of membrane proteins. Nonpolar amino acids ( ) cluster in the interior of soluble proteins. Soluble protein Membrane protein Figure 1.5 Comparison of the secondary amino group found in proline with the primary amino group found in other amino acids, such as alanine. C +H3N COOH H CH3 Alanine COOH H Proline C CH2 +H2N H2C Primary amino group Secondary amino group CH2 168397_P001-012.qxd7.0:02 Protein structure 5-20-04 2010.4.4 9:45 AM Page 4

C. Amino acids with acidic side chains The amino acids aspartic and glutamic acid are proton donors. At physiologic pH, the side chains of these amino acids are fully ionized, containing a negatively charged carboxylate group (–COO– ). They are, therefore, called aspartate or glutamate to emphasize that these amino acids are negatively charged at physiologic pH (see Figure 1.3). D. Amino acids with basic side chains The side chains of the basic amino acids accept protons (see Figure 1.3). At physiologic pH the side chains of lysine and arginine are fully ionized and positively charged. In contrast, histidine is weakly basic, and the free amino acid is largely uncharged at physiologic pH. However, when histidine is incorporated into a protein, its side chain can be either positively charged or neutral, depending on the ionic environment provided by the polypeptide chains of the protein. This is an important property of histidine that contributes to the role it plays in the functioning of proteins such as hemoglobin (see p. 31). E. Abbreviations and symbols for commonly occurring amino acids Each amino acid name has an associated three-letter abbreviation and a one-letter symbol (Figure 1.7). The one-letter codes are determined by the following rules: 1. Unique first letter: If only one amino acid begins with a particular letter, then that letter is used as its symbol. For example, I = isoleucine. 2. Most commonly occurring amino acids have priority: If more than one amino acid begins with a particular letter, the most common of these amino acids receives this letter as its symbol. For example, glycine is more common than glutamate, so G = glycine. 3. Similar sounding names: Some one-letter symbols sound like the amino acid they represent. For example, F = phenylalanine, or W = tryptophan (“twyptophan” as Elmer Fudd would say). 4. Letter close to initial letter: For the remaining amino acids, a oneletter symbol is assigned that is as close in the alphabet as possible to the initial letter of the amino acid, for example, K = lysine. Furthermore, B is assigned to Asx, signifying either aspartic acid or asparagine, Z is assigned to Glx, signifying either glutamic acid or glutamine, and X is assigned to an unidentified amino acid. F. Optical properties of amino acids The α-carbon of an amino acid is attached to four different chemical groups and is, therefore, a chiral or optically active carbon atom. Glycine is the exception because its α-carbon has two hydrogen substituents and, therefore, is optically inactive. Amino acids that have an asymmetric center at the α-carbon can exist in two forms, designated D and L, that are mirror images of each other (Figure 1.8). The two forms in each pair are termed stereoisomers, optical isomers, or enantiomers. All amino acids found in proteins are of the L-configuration. However, D-amino acids are found in some antibiotics and in plant and bacterial cell walls. (See p. 253 for a discussion of D-amino acid metabolism.) Figure 1.7 Abbreviations and symbols for the commonly occurring amino acids. Cysteine = Cys = C Histidine = His = H Isoleucine = Ile = I Methionine = Met = M Serine = Ser = S Valine = Val = V Alanine = Ala = A Glycine = Gly = G Leucine = Leu = L Proline = Pro = P Threonine = Thr = T Arginine = Arg = R (“aRginine”) Asparagine = Asn = N (contains N) Aspartate = Asp = D ("asparDic") Glutamate = Glu = E ("glutEmate") Glutamine = Gln = Q (“Q-tamine”) Phenylalanine = Phe = F (“Fenylalanine”) Tyrosine = Tyr = Y (“tYrosine”) Tryptophan = Trp = W (double ring in the molecule) Aspartate or = Asx = B (near A) asparagine Glutamate or = Glx = Z glutamine Lysine = Lys = K (near L) Undetermined = X amino acid Unique first letter: Most commonly occurring amino acids have priority: Similar sounding names: Letter close to initial letter: 1 2 3 4 Figure 1.8 D and L forms of alanine are mirror images. H3C HOOC D-Alanine H C NH3 + CH3 COOH L-Alanine H C + H3N II. Structure of the Amino Acids 5 168397_P001-012.qxd7.0:02 Protein structure 5-20-04 2010.4.4 9:45 AM Page 5

III. ACIDIC AND BASIC PROPERTIES OF AMINO ACIDS Amino acids in aqueous solution contain weakly acidic α-carboxyl groups and weakly basic α-amino groups. In addition, each of the acidic and basic amino acids contains an ionizable group in its side chain. Thus, both free amino acids and some amino acids combined in peptide linkages can act as buffers. Recall that acids may be defined as proton donors and bases as proton acceptors. Acids (or bases) described as “weak” ionize to only a limited extent. The concentration of protons in aqueous solution is expressed as pH, where pH = log 1/[H+] or –log [H+]. The quantitative relationship between the pH of the solution and concentration of a weak acid (HA) and its con jugate base (A– ) is described by the Henderson-Hasselbalch equation. A. Derivation of the equation Consider the release of a proton by a weak acid represented by HA: HA →← H+ + A– weak proton salt form acid or conjugate base The “salt” or conjugate base, A– , is the ionized form of a weak acid. By definition, the dissociation constant of the acid, Ka, is [Note: The larger the Ka, the stronger the acid, because most of the HA has dissociated into H+ and A– . Conversely, the smaller the Ka, the less acid has dissociated and, therefore, the weaker the acid.] By solving for the [H+] in the above equation, taking the logarithm of both sides of the equation, multiplying both sides of the equation by –1, and substituting pH = –log [H+ ] and pKa = –log Ka, we obtain the Henderson-Hasselbalch equation: B. Buffers A buffer is a solution that resists change in pH following the addition of an acid or base. A buffer can be created by mixing a weak acid (HA) with its conjugate base (A– ). If an acid such as HCl is then added to such a solution, A– can neutralize it, in the process being converted to HA. If a base is added, HA can neutralize it, in the process being converted to A– . Maximum buffering capacity occurs at a pH equal to the pKa, but a conjugate acid/base pair can still serve as an effective buffer when the pH of a solution is within approximately ±1 pH unit of the pKa. If the 6 1. Amino Acids Figure 1.9 Titration curve of acetic acid. 03 4567 0 0.5 1.0 pH Equivalents OH– added Buffer region CH3COOH CH3COO– H20 FORM I (acetic acid, HA) FORM II (acetate, A– ) [I] = [II] pKa = 4.8 OH– H+ [I] > [II] [II] > [I] pH pKa log [A–] [HA] + Ka [A–] [HA] [H+] 168397_P001-012.qxd7.0:02 Protein structure 5-20-04 2010.4.4 9:45 AM Page 6

amounts of HA and A– are equal, the pH is equal to the pKa. As shown in Figure 1.9, a solution containing acetic acid (HA = CH3 –COOH) and acetate (A– = CH3 –COO– ) with a pKa of 4.8 resists a change in pH from pH 3.8 to 5.8, with maximum buffering at pH 4.8. At pH values less than the pKa, the protonated acid form (CH3 – COOH) is the predominant species. At pH values greater than the pKa, the deprotonated base form (CH3 – COO– ) is the predominant species in solution. C. Titration of an amino acid 1. Dissociation of the carboxyl group: The titration curve of an amino acid can be analyzed in the same way as described for acetic acid. Consider alanine, for example, which contains both an α-carboxyl and an α-amino group. At a low (acidic) pH, both of these groups are proton ated (shown in Figure 1.10). As the pH of the solution is raised, the – COOH group of Form I can dissociate by donating a proton to the medium. The release of a proton results in the formation of the carboxylate group, – COO– . This structure is shown as Form II, which is the dipolar form of the molecule (see Figure 1.10). This form, also called a zwitterion, is the isoelectric form of alanine, that is, it has an overall (net) charge of zero. 2. Application of the Henderson-Hasselbalch equation: The dissociation constant of the carboxyl group of an amino acid is called K1, rather than Ka, because the molecule contains a second titratable group. The Henderson-Hasselbalch equation can be used to analyze the dissociation of the carboxyl group of alanine in the same way as described for acetic acid: where I is the fully protonated form of alanine, and II is the isoelectric form of alanine (see Figure 1.10). This equation can be re arranged and converted to its logarithmic form to yield: III. Acidic and Basic Properties of Amino Acids 7 Figure 1.10 Ionic forms of alanine in acidic, neutral, and basic solutions. COOH FORM I Alanine in acid solution (pH less than 2) Net charge = +1 CH3 C +H3N H COO– FORM II Alanine in neutral solution (pH approximately 6) Net charge = 0 (isoelectric form) CH3 C +H3N H COO– FORM III Alanine in basic solution (pH greater than 10) Net charge = –1 CH3 H2N C H OH H20 – H+ OH H20 – H+ pK1 = 2.3 pK2 = 9.1 K1 [II] [I] [H+] 168397_P001-012.qxd7.0:02 Protein structure 5-20-04 2010.4.4 9:45 AM Page 7

3. Dissociation of the amino group: The second titratable group of alanine is the amino (– NH3 +) group shown in Figure 1.10. This is a much weaker acid than the – COOH group and, therefore, has a much smaller dissociation constant, K2. [Note: Its pKa is therefore larger.] Release of a proton from the protonated amino group of Form II results in the fully deprotonated form of alanine, Form III (see Figure 1.10). 4. pKs of alanine: The sequential dissociation of protons from the carboxyl and amino groups of alanine is summarized in Figure 1.10. Each titratable group has a pKa that is numer ically equal to the pH at which exactly one half of the protons have been removed from that group. The pKa for the most acidic group (–COOH) is pK1, whereas the pKa for the next most acidic group (– NH3 +) is pK2. 5. Titration curve of alanine: By applying the Hender sonHasselbalch equation to each dissociable acidic group, it is possible to calculate the complete titration curve of a weak acid. Figure 1.11 shows the change in pH that occurs during the addition of base to the fully protonated form of alanine (I) to produce the completely deprotonated form (III). Note the following: a. Buffer pairs: The – COOH/– COO– pair can serve as a buffer in the pH region around pK1, and the – NH3 +/– NH2 pair can buffer in the region around pK2. b. When pH = pK: When the pH is equal to pK1 (2.3), equal amounts of Forms I and II of alanine exist in solution. When the pH is equal to pK2 (9.1), equal amounts of Forms II and III are present in solution. c. Isoelectric point: At neutral pH, alanine exists predominantly as the dipolar Form II in which the amino and carboxyl groups are ionized, but the net charge is zero. The isoelectric point (pI) is the pH at which an amino acid is electrically neutral, that is, in which the sum of the positive charges equals the sum of the negative charges. For an amino acid, such as alanine, that has only two dissociable hydrogens (one from the α-carboxyl and one from the α-amino group), the pI is the average of pK1 and pK2 (pI = [2.3 + 9.1]/2 = 5.7, see Figure 1.11). The pI is thus midway between pK1 (2.3) and pK2 (9.1). pI corresponds to the pH at which the Form II (with a net charge of zero) predominates, and at which there are also equal amounts of Forms I (net charge of +1) and III (net charge of –1). 8 1. Amino Acids Figure 1.11 The titration curve of alanine. 0 2 4 6 8 10 0 1.0 2.0 pH Equivalents OH– added pK2 = 9.1 [II] = [III] 0.5 1.5 pK1 = 2.3 [I] = [II] pI = 5.7 Region of buffering Region of buffering 0 2 4 0 p [II] = [III] Region of buffering 6 8 10 pH pK2 = 9. = 2.3 p COOH FORM I CH3 C +H3N H COO– FORM III CH3 H2N C H COO– FORM II CH3 C +H3N H pH pK1 log [II] [I] + 168397_P001-012.qxd7.0:02 Protein structure 5-20-04 2010.4.4 9:45 AM Page 8

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