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CHE 120 - Introduction to Organic Chemistry - Textbook

Opening Essay

The 1923 Nobel Prize in Medicine or Physiology was awarded to Frederick Grant Banting and John James Richard Macleod for their discovery of the protein insulin. In 1958, the Nobel Prize in Chemistry was awarded to Frederick Sanger for his discoveries concerning the structure of proteins and, in particular, the structure of insulin. What is so important about insulin that two Nobel Prizes have been awarded for work on this protein?

Insulin is a hormone that is synthesized in the pancreas. (For more information about hormones, see Chapter 7 "Lipids", Section 7.4 "Steroids".) Insulin stimulates the transport of glucose into cells throughout the body and the storage of glucose as glycogen. People with diabetes do not produce insulin or use it properly. The isolation of insulin in 1921 led to the first effective treatment for these individuals.

Figure 8.1 An Insulin Pump

Proteins may be defined as compounds of high molar mass consisting largely or entirely of chains of amino acids. Their masses range from several thousand to several million daltons (Da). In addition to carbon, hydrogen, and oxygen atoms, all proteins contain nitrogen and sulfur atoms, and many also contain phosphorus atoms and traces of other elements. Proteins serve a variety of roles in living organisms and are often classified by these biological roles, which are summarized in Table 8.1 "Classification of Proteins by Biological Function". Muscle tissue is largely protein, as are skin and hair. Proteins are present in the blood, in the brain, and even in tooth enamel. Each type of cell in our bodies makes its own specialized proteins, as well as proteins common to all or most cells.

Note

The dalton is a unit of mass used by biochemists and biologists. It is equivalent to the atomic mass unit. A 30,000 Da protein has a molar mass of 30,000 u.

Table 8.1 Classification of Proteins by Biological Function

Classification Biological Function Example
enzymes accelerate biological reactions α-Amylase catalyzes the hydrolysis of starch and glycogen.
structural provide strength and structure Keratin is the primary protein of hair and wool.
contractile muscle contraction; cell division Myosin is one protein needed for the contraction of muscles.
transport transport substances from one place to another Hemoglobin transports oxygen from the lungs throughout the body.
regulatory regulate the functioning of other proteins Insulin regulates the activity of specific enzymes in the body.
storage provide storage of essential nutrients Ovalbumin stores amino acids in the egg white that will be used by the developing bird.
protection protect cells or the organism from foreign substances Immunoglobulins recognize and breakdown foreign molecules.

We begin our study of proteins by looking at the properties and reactions of amino acids, which is followed by a discussion of how amino acids link covalently to form peptides and proteins. We end the chapter with a discussion of enzymes—the proteins that act as catalysts in the body.

8.1 Properties of Amino Acids

Learning Objective

  1. Recognize amino acids and classify them based on the characteristics of their side chains.

The proteins in all living species, from bacteria to humans, are constructed from the same set of 20 amino acids, so called because each contains an amino group attached to a carboxylic acid. (For more information about amino groups, see Chapter 4 "Carboxylic Acids, Esters", Section 4.1 "Functional Groups of the Carboxylic Acids and Their Derivatives".) The amino acids in proteins are α-amino acids, which means the amino group is attached to the α-carbon of the carboxylic acid. (For more information about the α-carbon, see Chapter 4 "Carboxylic Acids, Esters", Section 4.2 "Carboxylic Acids: Structures and Names".) Humans can synthesize only about half of the needed amino acids; the remainder must be obtained from the diet and are known as essential amino acids.

Note

Two more amino acids have been found in limited quantities in proteins. Selenocysteine was discovered in 1986, while pyrrolysine was discovered in 2002.

The amino acids are colorless, nonvolatile, crystalline solids, melting and decomposing at temperatures above 200°C. These melting temperatures are more like those of inorganic salts than those of amines or organic acids and indicate that the structures of the amino acids in the solid state and in neutral solution are best represented as having both a negatively charged group and a positively charged group. Such a species is known as a zwitterion.

Classification

In addition to the amino and carboxyl groups, amino acids have a side chain or R group attached to the α-carbon. Each amino acid has unique characteristics arising from the size, shape, solubility, and ionization properties of its R group. As a result, the side chains of amino acids exert a profound effect on the structure and biological activity of proteins. Although amino acids can be classified in various ways, one common approach is to classify them according to whether the functional group on the side chain at neutral pH is nonpolar, polar but uncharged, negatively charged, or positively charged. The structures and names of the 20 amino acids, their one- and three-letter abbreviations, and some of their distinctive features are given in Table 8.2 "Common Amino Acids Found in Proteins".

Table 8.2 Common Amino Acids Found in Proteins

Amino acids with a nonpolar R group
Common Name Abbreviation Structural Formula (at pH 6) Molar Mass Distinctive Feature
glycine gly (G) 75 the only amino acid lacking a chiral carbon
alanine ala (A) 89
valine val (V) 117 a branched-chain amino acid
leucine leu (L) 131 a branched-chain amino acid
isoleucine ile (I) 131 an essential amino acid because most animals cannot synthesize branched-chain amino acids
phenylalanine phe (F) 165 also classified as an aromatic amino acid
tryptophan trp (W) 204 also classified as an aromatic amino acid
methionine met (M) 149 side chain functions as a methyl group donor
proline pro (P) 115 contains a secondary amine group; referred to as an α-imino acid
Amino acids with a polar but neutral R group
Common Name Abbreviation Structural Formula (at pH 6) Molar Mass Distinctive Feature
serine ser (S) 75 found at the active site of many enzymes
threonine thr (T) 119 named for its similarity to the sugar threose
cysteine cys (C) 121 oxidation of two cysteine molecules yields cystine
tyrosine tyr (Y) 181 also classified as an aromatic amino acid
asparagine asn (N) 132 the amide of aspartic acid
glutamine gln (Q) 146 the amide of glutamic acid
Amino acids with a negatively charged R group
Common Name Abbreviation Structural Formula (at pH 6) Molar Mass Distinctive Feature
aspartic acid asp (D) 132 tcarboxyl groups are ionized at physiological pH; also known as aspartat
glutamic acid glu (E) 146 arboxyl groups are ionized at physiological pH; also known as glutamate
Amino acids with a positively charged R group
Common Name Abbreviation Structural Formula (at pH 6) Molar Mass Distinctive Feature
histidine his (H) 155 the only amino acid whose R group has a pKa (6.0) near physiological pH
lysine lys (K) 147
arginine arg (R) 175 almost as strong a base as sodium hydroxide

The first amino acid to be isolated was asparagine in 1806. It was obtained from protein found in asparagus juice (hence the name). Glycine, the major amino acid found in gelatin, was named for its sweet taste (Greek glykys, meaning “sweet”). In some cases an amino acid found in a protein is actually a derivative of one of the common 20 amino acids (one such derivative is hydroxyproline). The modification occurs after the amino acid has been assembled into a protein.

Configuration

Notice in Table 8.2 "Common Amino Acids Found in Proteins" that glycine is the only amino acid whose α-carbon is not chiral. Therefore, with the exception of glycine, the amino acids could theoretically exist in either the D- or the L-enantiomeric form and rotate plane-polarized light. As with sugars, chemists use glyceraldehyde as the reference compound for the assignment of configuration to amino acids. (For more information about stereoisomers and configuration, see Chapter 6 "Carbohydrates", Section 6.2 "Classes of Monosaccharides".) Its structure closely resembles an amino acid structure except that in the latter, an amino group takes the place of the OH group on the chiral carbon of the sugar.

We learned in Chapter 6 "Carbohydrates" that all naturally occurring sugars belong to the D series. It is interesting, therefore, that nearly all known plant and animal proteins are composed entirely of L-amino acids. However, certain bacteria contain D-amino acids in their cell walls, and several antibiotics (e.g., actinomycin D and the gramicidins) contain varying amounts of D-leucine, D-phenylalanine, and D-valine.

Concept Review Exercises

1. What is the general structure of an α-amino acid?

2. Identify the amino acid that fits each description.

a. also known as aspartate

b. almost as strong a base as sodium hydroxide

c. does not have a chiral carbon

Answers

1.

 

2.

a. aspartic acid

b. arginine

c. glycine

Key Takeaways

  • Amino acids can be classified based on the characteristics of their distinctive side chains as nonpolar, polar but uncharged, negatively charged, or positively charged.
  • The amino acids found in proteins are L-amino acids.

Exercises

1. Write the side chain of each amino acid.

a. serine

b. arginine

c. phenylalanine

 

2. Write the side chain of each amino acid.

a. aspartic acid

b. methionine

c. valine

 

3. Draw the structure for each amino acid.

a. alanine

b. cysteine

c. histidine

 

4. Draw the structure for each amino acid.

a. threonine

b. glutamic acid

c. leucine

 

5. Identify an amino acid whose side chain contains a(n)

a. amide functional group.

b. aromatic ring.

c. carboxyl group.

 

6. Identify an amino acid whose side chain contains a(n)

a. OH group

b. branched chain

c. amino group

Answers

1.

a.                              CH2OH

b.

c.

3.

a.

b.

c.

5.

a. asparagine or glutamine

b. phenylalanine, tyrosine, or tryptophan

c. aspartic acid or glutamic acid

8.2 Reactions of Amino Acids

Learning Objective

  1. Explain how an amino acid can act as both an acid and a base.

The structure of an amino acid allows it to act as both an acid and a base. An amino acid has this ability because at a certain pH value (different for each amino acid) nearly all the amino acid molecules exist as zwitterions. If acid is added to a solution containing the zwitterion, the carboxylate group captures a hydrogen (H+) ion, and the amino acid becomes positively charged. If base is added, ion removal of the H+ ion from the amino group of the zwitterion produces a negatively charged amino acid. In both circumstances, the amino acid acts to maintain the pH of the system—that is, to remove the added acid (H+) or base (OH) from solution.

Example 1

  1. Draw the structure for the anion formed when glycine (at neutral pH) reacts with a base.
  2. Draw the structure for the cation formed when glycine (at neutral pH) reacts with an acid.

Solution

  1. The base removes H+ from the protonated amine group.

  2. The acid adds H+ to the carboxylate group.

Skill-Building Exercise

  1. Draw the structure for the cation formed when valine (at neutral pH) reacts with an acid.

  2. Draw the structure for the anion formed when valine (at neutral pH) reacts with a base.

The particular pH at which a given amino acid exists in solution as a zwitterion is called the isoelectric point (pI). At its pI, the positive and negative charges on the amino acid balance, and the molecule as a whole is electrically neutral. The amino acids whose side chains are always neutral have isoelectric points ranging from 5.0 to 6.5. The basic amino acids (which have positively charged side chains at neutral pH) have relatively high pIs. Acidic amino acids (which have negatively charged side chains at neutral pH) have quite low pIs (Table 8.3 "pIs of Some Representative Amino Acids").

Table 8.3 pIs of Some Representative Amino Acids

Amino Acid Classification pl
alanine nonpolar 6.0
valine nonpolar 6.0
serine polar, uncharged 5.7
threonine polar, uncharged 6.5
arginine positively charged (basic) 10.8
histidine positively charged (basic) 7.6
lysine positively charged (basic) 9.8
aspartic acid negatively charged (acidic) 3.0
glutamic acid negatively charged (acidic) 3.2

Amino acids undergo reactions characteristic of carboxylic acids and amines. The reactivity of these functional groups is particularly important in linking amino acids together to form peptides and proteins, as you will see later in this chapter. Simple chemical tests that are used to detect amino acids take advantage of the reactivity of these functional groups. An example is the ninhydrin test in which the amine functional group of α-amino acids reacts with ninhydrin to form purple-colored compounds. Ninhydrin is used to detect fingerprints because it reacts with amino acids from the proteins in skin cells transferred to the surface by the individual leaving the fingerprint.

Concept Review Exercises

1. Define each term.

a. zwitterion

b. isoelectric point

 

2. Draw the structure for the anion formed when alanine (at neutral pH) reacts with a base.

 

3. Draw the structure for the cation formed when alanine (at neutral pH) reacts with an acid.

Answers

1.

a. an electrically neutral compound that contains both negatively and positively charged groups

b. the pH at which a given amino acid exists in solution as a zwitterion

 

2.

3.

Key Takeaways

  • Amino acids can act as both an acid and a base due to the presence of the amino and carboxyl functional groups.
  • The pH at which a given amino acid exists in solution as a zwitterion is called the isoelectric point (pI).

Exercises

1. Draw the structure of leucine and determine the charge on the molecule in a(n)

a. acidic solution (pH = 1)

b. neutral solution (pH = 7)

c. a basic solution (pH = 11)

 

2. Draw the structure of isoleucine and determine the charge on the molecule in a(n)

a. acidic solution (pH = 1)

b. neutral solution (pH = 7)

c. basic solution (pH = 11)

Answer

1.

a.

b.

c.

8.3 Peptides

Learning Objectives

  1. Explain how a peptide is formed from individual amino acids.
  2. Explain why the sequence of amino acids in a protein is important.

Two or more amino acids can join together into chains called peptides. In Chapter 5 "Amines and Amides", Section 5.6 "Formation of Amides", we discussed the reaction between ammonia and a carboxylic acid to form an amide. In a similar reaction, the amino group on one amino acid molecule reacts with the carboxyl group on another, releasing a molecule of water and forming an amide linkage:

An amide bond joining two amino acid units is called a peptide bond. Note that the product molecule still has a reactive amino group on the left and a reactive carboxyl group on the right. These can react with additional amino acids to lengthen the peptide. The process can continue until thousands of units have joined, resulting in large proteins.

A chain consisting of only two amino acid units is called a dipeptide; a chain consisting of three is a tripeptide. By convention, peptide and protein structures are depicted with the amino acid whose amino group is free (the N-terminal end) on the left and the amino acid with a free carboxyl group (the C-terminal end) to the right.

The general term peptide refers to an amino acid chain of unspecified length. However, chains of about 50 amino acids or more are usually called proteins or polypeptides. In its physiologically active form, a protein may be composed of one or more polypeptide chains.

For peptides and proteins to be physiologically active, it is not enough that they incorporate certain amounts of specific amino acids. The order, or sequence, in which the amino acids are connected is also of critical importance. Bradykinin is a nine-amino acid peptide produced in the blood that has the following amino acid sequence:

arg-pro-pro-gly-phe-ser-pro-phe-arg

This peptide lowers blood pressure, stimulates smooth muscle tissue, increases capillary permeability, and causes pain. When the order of amino acids in bradykinin is reversed,

arg-phe-pro-ser-phe-gly-pro-pro-arg

the peptide resulting from this synthesis shows none of the activity of bradykinin.

Just as millions of different words are spelled with our 26-letter English alphabet, millions of different proteins are made with the 20 common amino acids. However, just as the English alphabet can be used to write gibberish, amino acids can be put together in the wrong sequence to produce nonfunctional proteins. Although the correct sequence is ordinarily of utmost importance, it is not always absolutely required. Just as you can sometimes make sense of incorrectly spelled English words, a protein with a small percentage of “incorrect” amino acids may continue to function. However, it rarely functions as well as a protein having the correct sequence. There are also instances in which seemingly minor errors of sequence have disastrous effects. For example, in some people, every molecule of hemoglobin (a protein in the blood that transports oxygen) has a single incorrect amino acid unit out of about 300 (a single valine replaces a glutamic acid). That “minor” error is responsible for sickle cell anemia, an inherited condition that usually is fatal.

Concept Review Exercises

  1. Distinguish between the N-terminal amino acid and the C-terminal amino acid of a peptide or protein.

  2. Describe the difference between an amino acid and a peptide.

  3. Amino acid units in a protein are connected by peptide bonds. What is another name for the functional group linking the amino acids?

Answers

  1. The N-terminal end is the end of a peptide or protein whose amino group is free (not involved in the formation of a peptide bond), while the C-terminal end has a free carboxyl group.

  2. A peptide is composed of two or more amino acids. Amino acids are the building blocks of peptides.

  3. amide bond

Key Takeaways

  • The amino group of one amino acid can react with the carboxyl group on another amino acid to form a peptide bond that links the two amino acids together. Additional amino acids can be added on through the formation of addition peptide (amide) bonds.
  • A sequence of amino acids in a peptide or protein is written with the N-terminal amino acid first and the C-terminal amino acid at the end (writing left to right).

Exercises

1. Draw the structure for each peptide.

a. gly-val

b. val-gly

 

2. Draw the structure for cys-val-ala.

 

3. Identify the C- and N-terminal amino acids for the peptide lys-val-phe-gly-arg-cys.

 

4. Identify the C- and N-terminal amino acids for the peptide asp-arg-val-tyr-ile-his-pro-phe.

Answers

1.

a.

b.

 

3. C-terminal amino acid: cys; N-terminal amino acid: lys