Organic Chemistry I & II
Organic Chemistry I & II

Organic Chemistry I & II

Lead Author(s): Steven Forsey

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Organic Chemistry I & II is designed for instructors who want an active, dynamic, and understandable approach to support their own efforts in the classroom. This ever-evolving textbook includes auto-graded questions, videos and approachable language in order to make difficult concepts easier to understand and implement.

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Steven Forsey, “Organic Chemistry”, Only one edition needed

Up to 40-60% more affordable

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Carey & Giuliano, “Organic Chemistry”, 10th Edition

$219

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Solomons et al., “Organic Chemistry”, 12th Edition

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Always up-to-date content, constantly revised by community of professors

Constantly revised and updated by a community of professors with the latest content

Top Hat

Steven Forsey, “Organic Chemistry”, Only one edition needed

McGraw-Hill

Carey & Giuliano, “Organic Chemistry”, 10th Edition

Wiley

Solomons et al., “Organic Chemistry”, 12th Edition

Wiley

David R. Klein, “Organic Chemistry”, 3rd Edition

In-book Interactivity

Includes embedded multi-media files and integrated software to enhance visual presentation of concepts directly in textbook

Top Hat

Steven Forsey, “Organic Chemistry”, Only one edition needed

McGraw-Hill

Carey & Giuliano, “Organic Chemistry”, 10th Edition

Wiley

Solomons et al., “Organic Chemistry”, 12th Edition

Wiley

David R. Klein, “Organic Chemistry”, 3rd Edition

Customizable

Ability to revise, adjust and adapt content to meet needs of course and instructor

Top Hat

Steven Forsey, “Organic Chemistry”, Only one edition needed

McGraw-Hill

Carey & Giuliano, “Organic Chemistry”, 10th Edition

Wiley

Solomons et al., “Organic Chemistry”, 12th Edition

Wiley

David R. Klein, “Organic Chemistry”, 3rd Edition

All-in-one Platform

Access to additional questions, test banks, and slides available within one platform

Top Hat

Steven Forsey, “Organic Chemistry”, Only one edition needed

McGraw-Hill

Carey & Giuliano, “Organic Chemistry”, 10th Edition

Wiley

Solomons et al., “Organic Chemistry”, 12th Edition

Wiley

David R. Klein, “Organic Chemistry”, 3rd Edition

About this textbook

Lead Authors

Dr. Steven Forsey, Ph.D.University of Waterloo

Steven Forsey is currently a Professor at University of Waterloo, teaching a variety of organic chemistry courses to Chemistry, Science, Chemical Engineering, Nanotechnology and distance education students. He received his Ph.D. (2004) for Synthetic Organic Chemistry from University of Waterloo, Ontario. He is a recipient of the Excellence of Science Teaching Award and has acted as the Teaching Fellow for the Department of Chemistry since 2016.

Contributing Authors

Felix NgassaGrand Valley State University

Neil GargUCLA

Jennifer ChaytorSaginaw Valley State University

Greg DomskiAugustana College

Christian E. MaduCollin Community College

Christopher NicholsonUniversity of West Florida

Franklin OwEast Los Angeles College, UCLA

Robert S. PhillipsUniversity of Georgia

Grigoriy SeredaUniversity of South Dakota

Simon E. LopezUniversity of Florida

Brannon McCulloughNorthern Arizona University

Jason JonesKennesaw State University

José BoquinAugustana College

Stephanie BrouetSaginaw Valley State University

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Chapter 28: Biomolecules

An illustration of the double helix structure of DNA, one of life's most important molecules. ​[1]


Table of Contents

28.0 Introduction

Chemistry in biology starts by understanding the basic structures and functions of four major classes of organic molecules or biomolecules: carbohydrates, lipids, nucleic acids, and proteins. These molecules make up nearly all (~90%) of the dry weight of the smallest functional unit of biology, the cell. The rest of a cell’s mass is primarily water (> 70%), but also contains inorganic ions, metabolites, and a vast array of interesting small molecules that are biologically important for regulating the activity of a cell and the overall physiology of an organism. However, fundamental biological processes can be described generally by these four major classes of biomolecules. In this chapter, we will cover the basic structures and components of these molecules, how they are generally synthesized in a cell, what their primary functions are in the cell, and why they are important for biology.

28.0.1 Water

The chemistry of all these biomolecules occurs in an aqueous environment, with many other molecules and inorganic ions. As the solvent for biological systems, water and the abundance of molecules and inorganic ions it carries, regulates the chemistry of biomolecules. The activity of all biomolecules depends on its attraction (or lack thereof) to water through hydrogen bonding and the polarity of water. Polarity exists when the electron density is greater on one side of the molecule than another. Polarity in a molecule occurs when the dipole moments created by polar bonds do not cancel. Hydrogen bonding and polarity allow molecules to strongly interact with each other. Therefore, biomolecules with these chemical properties interact strongly with water and are called hydrophilic (attracted to water), whereas other molecules or other regions of the same molecule that do not have these properties will tend to minimize their interaction with water and are called hydrophobic (fear of water). A biomolecule’s interaction (or lack thereof) with water or other aqueous molecules promotes it to adopt the proper structure and dynamics critical to function. For instance, a structurally abnormal protein will make the protein dysfunctional and can cause diseases known as proteopathies, such as Creutzfeldt–Jakob, Alzheimer’s, and Parkinson’s disease. The formation and functions of larger biological structures, like cell membranes, are also dependent on differences in hydrophobicity. In short, biology as we know, it would not exist without water and its unique chemical properties. (For more information on hydrogen bonding, see Chapter 1: Structure and Bonding, Section 3: Intermolecular Forces.)

28.0.2 Polymerization

Polymers are abundant in biology and serve many important roles. Polymers are central to organizing and transferring biological information as well as forming the larger structures necessary for a cell’s function. Many biomolecules are very large macromolecules, synthesized by polymerization from smaller subunits called monomers. These large macromolecules will then often assemble with other macromolecules to form a functional unit like the ribosome, which is composed of ribonucleic acid (RNA) polymers and amino acid polymers, known as proteins, and is responsible for making proteins from information encoded in messenger RNA. Macromolecules can also act as monomers themselves and assemble together to form larger polymers like the protein tubulin, which forms microtubules, and actin, which forms microfilaments that make up the skeletal structure of the cell. The genetic information of a skin cell that is 30 μm wide is encoded in a nucleic acid polymer called deoxyribonucleic acid (DNA), which would be about a 3 cm long molecule when stretched out, or ~1,000 times longer than the cell. Polymerization allows for the structural organization necessary for the central dogma of molecular biology, which describes the flow of genetic information within a biological system. It is important to keep in mind that specific polymerization and other types of molecular self-assembly reactions serve a set of complex and diverse functions that are the foundation of biology. In this chapter, we will focus on the biomolecules that make up these polymers and other large assemblies.

28.1 Carbohydrates

Carbohydrates perform many essential functions for living organisms, from storing energy (starch and glycogen) to creating the structure of tissues (cellulose in plants and chitin in arthropods). The 5-carbon monosaccharide ribose is the central component of RNA (DNA uses deoxyribose) and many organic non-protein coenzymes that are essential for the chemical activity of many biological enzymes like adenosine triphosphate (ATP), flavin adenine dinucleotide (FAD), nicotinamide adenine dinucleotide (NAD+), and coenzyme A (CoA).  

Carbohydrates are composed primarily of carbon (C), hydrogen (H), and oxygen (O) atoms, usually with twice as many H than O (as in water), and have an empirical formula that can be written as Cm(H2O)n. Therefore, carbohydrates appear to be carbon hydrates. However, these molecules are structurally classified as polyhydroxylated aldehydes or ketones and commonly referred to as sugars or saccharides (Greek for “sugar”).  

Q28.1 - Level 1

Carbohydrates _______\_\_\_\_\_\_\_.

A

have long hydrocarbon chains that are not soluble in water.

B

are produced through the formation of peptide (amide) bonds.

C

are composed of nucleobases (nitrogenous bases) linked to phosphorylated sugars.

D

have a carbon skeleton with many hydroxyl (OH) groups.


28.1.1 Classification

Carbohydrates are divided into four chemical groups based on the number of simple sugar subunits: monosaccharides, disaccharides, oligosaccharides, and polysaccharides. Monosaccharides are simple sugars that cannot be broken down into smaller components by simple non-enzymatic hydrolysis, whereas the other groups are composed of monosaccharides covalently attached to each other through a glycosidic bond. The reduction of sugars to form alditols is covered in Section 22.5.1 Reduction to Alcohols (Review Section 14.4.5) and the oxidation of sugars to form either aldonic (oxidation of C1 to a carboxylic acid), alduronic (oxidation of C6 to a carboxylic acid) or adaric (oxidation of both C1 and C6) acids is covered in Section 22.5.6: Aldehyde Oxidations (Figure 28.1). One glycosidic bond between two monosaccharides forms a disaccharide. More bonds between monosaccharide subunits (~up to 10’s) form oligosaccharides or even more (~100’s or more) form polysaccharides. Monosaccharides and disaccharides are commonly referred to as simple sugars, whereas oligosaccharides and polysaccharides are referred to as complex carbohydrates. 

Figure 28.1. Sugar reduction and oxidation reactions. D-glucose, a hexose sugar, can be reduced to D-glucitol (an alditol) or oxidized to form either D-gluconic acid (an aldonic acid) or D-glucaric acid (an aldaric acid).​​​


The fundamental units of carbohydrates are monosaccharides, which differ in the location of the carbonyl group, number of carbon atoms, and stereochemistry. A monosaccharide is either an aldehyde-containing aldose or a ketone-containing ketose, where the -ose suffix designates it as a carbohydrate. The number of carbon atoms is indicated by a numerical prefix (tri-, tetr-, pent-, hex-, hept-, etc.). Most common are pentoses and hexoses.  

Figure 28.2. D-aldoses​​


Question 28.2

Draw D-(+)-galactose. 

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28.1.2 Stereochemistry

To represent the stereochemistry at chiral centers, Fischer projections were developed in the study of carbohydrates. Bonds shown horizontally are coming out of the plane while bonds shown vertically are going into the plane. To determine the chirality (R or S) of a carbon in a carbohydrate using Fischer projections refer to Chapter 6.

Figure 28.3. Carbon numbering for aldoses and ketoses. Fischer projections of D-fructose and D-glucose. D-fructose has chiral centers at C3, C4, and C5. D-Glucose has chiral centers at C2, C3, C4, and C5.​​​


Each monosaccharide can also be characterized by the orientation of the hydroxyl group of the asymmetric carbon furthest from the carbonyl group, which is the highest numbered chiral carbon. The D (dextrorotatory) enantiomer indicates that the hydroxyl group is on the right side of the drawing while the L (levorotatory) enantiomer has the hydroxyl group on the left side of the drawing. Only D enantiomers are found naturally. The D and L notations do not indicate the direction the molecule will rotate plane-polarized light. This correlation of the D and L notation and polarized light rotation is only true for glyceraldehyde that has only one chiral center. Glyceraldehyde, which has the correct optical rotation, was the first carbohydrate to be studied and, subsequently, other natural carbohydrates with the same asymmetric carbon furthest from the carbonyl group also were assigned the common notation of D (or L). To designate the optical rotation, a (+) or (‒) sign is placed after the D or L notation. An L isomer is a mirror image enantiomer of its D isomer with the same name (Figure 28.5). If two disastereomers differ in configuration at only one stereogenic center, then they are called epimers. For example, D-erythrose and D-threose are C2 epimers and D-glucose and D-galactose are C4 epimers. 

Figure 28.4. Two-carbon epimers (erythrose and threose) and four-carbon epimers (glucose and galactose).​​



Figure 28.5. The D and L enantiomers of tagatose.​


Q28.3 - Level 2

How many stereoisomers exist for aldohexoses?


28.1.3 Anomers and Glycosides

Intermolecular cyclization of monosaccharides can occur when carbonyl groups of aldehydes and ketones undergo a rapid, reversible nucleophilic addition reaction with an alcohol group to form a cyclic hemiacetal. For more on this mechanism review Section 22.5.5: Acetal and Hemiacetal Formation. Induced strain during the formation of five- and six-membered rings is relatively low, making these cyclic hemiacetals particularly stable and, therefore, capable of existing in equilibrium with open-chain forms. A five-membered hemiacetal is called a furanose and a six-membered hemiacetal is called a pyranose. These names are derived from the 5- and 6-membered cyclic ethers shown in Figure 28.6.

Figure 28.6. Pyran and furan ring projections and carbon numbering.​​


When an open-chain monosaccharide cyclizes to form the hemiacetal, a new stereogenic center at carbon 1 is generated. Because this type of diastereomer formation is unique to sugars, monosaccharide diastereomers that differ at carbon 1 are called anomers. The new stereocenter is called the anomeric carbon. As seen in the mechanism given in Figure 28.7, nucleophilic attack of the hydroxyl group on the carbonyl carbon produces an ether and an alcohol group in either the axial or equatorial position. If the hydroxyl group on the anomeric carbon is in a trans conformation to the group (C or OH) on the chiral carbon furthest away in the ring (the axial position for a pyranose ring), then the molecule is the α anomer. Conversely, the β anomer has the hydroxyl group in a cis conformation to the to the furthest chiral carbon group (the equatorial position for a pyranose). 

Figure 28.7a. Mechanism of cyclization reaction and equilibrium.


Figure 28.7b. Anomeric carbon of the hemiacetal shown as a mixture of alpha an beta isomers.

The cyclic anomers often exist in an equilibrium with the open-chain aldehyde (or ketone). This open chain form can cyclize to form the other anomer. Mutarotation is a change in the optical rotation due to this equilibrium between anomers. The optical rotation depends on the relative ratio of each anomer. Mutarotation often occurs in an aqueous environment where cyclization is reversible as both anomers reach equilibrium, which can be catalyzed by either an acid or base.

28.8.png
Figure 28.8. Mutarotation​​


The chair conformation of the cyclic hemiacetal can be drawn in different ways to help in the drawing and visualization of the molecules. Figure 28.9 shows D-glucopyranose as the chair conformation, then redrawn as Fischer, Haworth, and Mills projections.

Figure 28.9. D-Glucopyranose: chair conformation, Haworth and Mills projections. Carbons are numbered.​​​

The Haworth projection is widely used because it simplifies the drawing, especially for polysaccharides. To convert the open-chain Fischer projection to a Haworth projection, rotate the Fischer projection clockwise until the aldehyde or ketone is horizontal as shown in Figure 28.10. By doing this rotation, atoms or groups on the right side of the Fischer projection are pointing down and atoms or groups on the left side of the Fischer projection point up. Note the term hemiacetal is a general term that can be used for both aldehyde and ketone ring formation. The hemiketal is specific for ketone cyclization. Thus, the cyclic form of fructose can be called either a hemiacetal (general) or, more specifically, a hemiketal.

Figure 28.10. Anomer pyranose formation of D-glucopyranose.


Figure 28.11. Anomer furanose formation of D-fructose.​​

Monosaccharides can form either a six- or five-membered cyclic furanose or six-membered cyclic pyranose ring. Fructose found in the the disaccharide sucrose, it is in the furanose form. In solution, the open-chain structure of D-Fructose rapidly equilibrates to a 68:32 ratio of D-fructopyranose and D-Fructofuranose (Figure 28.12) fructofuranose.

Figure 28.12. Equilibrium pyranose and furanose cyclization reactions for D-fructose.​​


Question 28.4

Draw α-D-fructofuranose.  

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Disaccharides contain a glycosidic bond between either an α or β anomeric carbon of one hemiacetal sugar and the hydroxyl group on any carbon of another (Figure 28.13). Maltose and cellobiose are disaccharides of glucopyranose, with a carbon 1→4 bond produced by the partial hydrolysis of starch and cellulose, respectively. However, maltose contains an α(1→4) glycosidic bond, whereas cellobiose contains a β(1→4) glycosidic bond. This difference makes maltose easily digested by humans and fermented by yeast and cellobiose not. Both maltose and cellobiose are reducing sugars; they have an unbound anomeric carbon that is in equilibrium with its aldehyde form and, therefore, also exhibits mutarotation. Like cellobiose, lactose is another disaccharide with a β(1→4) glycosidic bond that reduces and exhibits mutarotation but is instead between glucose and galactose. Not all disaccharides are reducing sugars that exhibit mutarotation. Sucrose, a very abundant disaccharide of glucose and fructose, is not a reducing sugar that exhibits mutarotation because it has a glycosidic bond between the anomeric carbons of both sugars: C1 of glucose and C2 of fructose.


Figure 28.13. Lactose, maltose, sucrose, and cellobiose structures.​​


Question 28.5

Draw β-lactose.

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Polysaccharides such as glycogen, amylose, and cellulose are polymers of glucose formed from glycosidic bonds between different carbons of the glucopyranose rings. Glycogen is a branched polysaccharide of α(1→4) linked linearly with α(1→6)-linked branches of D-glucopyranose units, which serve the main storage form of glucose in the body. Both amylose and cellulose are polysaccharides made entirely of glucose in plants. Amylose is made from α-D-glucopyranose connected through an α(1→4) glycosidic bond and is used to store energy from glucose, whereas cellulose is made from β-D-glucopyranose connected through a β(1→4) glycosidic bond and is used to create an important structural component of the primary cell wall of green plants. The alternating up and down structure of cellulose (adjacent pyranose units are flipped over) make it easy for these polymers to straighten, align, and pack tightly formed fibers that prevent easy enzymatic digestion, whereas the same-sided structure of an amylose polymer will likely curl and not pack, making enzymatic digestion easier (Figure 28.14).

Figure 28.14. Cellulose, a linear polymer of D-glucose units (two are highlighted) linked by β(1→4) glycosidic bonds that forms a straight structure and the amylose polymer of D-glucose units (two are highlighted) linked by α(1→4) glycosidic bonds that forms a curved structure that is not straight.​


Q28.6 - Level 1

Identify carbon 1 of this monosaccharide, β-D-glucopyranose.


Q28.7 - Level 1

Identify carbon 4 of this monosaccharide, β-D-glucopyranose.


Q28.8 - Level 1

Identify carbon 6 of this monosaccharide, β-D-glucopyranose.


Figure 28.15. Glucose α and β anomers.​​​


The treatment of a monosaccharide hemiacetal with an alcohol and acid catalyst yields an acetal called a glycoside, in which the anomeric hydroxyl group (–OH) is replaced with an –OR group. If the alcohol in this reaction is the hydroxyl group of another monosaccharide, then a disaccharide is formed through this glycosidic bond. This bond can either be alpha or beta depending on which anomer of the hemiacetal is used. The carbon bound to the hydroxyl group of the other monosaccharide is also used to designate the specific glycosidic bond formed.  


Q28.9 - Level 2

Why do you think humans eat amylose and make paper out of cellulose?

Need a hint? Or click here to see the answer to Question 28.9.

28.2 Lipids

Lipids comprise a group of biomolecules characterized by limited solubility in water, but that can often be extracted using nonpolar organic solvents. Lipids fall into two broad classes: those that contain ester linkages that can be hydrolyzed, like fats and waxes, and those without ester linkages that cannot be hydrolyzed, like cholesterol and steroids. Lipids have a wide range of functions, from energy storage to composing cell membranes to local and global signaling.  

Q28.10 - Level 1

Lipids [math]\text{____}[/math] .

A

have long hydrocarbon chains that are not soluble in water.

B

are produced through the formation of peptide (amide) bonds.

C

are composed of nucleobases (nitrogenous bases) linked to phosphorylated sugars.

D

have a carbon skeleton with many hydroxyl (OH) groups.


Figure 28.17. Structures of some common lipids. At the top are the steroid, cholesterol, and the fatty acid, oleic acid. The middle structure is a triglyceride composed of oleoyl, stearoyl, and palmitoyl chains attached to a glycerol backbone. At the bottom is the common phospholipid, phosphatidylcholine.​


28.2.1 Triacylglycerols, fatty acids, and phospholipids

Waxes, fats, and oils are the most common lipids and contain ester linkages that can be hydrolyzed. Waxes are a mixture of esters from long-chain carboxylic acids and alcohols. Fats are solid at room temperature, whereas oils are liquid. However, both fats and oils are chemically triacylglycerols (triglycerides), which are triesters of glycerol with long-chain carboxylic acids, called fatty acids.  

Figure 28.18. An unsaturated fat triglyceride. Left part: glycerol, right part from top to bottom: palmitic acid, oleic acid, and alpha-linolenic acid (the alpha in this name indicates the first isolated linolenic isomer and is not to be confused with the alpha carbon). ​​

More than 100 different fatty acids are known (~10-40 are common) and most of them have linear carbon chains. Systematic numbering of fatty acids starts with the C on the carboxylic acid group. The first carbon after the carboxyl group of the fatty acid is the α carbon and subsequently follow the greek alphabet (β, γ…). However, carbons on fatty acids are usually counted from the last carbon on the fatty acyl tail, which is the methyl group carbon, known as the omega (ω) carbon. To determine the location of the first carbon in a double bonds fatty acids are usually counted from the ω carbon rather than counting from the α carbon. Counting from the ω end is used to determine the methylene carbons that make up the double bonds (Figure 28.18). 

 Fatty acids are classified by the degree of unsaturation, which can be determined by the number of double bonds: saturated indicates no double bonds, monounsaturated has one double bond and polyunsaturated has many double bonds. A saturated fatty acid has a carbon chain that contains no unsaturated carbon double bonds and cannot incorporate any more hydrogens. α-linolenic acid (ALA) is a polyunsaturated fatty acid because it has more than one double bond in its hydrocarbon chain. Unsaturated fatty acids generally have lower melting points making these triacylglycerols oils. Conversely, saturated fatty acids have higher melting points and make triacylglycerol fats.

The melting points for fatty acids depend on the degree of unsaturation and hydrocarbon length. The melting point decreases primarily by the degree of unsaturation (number of double bonds). Secondarily, longer chains make fatty acids have higher melting points.

Q28.11 - Level 1

Identify the saturated part of this fatty acid, α-linolenic acid (ALA).


Q28.12 - Level 1

Identify the alpha (α) head of this fatty acid, α-linolenic acid (ALA).


Q28.13 - Level 1

Identify the omega (ω) tail of this fatty acid, α-linolenic acid (ALA).


Figure 28.19. A saturated and unsaturated fatty acid.​​


Table 28.1. Names, Molecular Formulas, Melting Points and Structures of Several Common Fatty Acids​


Question 28.14

Draw Linoleic Acid. 

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Q28.15 - Level 1

Sort these fatty acids in order of increasing melting points.

A

arachidic

B

lauric

C

linoleic

D

arachidonic

E

palmitic

F

palmitoleic


Hydrolysis of the triacylglycerol in an alkaline solution (NaOH or KOH) yields a glycerol and the sodium or potassium salts of the three fatty acids. This process is called saponification, or making soap, which is a mixture of sodium or potassium salts of long chain fatty acids. Soaps work by having both polar and nonpolar regions that can interact with both oils and water. When dispersed in water, the long hydrocarbon tails cluster together and the ionic heads interact with water forming sphere with a hydrophobic center and an ionic surface that interacts favorably with water. These structures are called micelles and are capable of attracting oils to the center while remaining soluble in water.

Figure 28.20. Saponification reaction.


Q28.16 - Level 2

A healthy concentration of triacylglycerol in the blood is 1 mM. The human body has about 5 L of blood. How many moles of carboxylate ions can be generated from 5 L of 1 mM triacylglycerol under alkaline aqueous conditions?


Figure 28.21. Glycerophospholipids.

Sphingolipids have a sphingosine or a related dihydroxyamine backbone linked through an amide bond to a fatty acid (Figure 28.22). In both cases, the phosphate group is most commonly bound to an ethanolamine, serine, or choline. 

Figure 28.22. Sphingolipids.​​

Micelles, liposomes or lipid bilayer sheets are formed because the charged ionic head group orients toward water, whereas the nonpolar fatty acid tails aggregate together (Figure 28.23). A lipid monolayer of can form a micelle with a hydrophobic center, whereas a lipid bilayer can form a spherical liposome or a bilayer sheet. Phospholipids comprise the membrane structures of all cells and their organelles by creating a lipid bilayer that also contains glycolipids and cholesterol. These are effective and dynamic barriers. 

Figure 28.23. Phospholipids self-organize into larger structures known as spherical micelles, liposomes, or larger lipid bilayer sheets.​​


Q28.17 - Level 2

Cold-blooded animals living in cold environments, like salmon, have a higher percentage of polyunsaturated fatty acids in their muscle tissue compared with warm blooded animals like mammals. Why do you think this is so?

Need a hint? Or click here to see the answer to Question 28.17.

28.2.2 Eicosanoids, Terpenoids, and Steroids

Eicosanoids are derivatives synthesized most commonly from arachidonic acid and are considered “local hormones.” The most common eicosanoids are prostaglandins, which contain a five-membered ring with two long side chains. Other types of eicosanoids are leukotrienes and thromboxanes. Leukotrienes are acyclic, whereas thromboxanes have a six-membered oxygen-containing ring. For each type of eicosanoid, arachidonic acid is first converted to prostaglandin H2 (PGH2) and subsequent reactions produce a wide range of eicosanoids such as prostaglandin E1.

Figure 28.24. Arachidonic acid.​​


Figure 28.25. Prostaglandin H2 (PGH2) and Prostaglandin E1​​​​​


Figure 28.26. Thromboxanes and Leukotrienes​



Question 28.18

Draw Prostaglandin H2.  

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Terpenoids are a class of lipids derived from the isoprene to form a molecule with multiple 5-carbon isoprene subunits. Terpenoids are a larger class of molecules with basic terpene structure, but with additional modifications to the original terpene. Terpenoids are classified by the number of 10- C subunits they contain: monoterpenoids have 10 carbons and are made from 2 isoprene molecules; sesquiterpenoids have 15 carbons and are made from 3 isoprene molecules (sesqui means 1.5); diterpenoids have 20 carbons and are made from 4 isoprenes; triterpenoids have 30 carbons and are made from 6 isoprene molecules; and tetraterpenoids have 40 carbons and are made from 8 isoprene units.

Terpenes can be viewed as being built from two or more C5 units, known as isoprene units.

Figure 28.27. Isoprene


Plants do not synthesize terpenes from isoprene; however, recognition of the isoprene unit as a component of the structure of terpenes has been a great aid in elucidating their structures.

Figure 28.28. Myrcene – a monoterpene (dimer of isoprene).​​


Figure 28.29. Naturally occurring terpenes and the individual isoprene units.


The triterpenoid lanosterol is the precursor for steroids. Smaller terpenoids are found more in bacteria, fungi, and plants, whereas larger terpenoids can be found primarily in plants and animals. Many natural products are terpenoids.  

Figure 28.30. Lanosterol formation.


Question 28.19

Draw Lanosterol. 

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Steroids in animals and fungi are derived from lanosterol, which is derived from squalene and has a tetracyclic ring structure with four rings, designated A–D. Steroids can have either a cis or trans conformation between rings A and B, whereas the other conformations are usually in the trans conformation. Rings A–C are six-membered (cyclohexane) rings that adopt the usual chair conformation, but cannot undergo ring flips observed in cyclohexane; ring D is a five-membered (cyclopentane) ring. In humans, most steroids other than cholesterol are hormones, which are signaling molecules secreted by glands and circulated through the blood to target tissues to regulate physiology and behavior. Hormones are classified as either sex hormones, which control maturation and reproduction, or adrenocortical hormones, which control processes related to metabolism. Pharmaceutical labs have also produced a range of synthetic hormones. Steroids like cholesterol also make up an important part of cell membranes. All steroids have the same basic structure, called a gonane (Figure 28.31), but each one varies by different functional modifications.

Figure 28.31. Gonane


Figure 28.32. Steroid ring designation and atom numbering. The parent steroid rings are labeled A, B, C, and D, with carbons numbered.​​


28.3 Amino Acids, Peptides, and Proteins

Proteins are synthesized by living organisms to carry out specific and unique biological functions. Proteins are responsible for regulating the skeletal structure of a cell so they can divide and move to generate an electrical potential across the cell membrane that allows neurons to quickly send messages or enzymatically catalyze a diverse set of specific biological reactions necessary for cell signaling and metabolism. Despite the wide range of biological functions for which proteins are uniquely adapted, they are all composed of amino acid residues joined through an amide (peptide) bond to form long biopolymer chains that fold up to form the protein’s three-dimensional structure. The peptide bond in a dipeptide is formed through a condensation reaction between two amino acids. Historically, a carboxylic acid is mixed with an amine to form a salt, then heated to drive off the water to form an amide (Figure 28.33). Subsequent reactions add more amino acids and lengthen the peptide chain until the complete protein is formed. Notice that in Figure 28.33 the two ends of the polypeptide differ: one end has an ammonium ion group, the other a carboxylate ion group, which are called the N-terminus and C-terminus, respectively. By convention, the numbering of a polypeptide begins at the N-terminus and ends at the C-terminus. The functional groups of a polypeptide are bonded to the α carbon of the amino acid and are called R-groups.

Figure 28.33a. General reaction for the formation of a peptide bond through a condensation reaction.


Figure 28.33b. Peptide bond formation in polypeptides through a condensation reaction. The RGD tripeptide, arginylglycylaspartic acid, is shown.


Figure 28.33c. Peptide bond formation in polypeptides through a condensation reaction. The RGD tripeptide, arginylglycylaspartic acid, is shown.​​


Question 28.20

Draw the peptide bond formation between two amino acids at neutral pH. Use the letter R to indicate the functional group. 

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Proteins are simply polypeptide chains that must be folded properly to serve a wide range of specific biological functions and exist in a wide range of sizes. The TRP-Cage protein, derived from the saliva of Gila monsters, is only 20 amino acid residues long, whereas titan, a human protein that gives elasticity to skeletal muscle, is longer than 1 μm and up to 33,000 amino acid residues long. Arginylglycylaspartic acid (RGD), a tripeptide, is a common sequence found in proteins involved in cellular communication and cell recognition (Figure 28.33). The three amino acids, L-arginine, L-glycine, and L-aspartic acid, are joined together by peptide bonds.

Solid-phase peptide synthesis (SPPS) allows for the synthesis of natural peptides that are hard to produce in cells (in vivo), and peptides from unnatural amino acids, and other chemical derivatives up to ~70 amino acids long. In general, the process alternates between de-protecting the terminal amine group of the peptide and coupling a protected amino acid to the end of the peptide followed by cleavage of the peptide from the resin to complete the process and form the peptide (Figure 28.34). Larger natural peptides are usually produced by cells genetically engineered to produce (express) them in quantity and then purified. 

Peptides can be sequenced using Edman degradation after larger peptides are cleaved at unique sequences of amino acids (using proteases) into smaller 30 amino acid long fragments. For each round of Edman degradation, the amino-terminal residue of a peptide is labeled with phenylthiohydantoin (PTH) and cleaved with heat and acid without breaking other peptide bonds (Figure 28.35).

Figure 28.34. Diagram of solid-phase peptide synthesis where the amine in the amino acid is protected by a Fluorenylmethyloxycarbonyl (Fmoc) group. Peptide synthesis occurs on a Rink amide resin using Fmoc-α-amine-protected amino acid.​​


Figure 28.35. Edman degradation of a peptide.​​


Proteins are classified as fibrous or globular. Fibrous proteins such as collagen in connective tissue or myosin in muscle have an elongated shape and are arranged side-by-side in long filaments to form a larger structure. Fibrous proteins are not very soluble in water and do not lose the structure that is important for function which is called denaturing. Proteins like hemoglobin and superoxide dismutase are globular, which indicates that they have more spherical shapes, are typically soluble in water, and can diffuse around a cell. The primary structure of a protein is the amino acid sequence. The secondary structure describes how the backbone may organize through hydrogen bonding into a repeating structure, known as an α-helix or β-pleated sheet. An α-helix is a right-handed coil protein backbone, whereas a β-pleated sheet is a series of fully extended parallel or anti-parallel runs. The tertiary structure is a complete three-dimensional structure of a protein molecule from a single peptide composed of α-helices, β-pleated sheets, and loops with no secondary structure. Finally, the quaternary structure is the functional complex of two or more protein molecules that bind together through intermolecular forces and can be formed from the same or different protein molecules with or without associated cofactors (Figure 28.36). 

Figure 28.36. Primary through quaternary protein structures. ​

An enzyme is usually a protein that acts as a catalyst for a biological reaction. A catalytic triad is a group of three amino acids involved in catalysis and found in the active sites of enzymes that lyse (break down) proteins and peptides, known as proteases. In the catalytic triad charge–relay system, an acid aligns and polarizes a base, which activates the nucleophile by reducing its pKa, which then attacks the substrate. The mechanism for the catalytic hydrolysis of an amide with a catalytic triad is shown in Figure 28.37.

Figure 28.37. Mechanism of action for a catalytic triad.​​



Q28.21 - Level 1

Proteins [math]\text{____}[/math] .

A

have long hydrocarbon chains that are not soluble in water.

B

are produced through the formation of peptide (amide) bonds.

C

are composed of nucleobases (nitrogenous bases) linked to phosphorylated sugars.

D

have a carbon skeleton with many hydroxyl (OH) groups.


28.3.1 Amino Acid Structure

α-Amino acids are composed of a basic amine group attached to the α carbon of an acidic carboxyl group and are commonly referred to as just amino acids. The simplest α-amino acid is called glycine as shown in Figure 28.39. Substitution of a hydrogen by an R-group creates the different amino acids. For example, alanine is the amino acid with a methyl side chain. Except for glycine, almost all naturally occurring amino acids are chiral because when an R-group is bonded to the α-carbon a chiral center is formed. Also, with the exception to glycine and cysteine, all naturally occurring amino acids have the (S) configuration. The Fischer projection of (S)-alanine is shown in Figure 28.38. Notice that its configuration is similar to (S)-glyceraldehyde, i.e., the -NH2 group is on the left. In the carbohydrate section, it was shown that an L designation was given to a carbohydrate when the alcohol is on the left of the chiral carbon furthest from the carbonyl group in a Fischer projection. All naturally occurring amino acids can be drawn with the -NH2 group on the left, the -COOH group on top, and the residue -R group on the bottom in a Fischer projection and are also classified as L-amino acids.

Figure 28.38. Amino acid stereoisomers.

At neutral pH, aqueous amino acids form dipolar ions called zwitterions (“zwitter” means “hybrid” in German). These dipolar ions have both positive and negative charged ions on the same molecule and have similar physical properties associated with other salts. Amino acids have large dipole moments, are relatively soluble in more polar solvents like water, and are crystalline, with high melting points. 

In an acidic aqueous solution, the weakly basic amine group accepts a proton, which yields a cation, or, in a basic aqueous solution, the carboxylic acid acts as an acid to donate a proton, which yields a carboxylate anion. Because you are closer to the pKa of -NH3+ group and not the -COOH at neutral pH, the acidic part of the molecule is the -NH3+ group and not the -COOH group (Table 28.2). Furthermore, at neutral pH, this makes the basic part of the molecule not the -NH2 group but the -COO- group. Together this indicates that because amino acids contain both an acidic group -NH3+ and a basic group -COO-, amino acids can act as either bases or acids, thus are amphiprotic. Although carboxylic acid groups are often shown in structures, they are actually negatively charged carboxylate ions and basic amine groups are actually positively charged ammonium ions at a physiological pH of 7.4. 

Table 28.2. Molecular Weights and pKa Values of Proteinogenic Amino Acids.


Figure 28.39. Glycine amino acid ions.​​


There are 20 amino acids used to make the proteins encoded by DNA. These common biological amino acids are characterized at physiological pH 7.4 as either acidic, basic, aliphatic (non-polar, open-chain, hydrophobic), aromatic (bulky, hydrophobic, non-charged), amidic (polar, non-charged, hydrophilic), hydroxylic or sulfur-containing. Acidic amino acids have a second carboxyl group and are polar and negatively charged at physiological pH. Basic amino acids are polar and positively charged at pH values below their pKa's. Amino acids that are charged at physiological pH 7.4 are either in the acidic and basic groups and are all very hydrophilic. Therefore, histidine is characterized as a basic amino acid although it is also aromatic. These side chains can also be further modified after being translated from RNA to form the polypeptide, which are called post-translational modifications.

As seen in Figure 28.40, all these amino acids are α-amino acids that have the amino group bonded to the α-carbon next to the carbonyl group. Nineteen of these amino acids are primary amines that differ only in the structure of the side chain. Proline is a secondary amine that forms a 5-membered pyrrolidine ring from the nitrogen and α-carbon. With the exception of glycine, the α-carbons also act as chirality centers, indicating that two enantiomers are possible for each. However, in biology, only the L enantiomers are naturally occurring in proteins.

Figure 28.40. Amino acids that make up proteins.​​​


Question 28.22

Draw aspartame, which is the Asp-Phe dipeptide. 

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Q28.23 - Level 1

Match the category to the structure of the amino acids. Categories: aliphatic (6), aromatic (3), acidic (2), basic (3), hydroxylic (2), sulfur-containing (2), and amidic (2).

question description
Premise
Response
1

Compound 1

A

Sulfur-containing

2

Compound 2

B

Amidic

3

Compound 3

C

Acidic

4

Compound 4

D

Amidic

5

Compound 5

E

Aliphatic

6

Compound 6

F

Basic

7

Compound 7

G

Acidic


Q28.24 - Level 2

Match the category to the structure of the amino acids. Categories: aliphatic (6), aromatic (3), acidic (2), basic (3), hydroxylic (2), sulfur-containing (2), and amidic (2).

question description
Premise
Response
1

Compound 8

A

Aliphatic

2

Compound 9

B

Aliphatic

3

Compound 10

C

Aliphatic

4

Compound 11

D

Sulfur-containing

5

Compound 12

E

Basic

6

Compound 13

F

Aromatic

7

Compound 14

G

Basic


Q28.25 - Level 2

Match the category to the structure of the amino acids. Categories: aliphatic