Biochemistry: The Molecular Basis of Life (1st Semester) PDF

Biochemistry: An CHAPTER 1 Introduction Biochemistry and the Life Sciences Throughout most of its history, biochemical research has provided the life sciences with biochemical knowledge and ever more sophisticated technologies that have revealed living processes at the molecular level. Current examples of the medical relevance of biochemistry include immunotherapy (harnessing a patient’s immune system to treat diseases such as cancer) and CRISPR (clustered regularly interspaced short palindromic repeats—a gene-editing technique used to alter DNA in living cells). OUTLINE WHY STUDY BIOCHEMISTRY? 1.1 WHAT IS LIFE? 1.2 BIOMOLECULES Functional Groups of Organic Biomolecules Major Classes of Small Biomolecules 1.3 IS THE LIVING CELL A CHEMICAL FACTORY? Biochemical Reactions Energy Overview of Metabolism Biological Order 1.4 SYSTEMS BIOLOGY Emergence Robustness Systems Biology Model Concepts Living Organisms and Robustness Biochemistry in the Lab An Introduction AVAILABLE ONLINE Life: It Is a Mystery! Why Study Biochemistry? W hy study biochemistry? For students embarking on careers in the life sciences, the answer should be obvious: biochemistry, the scientific discipline concerned with chemical processes within living organisms, is the bedrock on which all of the modern life sciences are built. During the past two decades, the influence of biochemistry and the allied field of molecular biology has increased exponentially. Life sciences as diverse as agronomy (the science of soil management and crop production), forensics, marine biology, plant biology, and ecology are now being explored with powerful biotechnological tools. As a result, there is now a vast array of career opportunities in federal or state government agencies and industry (e.g., pharmaceutical, biotechnology, and agribusiness companies) for recent graduates with life science degrees. Examples of such fields include biomedical and clinical research, forensic analysis, plant or animal genetics, environmental protection, and wildlife biology. Economic conditions often dictate life science career choices. (The Occupational Outlook Handout on the U.S. Bureau of Labor Statistics website offers an unbiased assessment of future employment prospects.) No matter the economic conditions when students graduate, employment opportunities are always better for those who have undergraduate research experience. Developing a network of connections beginning with professors and expanding into the student’s field or interests (e.g., by attending science career fairs or professional society conferences) also increases employment opportunities. Furthermore, writing, data analysis, problem solving, and communication are skills that employers always value highly. For students not interested in research careers, there are opportunities in science journalism, education, and software engineering. Examples of alternative careers where a life science degree is an asset include public policy (e.g., public health risk assessment and health product regulation), law (e.g., lawyers for pharmaceutical and biotech companies and environmental organizations), and marketing and sales (e.g., drugs and medical devices). Overview FROM MODEST BEGINNINGS IN THE LATE NINETEENTH CENTURY, THE SCIENCE OF BIOCHEMISTRY HAS PROVIDED INCREASINGLY MORE sophisticated intellectual and laboratory tools for the investigation of living processes. Today, in the early years of the twenty- first century, we find ourselves in the midst of a previously unimagined biotechnological revolution. Life sciences as diverse as medicine, agriculture, and forensics have generated immense amounts of information. The capacity to understand and appreciate the significance of this phenomenon begins with a thorough knowledge of biochemical principles. This chapter provides an overview of these principles. The chapters that follow focus on the structure and functions of the most important biomolecules and the major biochemical processes that sustain life. T his textbook is designed to provide an introduction to the basic principles of biochemistry. This opening chapter provides an overview of the major components of living organisms and the processes that sustain the living state. A brief description of the nature of the living state is followed by an introduction to the structures and functions of the major biomolecules and then an overview of the most important biochemical processes. The chapter concludes with a brief discussion of the concepts of modern experimental biochemistry and an introduction to systems biology, an investigative strategy used to improve our understanding of living organisms as integrated systems rather than collections of isolated components and chemical reactions. 1.1 WHAT IS LIFE? What is life? Despite the work of life scientists over several centuries, a definitive answer to this deceptively simple question has been elusive. Much of the difficulty in delineating the precise nature of living organisms lies in the overwhelming diversity of the living world and the apparent overlap in several properties of living and nonliving matter. Consequently, life has been viewed as an intangible property and is usually described in operational terms, such as movement, reproduction, adaptation, and responsiveness to external stimuli. The work of life scientists, made possible by the experimental approaches of biochemistry, has revealed that all organisms obey the same chemical and physical laws that rule the universe. Life’s diverse properties include the following: 1. Life is complex and dynamic. All organisms are composed of the same set of chemical elements, primarily carbon, nitrogen, oxygen, hydrogen, sulfur, and phosphorus. Biomolecules, the molecules synthesized by living organisms, are organic (carbon-based). Living processes, such as growth and development, involve thousands of chemical reactions in which vast quantities and varieties of vibrating and rotating molecules interact, collide, and rearrange into new molecules. 2. Life is organized and self-sustaining. Living organisms are hierarchically organized systems: they consist of patterns of organization from smallest (atom) to largest (organism) (Figure 1.1). In biological systems, the functional capacities of each level of organization are derived from the structural and chemical properties of the level below it. Biomolecules are composed of atoms, which in turn are formed from subatomic particles. Certain biomolecules become linked to form polymers called macromolecules. Examples include nucleic acids, proteins, and polysaccharides, which are formed from nucleotides, amino acids, and sugars, respectively. Cells are composed of a diversity of biomolecules and macromolecules, some of which form more complex supermolecular structures. At the molecular level, there are hundreds of biochemical reactions that together sustain the living state. Catalyzed by biomolecular catalysts called enzymes, these reactions are organized into pathways. (A biochemical pathway is a series of reactions in which a specific molecule is converted through a single or many steps into a terminal product.) The sum of all the reactions in a living organism is referred to as metabolism. The capacity of living organisms to regulate metabolic processes despite variability in their internal and external environments is called homeostasis. In multicellular organisms, other levels of organization include tissues, organs, and organ systems. 3. Life is cellular. Cells, the basic units of living organisms, differ widely in structure and function, but each is surrounded by a membrane that controls the transport of substances into and out of the cell. The membrane also mediates the response of the cell to the extracellular environment. If a cell is divided into its component parts, it will cease to function in a life-sustaining way. Cells arise only from the division of existing cells. 4. Life is information-based. Organization requires information. Living organisms can be considered information-processing systems because maintenance of their structural integrity and metabolic processes involves interactions among a vast array of molecules within and between cells. Biological information is expressed in the form of coded messages that are inherent in the unique three-dimensional structure of biomolecules. Genetic information stored in genes, the linear sequences of nucleotides in deoxyribonucleic acid (DNA), in turn specifies the linear sequence of amino acids in proteins and how and when those proteins are synthesized. Proteins perform their function by interacting with other molecules. The unique three-dimensional structure of each protein allows it to bind to, and interact with, a specific molecule that has a precise complementary shape. Information is transferred by the binding process. For example, the binding of the protein insulin to insulin receptor molecules on the surface of certain cells is a signal that initiates the uptake of the nutrient molecule glucose. FIGURE 1.1 Hierarchical Organization of a Multicellular Organism: The Human Being Multicellular organisms have several levels of organization: organ systems, organs, tissues, cells, organelles, molecules, and atoms. The digestive system and one of its component organs (the liver) are shown. The liver is a multifunctional organ that has several digestive functions. For example, it produces bile, which facilitates fat digestion, and it processes and distributes the food molecules absorbed in the small intestine to other parts of the body. DNA contains the genetic information that controls cell function. 5. Life adapts and evolves. All life on Earth has a common origin, with new forms arising from older forms. When an individual organism in a population reproduces itself, mutations or sequence changes can arise as a result of stress-induced DNA modifications and errors that occur when DNA molecules are copied. Most mutations are silent: they either are repaired or have no effect on the functioning of the organism. Some, however, are harmful, serving to limit the reproductive success of the offspring. On rare occasions, mutations may contribute to an increased ability of the organism to survive, to adapt to new circumstances, and to reproduce. A principal driving force in this process is the capacity to exploit energy sources. Individuals possessing traits that allow them to better exploit a specific energy source within their habitat may have a competitive advantage when resources are limited. Over many generations, the interplay of environmental change and genetic variation can lead to the accumulation of favorable traits and eventually to increasingly different forms of life. KEY CONCEPTS All living organisms obey the chemical and physical laws. Life is complex, dynamic, organized, and self-sustaining. Life is cellular and information-based. Life adapts and evolves. 1.2 BIOMOLECULES Living organisms are composed of thousands of different kinds of inorganic and organic molecules. Water, an inorganic molecule, may constitute 50 to 95% of a cell’s content by weight, and ions such as sodium (Na+), potassium (K+), magnesium (Mg2+), and calcium (Ca2+) may account for another 1%. Almost all the other molecules in living organisms are organic. Life’s organic molecules are principally composed of six elements: carbon, hydrogen, oxygen, nitrogen, phosphorus, and sulfur, and they contain trace amounts of certain metallic and other nonmetallic elements. The atoms of each of the most common elements found in living organisms can readily form stable covalent bonds, the kind that allow the formation of such important molecules as proteins. The remarkable structural complexity and diversity of organic molecules are made possible by the capacity of carbon atoms to form four strong, single covalent bonds either to other carbon atoms or to atoms of other elements. Organic molecules with many carbon atoms can form complicated shapes such as long, straight structures or branched chains and rings. Functional Groups of Organic Biomolecules Most biomolecules can be considered derived from the simplest type of organic molecule, called the hydrocarbons. Hydrocarbons (Figure 1.2) are carbon- and hydrogen-containing molecules that are hydrophobic, or insoluble in water. All other organic molecules are formed by attaching other atoms or groups of atoms to the carbon backbone of the hydrocarbon. The chemical properties of these derivative molecules are determined by the specific arrangement of atoms called functional groups (Table 1.1). For example, alcohols result when hydrogen atoms are replaced by hydroxyl groups (—OH). Thus methane (CH4), a component of natural gas, can be converted into methanol (CH3OH), a toxic liquid that is used as a solvent in many industrial processes. FIGURE 1.2 Structural Formulas of Several Hydrocarbons Most biomolecules contain more than one functional group. For example, many simple sugar molecules have several hydroxyl groups and an aldehyde group. Amino acids, the building-block molecules of proteins, have both an amino group and a carboxyl group. The distinct chemical properties of each functional group contribute to the behavior of any molecule that contains it. TABLE 1.1 Important Functional Groups in Biomolecules Family Group Group Name Structure Name Significance Alcohol Hydroxyl Polar (and therefore water-soluble), forms hydrogen bonds Aldehyde Carbonyl Polar, found in some sugars Ketone Carbonyl Polar, found in some sugars Acids Carboxyl Weakly acidic, bears a negative charge when it donates a proton Amine Amino Weakly basic, bears a positive charge when it accepts a proton Amide Amido Polar but does not bear a charge Thiol Thiol Easily oxidized; can form —S—S—(disulfide) bonds readily Ester Ester Found in certain lipid molecules Alkene Double Important structural component of many biomolecules (e.g., bond found in lipid molecules) Major Classes of Small Biomolecules Many of the organic compounds found in cells are relatively small, with molecular masses of less than 1000 daltons (Da). (One dalton, one atomic mass unit, is equal to 1/12 of the mass of one atom of 12C.) Cells contain four families of small molecules: amino acids, sugars, fatty acids, and nucleotides (Table 1.2). Members of each group serve several functions. First, they are used in the synthesis of larger molecules, many of which are polymers. For example, proteins, certain carbohydrates, and nucleic acids are polymers composed of amino acids, sugars, and nucleotides, respectively. Fatty acids are components of lipid (water-insoluble) molecules of several types. TABLE 1.2 Major Classes of Biomolecules Small Molecule Polymer General Functions Amino acids Proteins Catalysts and structural elements Sugars Carbohydrates Energy sources and structural elements Fatty acids N.A. Energy sources and structural elements of complex lipid molecules Nucleotides DNA Genetic information RNA Protein synthesis Second, some molecules have special biological functions. For example, the nucleotide adenosine triphosphate (ATP) serves as a cellular reservoir of chemical energy. Finally, many small organic molecules are involved in complex reaction pathways. Examples of each class of molecule are described next. FIGURE 1.3 General Formula for α-Amino Acids For 19 of the 20 standard amino acids found in proteins, the α-carbon is bonded to a hydrogen atom, a carboxyl group, an amino group, and an R group. AMINO ACIDS AND PROTEINS There are hundreds of naturally occurring amino acids, each of which contains an amino group and a carboxyl group. Amino acids are classified α, β, or γ according to the location of the amino group in reference to the carboxyl group. In α-amino acids, the most common type, the amino group is attached to the carbon atom (the α-carbon) immediately adjacent to the carboxyl group (Figure 1.3). In β- and γ-amino acids, the amino group is attached to the second and third carbon, respectively, from the carboxyl group. Also attached to the α- carbon is another group, referred to as the side chain or R group. The chemical properties of each amino acid, once incorporated into protein, are determined largely by the properties of its side chain. For example, some side chains are hydrophobic (i.e., they have low solubility in water), whereas others are hydrophilic (i.e., they dissolve easily in water). Several examples of α-amino acids are presented in Figure 1.4. Twenty standard α-amino acids occur in proteins. Some standard amino acids have unique functions in living organisms. For example, glycine and glutamic acid function in animals as neurotransmitters, signal molecules released by nerve cells. Proteins also contain nonstandard amino acids that are modified versions of the standard amino acids. The structure and function of protein molecules are often altered by conversion of certain amino acid residues to derivatives via phosphorylation, hydroxylation, and other chemical modifications. (The term residue refers to a small biomolecule that is incorporated in a macromolecule, e.g., amino acid residues in a protein.) For example, many of the residues of proline are hydroxylated in collagen, the connective tissue protein. Many naturally occurring amino acids are not α-amino acids. Prominent examples include β-alanine, a precursor of the vitamin pantothenic acid, and γ-aminobutyric acid (GABA), a neurotransmitter found in the brain (Figure 1.5). Amino acid molecules are used primarily in the synthesis of long, complex polymers known as polypeptides. Up to a length of about 50 amino acids, these molecules are called peptides. Proteins consist of one or more polypeptides. Polypeptides play a variety of roles in living organisms, including transport, structure, and catalysis. The individual amino acids are connected in peptides (Figure 1.6) and polypeptides by peptide bonds. Peptide bonds are amide linkages that form in a nucleophilic substitution reaction (p. P- 30) in which the amino group nitrogen of one amino acid attacks the carbonyl carbon in the activated carboxyl group of another. For many proteins, their three-dimensional structure and biological function result largely from interactions among the R groups (Figure 1.7). FIGURE 1.4 Structural Formulas for Several α-Amino Acids An R group (highlighted) in an amino acid structure can be a hydrogen atom (e.g., in glycine), a hydrocarbon group (e.g., the isopropyl group in valine), or a hydrocarbon derivative (e.g., the hydroxy methyl group in serine). FIGURE 1.5 Select Examples of Naturally Occurring Amino Acids That Are Not α-Amino Acids: β-Alanine and γ- Aminobutyric Acid (GABA) WORKED PROBLEM 1.1 Living organisms generate a vast number of different biopolymers by linking monomers in different sequences. A set of tripeptides, each containing three amino acid residues, contains only two types of amino acids: A and B. How many possible tripeptides are in this set? SOLUTION The number of possible tripeptides is given by the formula Xn, where Substituting these values into the formula yields 23 = 8. The eight tripeptides are as follows: AAA, AAB, ABA, BAA, ABB, BAB, BBA, and BBB. SUGARS AND CARBOHYDRATES Sugars, the smallest carbohydrates, contain alcohol and carbonyl functional groups. They are described in terms of both carbon number and the type of carbonyl group they contain. Sugars that possess an aldehyde group are called aldoses, and those that possess a ketone group are called ketoses. For example, the six-carbon sugar glucose (an important energy source in most living organisms) is an aldohexose; fructose (fruit sugar) is a ketohexose (Figure 1.8). Sugars are the basic units of carbohydrates, the most abundant organic molecules found in nature. Carbohydrates range from the simple sugars, or monosaccharides, such as glucose and fructose, to the polysaccharides, polymers that contain thousands of sugar units. Examples of polysaccharides include starch and cellulose in plants and glycogen in animals. Carbohydrates serve a variety of functions in living organisms. Certain sugars are important energy sources. Glucose is the principal carbohydrate energy source in animals and plants. Plants use sucrose as an efficient means of transporting energy throughout their tissues. Some carbohydrates serve as structural materials. Cellulose is the major structural component of wood and certain plant fibers. Chitin, another type of polysaccharide, is found in the exoskeletons of insects and crustaceans. Some biomolecules contain carbohydrate components. Nucleotides, the building-block molecules of the nucleic acids, contain either of the pentoses ribose or deoxyribose. Certain proteins and lipids also contain carbohydrate. Glycoproteins and glycolipids occur on the external surface of cell membranes in multicellular organisms, where they play critical roles in the interactions between cells. FIGURE 1.6 Structure of Met-Enkephalin, a Pentapeptide Met-enkephalin is one of a class of molecules that have opiate-like activity. Found in the brain, met-enkephalin inhibits pain perception. (The peptide bonds are colored blue. The R groups are highlighted.) 3D animation of Met-Enkephalin FIGURE 1.7 Polypeptide Structure As a polypeptide folds into its unique three-dimensional form, hydrophobic R groups (yellow spheres) become buried in the interior away from water. Hydrophilic groups usually occur on the surface. FIGURE 1.8 Some Biologically Important Monosaccharides Glucose and fructose are important sources of energy in plants and animals. Ribose and deoxyribose are components of nucleic acids. These monosaccharides occur as ring structures in nature. 3D animation of fructose, d- 3D animation of ribose 3D animation of 2-deoxyribose 3D animation of fructose, l- FATTY ACIDS Fatty acids are monocarboxylic acids that usually contain an even number of carbon atoms. Fatty acids are represented by the chemical formula R—COOH, in which R is an alkyl group that contains carbon and hydrogen atoms. There are two types of fatty acids: saturated fatty acids, which contain no carbon–carbon double bonds, and unsaturated fatty acids, which have one or more double bonds (Figure 1.9). Under physiological conditions, the carboxyl group of fatty acids exists in the ionized state, R—COO–. For example, the 16-carbon saturated fatty acid called palmitic acid usually exists as palmitate, CH3(CH2)14COO–. Although the charged carboxyl group has an affinity for water, the long nonpolar hydrocarbon chains render most fatty acids insoluble in water. Fatty acids occur as independent (free) molecules in only trace amounts in living organisms. Most often they are components of several types of lipid molecules (Figure 1.10). Lipids are a diverse group of substances that are soluble in organic solvents such as chloroform or acetone, but they are not soluble in water. For example, triacylglycerols (fats and oils) are esters containing glycerol (a three-carbon alcohol with three hydroxyl groups) and three fatty acids. Phosphoglycerides contain two fatty acids. In these molecules, the third hydroxyl group of glycerol is coupled with phosphate, which is in turn attached to small polar compounds such as choline. Phosphoglycerides are an important structural component of cell membranes. NUCLEOTIDES AND NUCLEIC ACIDS Each nucleotide contains three components: a five- carbon sugar (either ribose or deoxyribose), a nitrogenous base, and one or more phosphate groups (Figure 1.11). The bases in nucleotides are heterocyclic aromatic rings with a variety of substituents. There are two classes of base: the bicyclic purines and the monocyclic pyrimidines (Figure 1.12). Nucleotides participate in a wide variety of biosynthetic and energy-generating reactions. For example, the energy obtained from food molecules is used to form the high-energy phosphate bonds of ATP. The energy, released when the phosphoanhydride bonds are hydrolyzed, drives cellular processes. Nucleotides also have an important role as the building-block molecules of the nucleic acids. In a nucleic acid, dozens to millions of nucleotides are linked by phosphodiester linkages to form long polynucleotide chains or strands. There are two types of nucleic acid: DNA and RNA. FIGURE 1.9 Fatty Acid Structure (a) A saturated fatty acid. (b) An unsaturated fatty acid. FIGURE 1.10 Lipid Molecules That Contain Fatty Acids (a) Triacylglycerol. (b) Phosphatidylcholine, a type of phosphoglyceride. 3D animation of triacylglycerol FIGURE 1.11 Nucleotide Structure Each nucleotide contains a nitrogenous base (in this case, adenine), a pentose sugar (ribose), and one or more phosphates. This nucleotide is adenosine triphosphate. FIGURE 1.12 The Nitrogenous Bases (a) The purines. (b) The pyrimidines. 3D animation of adenine 3D animation of Thymine 3D animation of Cytosine 3D animation of uracil DNA DNA is the repository of genetic information. Its structure consists of two antiparallel polynucleotide strands wound around each other to form a right-handed double helix (Figure 1.13). In addition to the pentose sugar deoxyribose and phosphate, DNA contains bases of four types: the purines adenine and guanine and the pyrimidines thymine and cytosine; adenine pairs with thymine and guanine pairs with cytosine. The double helix forms because of complementary pairing between the bases due to hydrogen bonding. A hydrogen bond is a force of attraction between a polarized hydrogen of one molecular group and the electronegative oxygen or nitrogen atoms of nearby aligned molecular groups. FIGURE 1.13 DNA (a) A diagrammatic view of DNA. The sugar-phosphate backbones of the double helix are represented by colored ribbons. The bases attached to the sugar deoxyribose are on the inside of the helix. (b) An enlarged view of two base pairs. Note that the two DNA strands run in opposite directions defined by the 5′ and 3′ groups of deoxyribose. The bases on opposite strands form pairs because of hydrogen bonds. Cytosine always pairs with guanine; thymine always pairs with adenine. An organism’s entire set of DNA sequences is called its genome. DNA consists of both coding and noncoding sequences. Coding sequences, called genes, specify the structure of functional gene products such as polypeptides and RNA molecules. Some noncoding sequences have regulatory functions (e.g., controlling the synthesis of certain proteins), whereas the functions of others are as yet undetermined. RNA Ribonucleic acid (RNA) is a polynucleotide that differs from DNA in that it contains the sugar ribose instead of deoxyribose and the base uracil instead of thymine. In RNA, as in DNA, the nucleotides are linked by phosphodiester linkages. In contrast to the double helix of DNA, RNA is single-stranded. RNA molecules fold into complex three-dimensional structures created by local regions of complementary base pairing. When the DNA double helix unwinds, one strand can serve as a template. RNA molecules are synthesized in a process called transcription. Complementary base pairing between DNA bases and the bases of incoming ribonucleotides specifies the base sequence of the RNA molecule. There are three major types of RNA: messenger RNA (mRNA), ribosomal RNA (rRNA), and transfer RNA (tRNA). Each unique sequence or molecule of mRNA possesses the information that codes directly for the amino acid sequence in a specific polypeptide. Ribosomes, large, complex, supramolecular structures composed of rRNA and protein molecules, convert the mRNA base sequence into the amino acid sequence of a polypeptide. Transfer RNA molecules deliver activated amino acids to the ribosome during protein synthesis. In recent years, large numbers of RNA molecules have been discovered that are not directly involved in protein synthesis. These molecules, called noncoding RNAs (ncRNA), have roles in a great variety of cellular processes. Examples include short interfering RNAs (siRNAs), micro RNAs (miRNAs), small nuclear RNAs (snRNAs), small nucleolar RNAs (snoRNAs), and long noncoding RNAs (lncRNAs). siRNAs are important components in RNA interference, an antiviral defense mechanism. miRNAs have diverse roles in gene regulation including binding to and silencing specific mRNAs. snRNAs facilitate the process by which mRNA precursor molecules are transformed into functional mRNA. snoRNAs assist in the maturation of ribosomal RNA during ribosome formation. lncRNAs play vital roles in gene expression. KEY CONCEPTS Most molecules in living organisms are organic. The chemical properties of organic molecules are determined by specific arrangements of atoms called functional groups. Cells contain four families of small molecules: amino acids, sugars, fatty acids, and nucleotides. Proteins, polysaccharides, and the nucleic acids are biopolymers composed of amino acids, sugars, and nucleotides, respectively. GENE EXPRESSION Gene expression controls when or if the information encoded in a gene will be accessed. The process begins with transcription, the mechanism whereby the base sequence of a DNA segment is used to synthesize a gene product. A class of proteins called transcription factors regulates the expression of protein-coding genes when they bind to specific regulatory DNA sequences referred to as response elements. Transcription factors are synthesized and/or regulated in response to an information-processing mechanism initiated by a signal molecule (e.g., insulin, a protein that regulates several metabolic processes) or an abiotic factor such as light. 1.3 IS THE LIVING CELL A CHEMICAL FACTORY? Even the simplest cells are so remarkable that they have often been characterized as chemical factories. Like factories, living organisms acquire raw materials, energy, and information from their environment. Components are manufactured, and waste products and heat are discharged back into the environment. However, for this analogy to hold true, human-made factories would not only manufacture and repair all their structural and functional components, but also clone themselves, that is, manufacture new factories. The term autopoiesis has been created to describe the remarkable properties of living organisms. In this view, each living organism is considered an autonomous, self-organizing, and self-maintaining entity. Life emerges from a self-regulating network of thousands of biochemical reactions. The constant flow of energy and nutrients through organisms and the functional properties of thousands of enzymes make possible the process of metabolism. The primary functions of metabolism are (1) acquisition and utilization of energy, (2) synthesis of molecules needed for cell structure and functioning (i.e., proteins, carbohydrates, lipids, and nucleic acids), (3) growth and development, and (4) removal of waste products. Metabolic processes require significant amounts of useful energy. This section begins with a review of the primary chemical reaction types and the essential features of energy-generating strategies observed in living organisms. A brief outline of metabolic processes and the means by which living organisms maintain ordered systems follows. Biochemical Reactions At first glance, the thousands of reactions that occur in cells appear overwhelmingly complex. However, several characteristics of metabolism allow us to simplify this picture: 1. Although the number of reactions is large, the number of reaction types is relatively small. 2. Biochemical reactions have simple organic reaction mechanisms. 3. Reactions of central importance in biochemistry (i.e., those used in energy production and the synthesis and degradation of major cell components) are relatively few. Among the most common reaction types encountered in biochemical processes are nucleophilic substitution, elimination, addition, isomerization, and oxidation-reduction. NUCLEOPHILIC SUBSTITUTION REACTIONS In nucleophilic substitution reactions, as the name suggests, one atom or group is substituted for another: In the general reaction shown, the attacking species (A) is called a nucleophile (“nucleus lover”). Nucleophiles are anions (negatively charged atoms or groups) or neutral species possessing nonbonding electron pairs. Electrophiles (“electron lovers”) are deficient in electron density and are therefore easily attacked by a nucleophile. As the new bond forms between A and B, the old one between B and X breaks. The outgoing nucleophile (in this case, X), called a leaving group, leaves with its electron pair. Several types of nucleophilic substitution reactions occur in living organisms. Examples include SN2 reactions (e.g., the methylation of epinephrine; refer to p. P-33), acyl group transfers, and phosphoryl group transfers. In nucleophilic substitution reactions involving acyl transfer, a nucleophile attacks the carbonyl carbon of a carboxylic acid derivative, forming a tetrahedral intermediate. The carbonyl group re- forms as the tetrahedral intermediate collapses and the leaving group is ejected. Biologically important examples of carboxylic acid derivatives include carboxylates (deprotonated carboxylic acids), esters, amides, thioesters, and acyl phosphates. These derivatives vary in their reactivity with nucleophiles. Acyl phosphates are the most reactive, followed by thioesters, esters, amides, and finally carboxylates. The biologically active form of fatty acids is the thioester of coenzyme A (p. 341). Carboxylates are not good substrates for nucleophilic substitution reactions because the carbonyl carbon is not sufficiently electrophilic. As a result, fatty acids must first be activated by the formation of an acyl adenosyl monophosphate derivative (Figure 1.14) at the expense of ATP bond energy. Once the activated fatty acyl-AMP is formed, its carbonyl carbon is easily attacked by the thiol sulfur of coenzyme A (CoASH) to yield the fatty acyl-SCoA product. Hydrolysis reactions are nucleophilic acyl substitution reactions in which the oxygen of a water molecule serves as the nucleophile. The electrophile is usually the carbonyl carbon of an ester, amide, or anhydride. (An anhydride is a molecule containing two carbonyl groups linked through an oxygen atom. A mixed anhydride is an anhydride formed from two different acids. For example, glycerate-1,3- bisphosphate is an important metabolic molecule.) The digestion of many food molecules involves hydrolysis. For example, the amide linkages of proteins are hydrolyzed in the stomach in an acid- catalyzed reaction that yields amino acids. The hydrolysis of ATP to yield ADP and inorganic phosphate (Pi) and the reaction of glucose with ATP provide two examples of nucleophilic substitution involving phosphoryl group transfer. The attack by the OH of water on the terminal phosphate of ATP (Figure 1.15) breaks the phosphoanhydride bond, thereby releasing energy that is used to drive many cellular processes. FIGURE 1.14 Activation of a Fatty Acid Before a fatty acid can be degraded to yield energy or used in the synthesis of a triacylglycerol, it must first be activated. In the first step, the carboxylate ion attacks a phosphate of ATP to form a fatty acyl-AMP intermediate and pyrophosphate (PPi). In the second step, the fatty acyl-AMP is attacked by the thiol group of coenzyme A (CoASH) to form the thioester fatty acyl-SCoA and AMP. The rapid hydrolysis of PPi to form two phosphates (Pi) drives the reaction forward. 3D animation of ATP 3D animation of AMP The reaction of glucose with ATP, yielding glucose-6-phosphate and ADP, is the first step in the utilization of glucose as an energy source (Figure 1.16). The hydroxyl oxygen on carbon 6 of the sugar molecule is the nucleophile, and phosphorus is the electrophile. Adenosine diphosphate is the leaving group. ELIMINATION REACTIONS In elimination reactions, a double bond is formed when atoms in a molecule are removed. The removal of H2O from biomolecules containing alcohol functional groups is a commonly encountered reaction. A prominent example is the dehydration of 2-phosphoglycerate, a reaction in glycolysis, which is a biochemical pathway in carbohydrate metabolism (Figure 1.17). As illustrated on pp. P-33–P-34, this reaction occurs via an E1cB mechanism. Other products of elimination reactions include ammonia (NH3), amines (RNH2), and alcohols (ROH). FIGURE 1.15 A Hydrolysis Reaction The hydrolysis of ATP, a nucleophilic substitution reaction involving phosphoryl transfer, is used to drive an astonishing diversity of energy-requiring biochemical reactions. FIGURE 1.16 Example of Nucleophilic Substitution In the reaction of glucose with ATP, the hydroxyl oxygen of glucose is the nucleophile. The phosphorus atom (the electrophile) is polarized by the oxygens bonded to it so that it bears a partial positive charge. As the reaction occurs, the unshared pair of electrons on the hydroxyl oxygen of CH2OH of the sugar attacks the phosphorus, resulting in the expulsion of ADP, the leaving group. FIGURE 1.17 An Elimination Reaction When 2-phosphoglycerate is dehydrated, a double bond is formed. This reaction involves an E1cB mechanism, which is illustrated on p. P-34. ADDITION REACTIONS In addition reactions, two molecules combine to form a single product. Hydration is one of the most common addition reactions. When water is added to an alkene, an alcohol results. The hydration of the metabolic intermediate fumarate to form malate is a typical example (Figure 1.18). ISOMERIZATION REACTIONS In isomerization reactions, atoms or groups undergo intramolecular shifts. One of the most common biochemical isomerizations is the interconversion between aldose and ketose sugars (Figure 1.19). The isomerization of dihydroxyacetone phosphate to glyceraldehyde-3-phosphate (Figure 1.19b) is a reaction in glycolysis. FIGURE 1.18 An Addition Reaction (a) When water is added to a molecule that contains a double bond, such as fumarate, an alcohol results. (b) The hydration of fumarate, catalyzed by the enzyme fumarase, begins with the removal of a proton from a water molecule by an amino acid side chain acting as a base. The resulting nucleophile attacks the carbon–carbon double bond. The initial product, a resonance-stabilized ion, is then protonated by an acidic side chain of the enzyme to yield the product malate. FIGURE 1.19 An Isomerization Reaction (a) The reversible interconversion of aldose and ketose isomers is a commonly observed biochemical reaction type. (b) The isomerization of dihydroxacetone phosphate to form glyceraldehyde-3-phosphate begins when a basic side chain of the enzyme, triose phosphate isomerase, removes a proton from carbon 1 and an acidic side chain donates a proton to the carbonyl oxygen. The intermediate product is an enediol (a molecule in which a hydroxyl group is attached to each of the carbon atoms in a carbon–carbon double bond). In the second step the enediol is deprotonated by a basic side chain and an acidic side chain adds a proton to carbon 2, yielding the product glyceraldehyde-3-phosphate. OXIDATION-REDUCTION REACTIONS Oxidation-reduction (redox) reactions occur when there is a transfer of electrons from a donor (called the reducing agent) to an electron acceptor (called the oxidizing agent). When reducing agents donate their electrons, they become oxidized. As oxidizing agents accept electrons, they become reduced. The two processes always occur simultaneously. It is not always easy to determine whether biomolecules have gained or lost electrons. However, two simple rules may be used to ascertain whether a carbon atom in a molecule has been oxidized or reduced: 1. Oxidation has occurred if a carbon atom gains oxygen or loses hydrogen: 2. Reduction has occurred if a carbon atom loses oxygen or gains hydrogen: KEY CONCEPTS The most common reaction types encountered in biochemical processes are nucleophilic substitution, elimination, addition, isomerization, and oxidation-reduction. Numerous biological processes involve redox reactions. Energy transformations, for example, involve electron transfers. In photosynthesis, light energy capture drives CO2 reduction and H2O oxidation to yield sugar molecules and O2 synthesis, respectively. In the reverse process called cell respiration, sugar molecules are oxidized to form CO2 and O2 is reduced to form H2O. In the intermediate steps in these redox processes, high-energy electrons are transferred to electron acceptors such as the nucleotide NAD+/NADH (nicotinamide adenine dinucleotide in its oxidized/reduced form). Energy Energy is defined as the capacity to do work, that is, to move matter. In contrast to human-made machines, which generate and use energy under harsh conditions such as high temperature, high pressure, and electrical currents, the relatively fragile molecular machines within living organisms must use more subtle mechanisms. Cells generate most of their energy by using redox reactions in which electrons are transferred from an oxidizable molecule to an electron-deficient molecule. In these reactions, electrons are removed or added as hydrogen atoms (H ) or hydride ions (H:–, i.e., an anion with one proton and two electrons). The more reduced a molecule is—that is, the more hydrogen atoms it possesses—the more energy it contains. For example, fatty acids contain proportionately more hydrogen atoms than sugars do and therefore yield more energy upon oxidation. When fatty acids and sugars are oxidized, their hydrogen atoms are removed by the redox coenzymes FAD (flavin adenine dinucleotide) or NAD+. (Coenzymes are small molecules that function in association with enzymes by serving as carriers of small molecular groups, or in this case electrons.) The reduced products of this process (FADH2 or NADH, respectively) can then transfer the electrons to another electron acceptor. Whenever an electron is transferred, energy is lost. Cells have complex mechanisms for exploiting this phenomenon in a way that permits some of the released energy to be captured for cellular work. The most prominent feature of energy generation in most cells is the electron transport pathway, a series of linked membrane-embedded electron carrier molecules. During a regulated process, energy is released as electrons are transferred from one electron carrier molecule to another. During several of these redox reactions, the energy released is sufficient to drive the synthesis of ATP, the energy carrier molecule that directly supplies the energy used to maintain highly organized cellular structures and functions. Despite their many similarities, groups of living organisms differ in the precise strategies they use to acquire energy from their environment. Autotrophs are organisms that transform the energy of the sun (photosynthesis) or various chemicals (chemosynthesis) into chemical bond energy; they are called, respectively, photoautotrophs and chemoautotrophs. The heterotrophs obtain energy by degrading preformed food molecules obtained by consuming other organisms. Chemoheterotrophs use preformed food molecules as their sole source of energy. Some prokaryotes and a small number of plants (e.g., the pitcher plant, which digests captured insects) are photoheterotrophs; that is, they use both light and organic biomolecules as energy sources. KEY CONCEPTS In living organisms, energy, the capacity to move matter, is usually generated by redox reactions. The ultimate source of the energy used by most life-forms on Earth is the sun. Photosynthetic organisms such as plants, certain prokaryotes, and algae capture light energy and use it to transform carbon dioxide (CO2) into sugar and other biomolecules. Chemotrophic species derive the energy required to incorporate CO2 into organic biomolecules by oxidizing inorganic substances such as hydrogen sulfide (H2S), nitrite (NO2–), or hydrogen gas (H2). The biomass produced in both types of process is, in turn, consumed by heterotrophic organisms that use it as a source of energy and structural materials. At each step, as molecular bonds are rearranged, some energy is captured and used to maintain the organism’s complex structures and activities. Eventually, energy becomes disorganized and is released in the form of heat. The metabolic pathways by which energy is generated and used by living organisms are briefly outlined next, followed by the basic mechanisms by which cellular order is maintained. Overview of Metabolism Metabolism is the sum of all the enzyme-catalyzed reactions in a living organism. These reactions are organized into pathways (Figure 1.20) in which an initial reactant molecule is modified in a step-by-step sequence into a product that can be used by the cell for a specific purpose. For example, glycolysis, the energy-generating pathway that degrades the six-carbon sugar glucose, is composed of 10 reactions. All of an individual organism’s metabolic processes consist of a vast web-like pattern of interconnected biochemical reactions that are regulated such that resources are conserved and energy use is optimized. There are three classes of biochemical pathways: metabolic, energy transfer, and signal transduction. FIGURE 1.20 A Biochemical Pathway In this three-step biochemical pathway, biomolecule A is converted into biomolecule D in three sequential reactions. Each reaction is catalyzed by a specific enzyme (E). METABOLIC PATHWAYS There are two types of metabolic pathway: anabolic and catabolic. In anabolic (biosynthetic) pathways, larger molecules are synthesized from smaller precursors. Building-block molecules (e.g., amino acids, sugars, and fatty acids), either produced or acquired from the diet, are incorporated into larger, more complex molecules. Anabolic processes include the synthesis of polysaccharides and proteins from sugars and amino acids, respectively. Because biosynthesis increases order and complexity, anabolic pathways require an input of energy. During catabolic pathways large complex molecules are degraded into smaller, simpler products. Some catabolic pathways release energy. A fraction of this energy is captured and used to drive anabolic reactions. The relationship between anabolic and catabolic processes is illustrated in Figure 1.21. As nutrient molecules are degraded, energy and reducing power (high-energy electrons) are conserved in ATP and NADH molecules, respectively. Biosynthetic processes use metabolites of catabolism, synthesized ATP and NADPH (reduced nicotinamide adenine dinucleotide phosphate, a source of reducing power), to create complex structure and function. ENERGY TRANSFER PATHWAYS Energy transfer pathways capture energy and transform it into forms that organisms can use to drive biomolecular processes. The absorption of light energy by chlorophyll molecules and the energy-releasing redox reactions required for its conversion to chemical bond energy in a sugar molecule is a prominent example. FIGURE 1.21 Anabolism and Catabolism In organisms that use oxygen to generate energy, catabolic pathways convert nutrients to small-molecule starting materials. The energy (ATP) and reducing power (NADPH) that drive biosynthetic reactions are generated during catabolic processes as certain nutrient molecules are converted to waste products such as carbon dioxide, ammonia, and water. SIGNAL TRANSDUCTION Signal transduction pathways allow cells to receive and respond to signals from their surroundings. In the initial or reception phase, a signal molecule such as a hormone or a nutrient molecule binds to a receptor protein. This binding event initiates the transduction phase, a cascade of intracellular reactions that triggers the cell’s response to the original signal. For example, glucose binds to its receptor on pancreatic insulin-secreting cells, whereupon insulin is released into the blood. Most commonly, such responses are an increase or a decrease in the activity of already existing enzymes or the synthesis of new enzyme molecules. KEY CONCEPTS Metabolism is the sum of all the enzyme-catalyzed reactions in a living organism. There are three classes of biochemical pathway: metabolic (anabolic and catabolic), energy transfer, and signal transduction. Biological Order The coherent unity that is observed in all living organisms involves the functional integration of millions of molecules. In other words, life is highly organized complexity. Despite the rich diversity of living processes that contribute to generating and maintaining biological order, most can be classified into the following categories: (1) synthesis and degradation of biomolecules, (2) transport of ions and molecules across cell membranes, (3) production of force and movement, and (4) removal of metabolic waste products and other toxic substances. SYNTHESIS OF BIOMOLECULES Cellular components are synthesized in a vast array of chemical reactions, many of which require energy, supplied directly or indirectly by ATP molecules. The molecules formed in biosynthetic reactions perform several functions. They can be assembled into supramolecular structures (e.g., the proteins and lipids that constitute membranes) or serve as informational molecules (e.g., DNA and RNA) or catalyze chemical reactions (i.e., the enzymes). TRANSPORT ACROSS MEMBRANES Cell membranes regulate the passage of ions and molecules from one compartment to another. For example, the plasma membrane (the animal cell’s outer membrane) is a selective barrier. It is responsible for the transport of certain substances such as nutrients from a relatively disorganized environment into the more orderly cellular interior. Similarly, ions and molecules are transported into and out of organelles (p. 59) during biochemical processes. For example, fatty acids are transported into organelles known as mitochondria so that they may be broken down to generate energy. CELL MOVEMENT Organized movement is one of the most obvious characteristics of living organisms. The intricate and coordinated activities required to sustain life require the movement of cell components. Examples in eukaryotic cells include cell division and organelle movement, two processes that depend to a large extent on the structure and function of a complex network of protein filaments known as the cytoskeleton. The forms of cellular motion profoundly influence the ability of all organisms to grow, reproduce, and compete for limited resources. As examples, consider the movement of protist cells as they search for food in a pond or the migration of human white blood cells as they search for infectious foreign cells throughout the body. More subtle examples include the movement of specific enzymes along a DNA molecule during the chromosome replication that precedes cell division and the secretion of insulin by certain pancreatic cells. WASTE REMOVAL All living cells produce waste products. For example, animal cells ultimately convert food molecules, such as sugars and amino acids, into CO2, H2O, and NH3. These molecules, if not disposed of properly, can be toxic. Some substances are readily removed. In animals, for example, CO2 diffuses out of cells and (after a brief and reversible conversion to bicarbonate by red blood cells) is quickly exhaled through the respiratory system. Excess H2O is excreted through the kidneys. Other molecules, however, are so toxic that specific processes have evolved to provide for their disposal. The urea cycle (described in Chapter 15) provides a mechanism for converting free ammonia and excess amino nitrogen into urea, a less toxic molecule. The urea molecule is then removed from the body through the kidney as a major component of the urine. Living cells also contain a wide variety of potentially toxic molecules that must be disposed of. Plant cells solve this problem by transporting such molecules into a vacuole, where they are either broken down or stored. Animals, however, must use disposal mechanisms that depend on water solubility (e.g., the formation of urine by the kidney). Hydrophobic substances such as steroid hormones, which cannot be broken down into simpler molecules, are converted during a series of reactions into water-soluble derivatives. This mechanism is also used to solubilize some exogenous organic molecules such as drugs and environmental contaminants. KEY CONCEPTS In living organisms, processes of highly ordered complexity are sustained by a constant input of energy. 1.4 SYSTEMS BIOLOGY Information in the overview of biochemical processes that you have just read about was discovered using a method of inquiry based on reductionism. In this powerful, mechanistic strategy a complex, living “whole” is studied by “reducing” it to its component parts. Each individual part is then further broken down so that the chemical and physical properties of its molecules and the connections between them can be determined. Most of the accomplishments of the modern life sciences would have been impossible without the reductionist philosophy. However, reductionism has its limitations because of the assumption that detailed knowledge of all the properties of the parts will of itself ultimately provide a complete understanding of the functioning of the whole. Despite intense efforts, a coherent understanding of dynamic living processes continues to elude investigators. In recent decades, a new approach called systems biology has been utilized to achieve a deeper understanding of living organisms. Based on the engineering principles originally developed to build jet aircraft, systems biology regards living organisms as integrated systems. Each system allows certain functions to be performed. One such system in animals is the digestive system, which comprises a group of organs that is tasked to break down food into molecules that can be absorbed by the body’s cells. Although human-engineered systems and living systems are remarkably similar in some respects, they are significantly different in others. The most important difference is the design issue. When engineers plan a complex mechanical or electrical system, each component is designed to fulfill a precise function, and there are no unnecessary or unforeseen interactions between network components. For example, the individual electrical wires in the cables that control aircraft are insulated to prevent damage caused by short circuits. In contrast, biological systems have evolved by trial and error over several billion years. Evolution, the adaptation of populations of living organisms in response to selection pressure, is made possible by the capacity to generate genetic diversity through various forms of mutation, gene duplications, or the acquisition of new genes from other organisms. The components of living organisms, unlike engineer-designed parts, have no fixed functions, and overlapping functions are permissible. Living systems have become increasingly more complex, in part because of the unavoidability of interactions among established system components and potentially useful new parts (e.g., derived from gene duplications followed by mutations). The systems approach is especially useful because the human mind cannot analyze the hundreds of biochemical reactions that are taking place at once in a living organism. To tackle this problem, systems biologists have invented mathematical and computer models to derive from biochemical reaction pathways an understanding of how these processes operate over time and under varying conditions. The success of these models is reliant on huge data sets containing accurate information about cellular concentrations of biomolecules and the rates of biochemical reactions as they occur in living, functioning cells. Although these data sets are incomplete, this analytic method has produced some notable successes. The technology required to identify and quantify biomolecules of all types continues to be refined. System biologists have identified two core principles that underpin the complex and diverse biochemical pathways described in this textbook: emergence and robustness. In addition, systems biologists organize the vast complexities of living cells with concepts such as systems, networks, modules, and motifs, which are also briefly described. Emergence As we have discovered, the behavior of complex systems cannot be understood simply by knowing the properties of constituent parts. At each level of organization of the system, new and unanticipated properties emerge from interactions among parts. In other words, emergent properties of a complex system have different characteristics than those of its component parts. For example, hemoglobin (the protein that transports oxygen in the blood to the body’s cells) requires ferrous iron (Fe2+) to be functional. Whereas iron easily oxidizes in the inanimate world, the iron in hemoglobin does not usually oxidize, even though it is linked directly to oxygen during the transport process. The amino acid residues that line the iron-binding site protect Fe2+ from oxidation. The protection of ferrous iron in hemoglobin is an emergent property, that is, a property conferred by the complexity and dynamics of the system and not anticipated by knowledge of the chemical properties of hemoglobin’s amino acids. Robustness Systems that remain stable despite diverse perturbations such as fluctuations or damage are described as robust. Autopilot systems in aircraft, for example, maintain a designated flight path despite expected fluctuations in conditions such as wind speed or the plane’s mechanical functions. All robust systems are necessarily complex because failure prevention requires an integrated set of automatic fail-safe mechanisms. The robust (fail-safe) properties of human-made mechanical systems are created by redundancy, the use of duplicate parts (e.g., backup electric generators in an airplane). Although the design of living organisms does include some redundant parts, the robust properties of living systems are largely the result of degeneracy, the capacity of structurally different parts to perform the same or similar functions. The genetic code is a simple, well-recognized example. Of the 64 possible three-base sequences (called codons) on an mRNA molecule, 61 base triplets code for 20 amino acids during protein synthesis. Since most amino acids have more than one codon, degeneracy of the code provides a measure of protection against base substitution mutations. Similarly, the inactivation of a specific type of hormone receptor may be compensated for by similar receptors with partial overlapping functions. Systems Biology Model Concepts The research efforts of systems biologists have resulted in the development of simplifying models, which facilitate the efforts of life science researchers, as well as students, to understand the vast complexities of living organisms. Terminology used in systems biology includes system, network, module, and motif. SYSTEM A system is defined as an interconnected and interacting assembly of biomolecules. Systems under investigation can be organisms, organs, cells, or organelles. For example, the mitochondrion is an organelle (a type of cell compartment in the cells of organisms such as animals and plants). It possesses structural features and biochemical pathways that convert the energy in food molecules into the chemical energy required to drive cell processes and synthesize numerous biomolecules, among other functions. NETWORK Systems can be thought of as the dynamic interaction of networks, each of which is a group of interconnected molecules that performs one or more functions. Living organisms possess metabolic, signaling, and regulatory networks. A metabolic network consists of interconnected biochemical reaction pathways that synthesize and degrade biomolecules. Reactant and product molecules connect these pathways to each other. For example, glycolysis, the pathway that degrades the sugar glucose, is linked to energy capture pathways within mitochondria by pyruvate, the product of glycolysis. Pyruvate is transported into the mitochondrion, where biochemical reactions in another pathway begin the process of capturing the energy in its hydrogen atoms. Glycolysis is also linked to amino acid biosynthetic pathways because certain glycolytic intermediates serve as precursor molecules. Living organisms must perceive and correctly respond to both their internal and external environments. Cells acquire and process information through vast, intricate signaling networks composed of receptor proteins that receive information and signaling pathways, whose components process it. For example, the binding of epinephrine (p. 319) to its receptor on the surface of liver cells initiates a signaling mechanism that results in the activation of enzymes that degrade glycogen. Living organisms have elaborate, robust mechanisms that tightly control metabolic pathways. This control is accomplished by regulatory networks that switch on and off the genes that code for the synthesis of enzymes and all other biomolecules. For example, the binding of the hormone insulin to its receptor on the surface of its target cells sets in motion a signaling mechanism that alters the expression of numerous genes (e.g., enzymes in glycogen and triacylglycerol synthesis). However, gene regulatory networks in living organisms are inextricably integrated with other networks. For example, insulin receptor binding also triggers a signaling pathway that quickly modifies the activity of several biochemical pathways by stimulating the activity of certain enzymes while inhibiting others. MODULE Complex systems are composed of modules, components or subsystems that perform specific functions. Living organisms utilize modules because they are easily assembled, rearranged, and repaired, as well as eliminated when necessary. Although modules (e.g., enzymes extracted from cells in the lab) can often be isolated with some or even most of their functional properties, their function is meaningful only within the context of the larger system. In living organisms, modularity occurs at all system levels. Examples within a cell include amino acids, proteins, and biochemical pathways. Modularity is especially important because it provides the capacity to limit damage to components that can be easily removed and replaced. For example, glycolysis can be considered a module. Functional relationships between modules in a system are managed by protocols, or sets of rules that specify how and whether modules will interact. The mechanism that facilitates pyruvate transport into a mitochondrion is an example of a protocol. MOTIF Network motifs are recurring regulatory circuits that have many different uses. In living organisms, the most common type is feedback control (Figure 1.22), a self-regulating mechanism in which the product of a process acts to modify the process, either negatively or positively. In negative feedback, the most common form, an accumulating product slows its own production. Many biochemical pathways are regulated by negative feedback. Typically, a pathway product inhibits an enzyme near the beginning of the pathway. In positive feedback control, a product increases its own production. Positive feedback control is found less often in living organisms because the mechanism is potentially destabilizing. If not carefully controlled, the amplifying effect of a positive feedback loop can result in the collapse of the system. In blood clotting, for example, the platelet plug that seals a damaged blood vessel does not expand continuously because inhibitors are released by nearby undamaged blood vessel cells. FIGURE 1.22 Feedback Mechanisms (a) Negative Feedback. As a product molecule accumulates, it binds to and inhibits the activity of an enzyme in the pathway. The result is the decreased production of the product. (b) Positive Feedback. As product molecules accumulate, they stimulate an enzyme in the pathway, thereby causing an increased rate of product synthesis. Living Organisms and Robustness Fail-safe control mechanisms, whether in human-made systems or in living organisms, are expensive. Constraints such as energy availability require priorities in resource allocation. As a result, systems are generally protected from commonly encountered environmental changes, but they are vulnerable to unusual or rare events that cause damage. This vulnerability, referred to as fragility, is an inescapable feature of robust systems. Cancer, a group of diseases in which cell cycle control is disrupted, is an example of the “robust, yet fragile” nature of robust systems. Despite the elaborate controls on cell division in animal bodies, mutations in just a few of the genes that code for cell cycle regulatory proteins can result in a robust uncontrolled proliferation of the affected cell. KEY CONCEPTS Systems biology is an attempt to reveal the functional properties of living organisms by developing mathematical models of interactions from available data sets. The systems approach has provided insights into the emergent properties, robustness, and modularity of living organisms. Biochemistry IN THE LAB An Introduction B iochemical technologies exploit the chemical and physical properties of biomolecules: chemical reactivity, size, solubility, net electrical charge, movement in an electric field, and absorption of electromagnetic radiation. As life science research has become increasingly more sophisticated, scientists have provided a progressively more coherent view of the living state. The Human Genome Project was a landmark event in this process. The goal of this international research effort, begun in the late 1980s, was to determine the nucleotide base sequence of human DNA. The subsequent development of automated DNA sequencing technology revolutionized life science research because it provided scientists with a “high-throughput” (i.e., rapid, high-volume, relatively inexpensive) means of investigating the information content of genomes, a field now referred to as genomics. Genomics has been especially useful in medical research. A large number of human diseases have been linked to errors in one or more gene sequences or to faulty regulation of gene expression. Among the early benefits of this work are rapid, accurate tests for predisposition to pathological conditions such as cystic fibrosis, breast cancer, and some liver diseases. Several recently developed technologies have created additional opportunities to investigate the molecular basis of disease. For example, DNA microchips (thousands of DNA molecules arrayed on a solid surface) are now routinely used to monitor gene expression of cells. Proteins can also be rapidly analyzed by mass spectrometry in combination with new technologies. Among the new fields created by high-throughput methods are functional genomics (the investigation of gene expression patterns) and proteomics (the investigation of protein synthesis patterns and protein–protein interactions). The science of bioinformatics is the computer-based field that facilitates analysis of the massive amounts of protein and nucleic acid sequence data that are being generated. System biologists take advantage of all of these methods to decipher biological networks such as metabolic process control, gene regulation, and signal transduction (information-processing) mechanisms. In the past, biochemists and other scientists have often benefited from each other’s work. For example, technologies created by physicists such as X-ray diffraction, electron microscopy, and radioisotope labeling made biomolecular structure and function investigations possible. In recent years, the life sciences have also benefited from the services provided by computer scientists, mathematicians, chemists, and engineers. As the biological knowledge base has continued to expand, it has become increasingly obvious that future advances in life science and medical research will require the efforts of multidisciplinary teams of scientists. Chapter Summary 1. Biochemistry may be defined as the study of the molecular basis of life. Biochemists have contributed to the following insights into life: (1) life is complex and dynamic, (2) life is organized and self-sustaining, (3) life is cellular, (4) life is information-based, and (5) life adapts and evolves. 2. Animal and plant cells contain thousands of different types of molecules. Water constitutes 50 to 90% of a cell’s content by weight, and ions such as Na+, K+, and Ca2+ may account for another 1%. Almost all the other kinds of biomolecules are organic. Many biomolecules are proteins, which play a variety of roles in living organisms: transport proteins, structural proteins, and catalytic proteins (enzymes). 3. Many of the biomolecules found in cells are relatively small, with molecular weights of less than 1000 daltons. Cells contain four families of small molecules: amino acids, sugars, fatty acids, and nucleotides. 4. DNA, consisting of two antiparallel polynucleotide strands, is the repository of genetic information in living organisms. DNA contains coding sequences, referred to as genes, and noncoding sequences, some of which have regulatory functions. RNA is a single-stranded polynucleotide that differs from DNA in that it contains the sugar ribose instead of deoxyribose and the base uracil instead of thymine. RNAs have numerous functions. Examples include protein synthesis and transcription regulation. Gene expression, the process that controls if or when a gene will be transcribed, involves the binding of transcription factors to specific regulatory DNA sequences called response elements. 5. All life processes consist of chemical reactions catalyzed by enzymes. Among the most common reaction types encountered in biochemical processes are nucleophilic substitution, elimination, addition, isomerization, and oxidation-reduction. Biochemical reactions are organized into pathways where a reactant is converted to a product in a step-by-step sequence where each reaction is catalyzed by a separate enzyme. 6. Living organisms require a constant flow of energy to prevent disorganization. The principal means by which cells obtain energy is oxidation of biomolecules or certain minerals. 7. Metabolism is the sum of all the reactions in a living organism. There are two types of metabolic pathway: anabolic and catabolic. Energy transfer pathways capture energy and transform it into forms that organisms can use to drive biomolecular processes. Signal transduction pathways, which allow cells to receive and respond to signals from their environment, consist of three phases: reception, transduction, and response. 8. The complex structure of cells requires a high degree of internal order. This is accomplished by four primary means: synthesis of biomolecules, transport of ions and molecules across cell membranes, production of movement, and removal of metabolic waste products and other toxic substances. 9. Systems biology is a new field that attempts to provide understanding of the functional properties of living organisms by applying mathematical modeling strategies to amassed biological data. Among the early benefits of the systems approach are the insights associated with emergence, robustness, and modularity. Take your learning further by visiting the companion website for Biochemistry at www.oup.com/us/mckee, where you can complete a multiple-choice quiz on this introductory chapter to help you prepare for exams. Chapter 1 Review Quiz Suggested Readings Cai L, Fisher AL, Huang H, Xie Z. 2016. CRISPR-mediated genome editing and human diseases. Genes and Diseases 3:244–51. Collins FS, Varmus HA. 2015. New initiative on precision medicine. New Eng J Med 372(9):793–5. Goodsell DS. 2009. The machinery of life, 2nd ed. New York (NY): Springer. Rothman S. 2002. Lessons from the living cell: the limits of reductionism. New York (NY): McGraw- Hill. Tudge C. 2000. The variety of life: a survey and a celebration of all the creatures that have ever lived. New York (NY): Oxford. Key Words addition reaction, 17 amino acid, 7 anabolic pathway, 20 anhydride, 14 autopoiesis, 13 autotroph, 19 bioinformatics, 26 biomolecule, 3 catabolic pathway, 20 chemoautotroph, 19 chemoheterotroph, 19 chemosynthesis, 19 degeneracy, 23 electrophile, 14 elimination reaction, 15 emergent property, 23 energy, 19 enzyme, 3 fatty acid, 10 feedback control, 24 functional genomics, 26 functional group, 5 gene, 12 gene expression, 13 genome, 12 genomics, 26 heterotroph, 19 homeostasis, 3 hydration reaction, 17 hydrocarbon, 5 hydrolysis, 14 hydrophilic, 7 hydrophobic, 5 isomerization, 17 leaving group, 14 lipid, 10 macromolecule, 3 metabolism, 3 mixed anhydride, 14 modules, 24 monosaccharide, 8 mutation, 5 negative feedback, 25 neurotransmitter, 7 noncoding RNA, 13 nucleic acid, 11 nucleophile, 14 nucleophilic substitution, 14 nucleotide, 10 oxidation-reduction (redox) reaction, 18 oxidize, 18 oxidizing agent, 18 peptide, 7 peptide bond, 7 photoautotroph, 19 photoheterotroph, 19 photosynthesis, 19 polypeptide, 7 polysaccharide, 8 positive feedback, 25 protein, 7 proteomics, 26 purine, 11 pyrimidine, 11 reduce, 18 reducing agent, 18 reductionism, 22 response element, 13 robust, 23 saturated, 10 signal transduction, 21 sugar, 8 systems biology, 22 transcription, 12 transcription factor, 13 unsaturated, 10 Review Questions SECTION 1.1 Comprehension Questions 1. Define the following terms: a. biomolecules b. macromolecules c. metabolism d. homeostasis e. enzymes 2. Define the following terms: a. deoxyribonucleic acid b. genetic information c. insulin receptor d. mutation e. hierarchically organized system Fill in the Blanks 3. The sum of all the reactions in a living organism is called its _____________. 4. _____________ are the linear sequences of nucleotides in an organism’s genetic information. 5. In multicellular organisms, the levels of organization are _____________, _____________, _____________ and _____________. 6. _____________ is a series of reactions in which a specific biomolecule is converted into a product molecule. Short-Answer Questions 7. Distinguish between silent and harmful mutations. 8. Describe why insulin is considered a signal molecule. 9. List three life science fields that require a solid understanding of biochemical principles. Critical-Thinking Questions 10. Describe in general terms how mutations are involved in the evolution of species. 11. Describe the properties that all cells have in common. SECTION 1.2 Comprehension Questions 12. Define the following terms: a. hydrocarbon b. hydrophilic c. hydrophobic d. functional group e. R group 13. Define the following terms: a. carbonyl group b. carboxyl group c. amino group d. hydroxyl group e. peptide bond 14. Define the following terms: a. polypeptide b. peptide c. protein d. standard amino acids e. neurotransmitter 15. Define the following terms: a. sugar b. glucose c. monosaccharide d. polysaccharide e. cellulose 16. Define the following terms: a. triacylglycerol b. phosphoglyceride c. fatty acid d. saturated fatty acid e. unsaturated fatty acid 17. Define the following terms: a. nucleic acid b. nucleotide c. purine d. pyrimidine e. deoxyribose 18. Define the following terms: a. DNA b. RNA c. genome d. transcription e. fructose 19. Define the following terms: a. rRNA b. tRNA c. mRNA d. siRNA e. miRNA 20. Define the following terms: a. ribosome b. transcription factor c. signal molecule d. response element e. RNA interference Fill in the Blanks 21. The biologically active form of a fatty acid is the thioester of _______________. 22. The genome’s functional gene products are either _____________ or _____________. 23. _____________ is an antiviral defense mechanism involving siRNA molecules. Short-Answer Questions 24. Identify the functional groups in the following molecules: 25. What are the (c) six major (a) (d) (e) elements (b) present in living organisms? (g) 26. Assign each of the (f) (h) following molecules to one of the major classes of biomolecule: 27. Carbohydrates are widely (c) (a) (b) (d) (e) Name four classes of small biomolecules. In what larger molecules are they found? recognized as sources of metabolic energy. What are the two other critical roles that carbohydrates play in living organisms? 28. Nucleotides have roles in addition to being components of DNA and RNA. Give an example. 29. List two functions of each of the following biomolecules: a. fatty acids b. sugars c. nucleotides d. amino acids Critical-Thinking Questions 31. Elements such as carbon, hydrogen, and oxygen that occur in biomolecules form stable covalent bonds. What would be the result if the bonds between these atoms were either slightly less or more stable than the naturally occurring bonds? 32. Why are fatty acids the principal long-term energy reserve of the body? 33. Hundreds of thousands of proteins have been discovered in living organisms. Yet, as astonishing as this diversity is, these molecules constitute only a small fraction of the possible protein molecules. Calculate the total number of possible decapeptides (molecules with 10 amino acid residues linked by peptide bonds) that can be synthesized from the 20 standard amino acids. If you were to spend 5 minutes writing out the molecular structure of each decapeptide, how long would the task take? 34. When a substance such as sodium chloride is dissolved in water, the ions become completely surrounded by water molecules, forming structures called hydration spheres. When the sodium salt of a fatty acid is mixed with water, the carboxylate group of the molecule becomes hydrated, but the hydrophobic portion of the molecule is poorly hydrated, if at all. Using a circle to represent the carboxylate group and an attached squiggly line to represent the hydrocarbon chain of a fatty acid, draw a picture of how fatty acids interact with water. SECTION 1.3 Comprehension Questions 35. Define the following terms: a. hydrolysis b. nucleophilic substitution c. elimination reaction d. hydration reaction e. isomerization reaction 36. Define the following terms: a. nucleophile b. electrophile c. leaving group d. addition reaction e. anhydride 37. Define the following terms: a. adenosine triphosphate b. redox reaction c. oxidizing agent d. reducing agent e. NADH 38. Define the following terms: a. hydride ion b. oxidation reaction c. energy d. FAD e. electron transport pathway 39. Define the following terms: a. coenzyme b. anabolic pathway c. catabolic pathway d. signal transduction pathway e. glycolysis 40. Define the following terms: a. autotroph b. chemoautotroph c. photoautotroph d. photoheterotroph e. chemoheterotroph Fill in the Blanks 41. The following is an example of a _______________ reaction. 42. Each organism is considered an autonomous self-organizing self-maintaining entity. This set of properties is referred to as _______________. 43. _______________ are organisms that transform the energy of the sun into chemical bond energy. 44. The sum of all reactions in a living organism is called its _______________. Short-Answer Questions 45. Distinguish between living organisms and human-made factories. 46. Compare anabolic and catabolic pathways. What molecules link these two processes? 47. How do cells obtain energy from chemical bonds? 48. List several important ions that are found in living organisms. 49. List three types of biochemical reactions involving acyl nucleophilic substitution. 50. Name three waste products that animal cells produce. How do plants dispose of waste products? 51. Identify the oxidizing and reducing agents in the following reaction: 52. What reaction is the first step in utilizing glucose as an energy source? 53. What are the primary functions of metabolism? Critical-Thinking Questions 54. The order of reactivity in nucleophilic substitution reactions is as follows: Explain this order on the basis of their pKa values: phosphoric acid (1 × 10−3), hydrogen sulfide (1 × 10−7), alcohols (1 × 10−16), and ammonia (1 × 10−36). (pKa is the negative log of the acid dissociation constant, which is a quantitative measure of the strength of an acid in a solution, i.e., the tendency of an acid to lose a proton.) 55. Carboxylic acids that undergo nucleophilic acyl substitution reactions are often first converted to thioesters, For example, acetic acid forms a thioester with a molecule called coenzyme A, which has a sulfhydryl group. What is the leaving group in these reactions? SECTION 1.4 Comprehension Questions 56. Define the following terms: a. systems biology b. emergence c. robustness d. degeneracy e. system 57. Define the following terms: a. network b. metabolic network c. signaling network d. module e. motif 58. Define the following terms: a. emergent property b. negative feedback control c. positive feedback control d. bioinformatics e. proteomics Fill in the Blanks 59. A property conferred by the complexity and dynamics of a system is called a(n) _______________ property. 60. A _______________ is an interconnected and interacting assembly of biomolecules. 61. _______________ are components or subsystems that perform specific functions in complex systems. 62. _______________ are recurring regulatory circuits that have many different uses in complex systems. Short-Answer Questions 63. Why is cancer, which occurs as the result of disrupted cell cycle control, an example of the fragility of a robust system? 64. Compare and contrast the feature of an airplane autopilot system with a biological system. 65. Provide several examples of emergent properties. Critical-Thinking Questions 66. How does the statement “the whole is more than the sum of its parts” apply to living organisms? Give an example. 67. Tay–Sachs disease is a devastating genetic neurological disorder caused by the lack of an enzyme that degrades a specific lipid molecule. When this molecule accumulates in brain cells, an otherwise healthy child undergoes motor and mental deterioration within months after birth and dies by the age of 3 years. In general terms, describe how a system biologist evaluates this phenomenon? 68. Humans synthesize most of the cholesterol required for cell membranes and for the synthesis of vitamin D and other steroid hormones. Keeping in mind that living organisms are self- regulating, what would you expect to happen if a person’s diet is high in cholesterol? Provide a reason for your response. 69. Unlike human-engineered system, the components of biological systems often have multiple functions. Is this phenomenon a strength or a weakness of biological systems? 70. The cancerous cells in a tumor proliferate uncontrollably, and treatment often involves the use of toxic drugs in attempts to kill them. Often, however, after initial success (i.e., shrinkage of the tumor), the cancer returns because resistance to the drugs develops. Biochemists have identified one of the major causes of this phenomenon called multidrug resistance. One or more cells in the tumor have expressed the gene for P-glycoprotein, a membrane transport protein that pumps the drugs out of the cells. In the absence of the toxic drug molecules, these cells again grow uncontrollably and eventually become the dominant cells in the tumor. What features of living organisms does this process illustrate? MCAT Study Questions 71. What are the possible products of a hydrolysis reaction of an amide? a. carboxylic acid and alcohol b. amino acid and carboxylic acid c. ether and aldehyde d. ketone and amine 72. The major roles of RNA include: i gene expression; ii. protein synthesis; iii. carbohydrate synthesis a. i b. ii c. i and ii d. ii and iii 73. When an carboxylic acid reacts with an alcohol, the product is called a(n) a. amide b. diester c. ester d. fatty acid 74. Which of the following molecules is the most polar? a. propane b. propanol c. acetic acid d. formaldehyde 75. The following compound has which functional groups? i = alcohol ii = ester iii = aromatic iv = carboxylic acid a. i, ii, and iv b. i, iii, and iv c. i and ii d. iii and iv Living Cells CHAPTER 2 The Immune System at Work: Antigen Presentation In this colored scanning electron micrograph, two white blood cells are performing a vital process that can result in the destruction of foreign cells or host- infected cells. After a macrophage (blue) has engulfed a foreign cell such as a bacterium, it proceeds to initiate a multifaceted process that will eliminate the threat. In the first step, the macrophage uses enzymes and toxic chemicals to destroy the bacterium. As it does so, the macrophage inserts bacterial protein fragments (antigens) into its own plasma membrane in a phenomenon referred to as antigen presentation. T cell activation occurs when a T helper lymphocyte (yellow) with surface proteins capable of binding to a specific foreign antigen interacts with the macrophage. The subsequent activation of the T cell leads to its proliferation, followed by activation of other immune system cells. The end result is the destruction of the invading bacteria. OUTLINE OUR BODIES, OUR SELVES 2.1 CORE BIOCHEMISTRY CONCEPTS Biochemistry and Water Biological Membranes Self-Assembly Molecular Machines Macromolecular Crowding Proteostasis Signal Transduction 2.2 STRUCTURE OF PROKARYOTIC CELLS Cell Wall Plasma Membrane Cytoplasm Pili and Flagella 2.3 STRUCTURE OF EUKARYOTIC CELLS Plasma Membrane Endoplasmic Reticulum Golgi Apparatus Vesicular Organelles and Lysosomes: The Endocytic Pathway Nucleus Mitochondria Peroxisomes Chloroplasts Cytoskeleton Biochemistry in Perspective Primary Cilia and Human Disease Biochemistry in the Lab Cell Technology AVAILABLE ONLINE Biochemistry in Perspective Organelles and Human Disease Biochemistry in Perspective Caveolar Endocytosis Our Bodies, Our Selves I t would surprise most humans that we are colonized by a vast number and diversity of microorganisms. Current estimates of microorganisms to human cell ratios range from 3:1 to 1:1. Most of these organisms, referred to as an indigenous flora or microbiota (Figure 2.1), are bacteria with smaller numbers of archaeans (another type of prokaryote), fungi, and viruses. Humans and their microbiota have evolved together into a dynamic, interdependent superorganism. This relationship is usually symbiotic (mutually beneficial in some way) or commensal (nonharmful). However, a few species in the normal human microbiota are pathogens that can cause disease if conditions permit (e.g., if the immune system is depressed). Our bodies begin acquiring microbes as soon as the amniotic sac ruptures. As babies proceed down the birth canal, colonization begins as they are exposed to their mother’s microbiota. Within a short time, a diverse array of microbes has taken up residence in all body surfaces that are exposed to the external environment: skin and certain parts of the respiratory, gastrointestinal (GI), and urogenital tracts. These ecosystems, each with its own set of environmental conditions (e.g., temperature, pH, and O2 availability), eventually possess their own characteristic communities of microorganisms. The majority of human microbiotic organisms occur in the intestines (between 500 and 1000 species by some estimates) where they provide a spectrum of beneficial services in exchange for a stable nutrient supply and favorable environmental conditions. For example, numerous bacteria contribute to dietary fiber digestion, a process that contributes about 5% of human energy requirements and produces a variety of bioactive molecules. Among these are the short-chain fatty acids (SCFAs) acetate, propionate, and butyrate, which are responsible for some of the beneficial effects of dietary fiber in human health (e.g., reduction in risk of colon cancer and metabolic disorders such as type 2 diabetes (pp. 615–17), cardiovascular disease, and obesity). Other examples of microbiotic roles include vitamin synthesis (vitamin K and several B vitamins), repression of pathogens (organisms that produce toxins or cause severe diarrhea), and robust immune system development. FIGURE 2.1 The Human Microbiota Each healthy human is host to an exceptionally large and unique set of highly adapted microorganisms. Examples of the major groups of organisms observed in the normal flora are given for each ecosystem. Note that although some bacterial groups occur at different body locations, the species often differ. Experiments with gnotobiotic (germ-free) mice have revealed that the absence of a microbiota has a profound effect on health. In addition to requiring 30% more calories to maintain body weight than conventional mice, germ-free mice were observed to have underdeveloped intestinal architecture and fat storage capacity, as well as smaller organs (heart, lungs, and liver). These mice are also highly susceptible to numerous infections caused by transient pathogens (e.g., respiratory or intestinal viruses) because their immune systems are immature. Defense Mechanisms Despite the many benefits of the human indigenous microbiota, the body must constantly protect itself from the microbiota’s potentially unrestricted growth. Strategies used to prevent damage include impenetrable epithelial tissue barriers and immune system cells. Epithelial barriers in the GI tract lining protect internal organs from invasion of microorganisms. Epithelial cells also produce antimicrobial proteins. Examples include the α-defensins, released from cells of the small intestine that kill bacteria by inserting into membranes and forming pores that cause cell rupture. The immune system normally strikes a fine balance of protection from pathogens and tolerance of nonpathogenic organisms and the body’s own cells. Approximately 70% of immune system cells (e.g., lymphocytes and macrophages) are located in and around the GI tract (especially the small and large intestine), where maintaining this balance is vital. Gut Flora and Human Health Each person has a unique microbiota that is the result of genetic inheritance, birth circumstances (e.g., vaginal delivery vs. Caesarean section and the mother’s microbiota), diet, and environment (e.g., exposure to antibiotics or acid-suppressing medications). Bacteria dominate the human gut microbiota. In most humans, more than 90% of the microorganisms in the intestines belong to two phyla: the Firmicutes and Bacteroidetes. A healthy gut flora is characterized as diverse, relatively stable, and resilient. The mechanism that maintains this condition, referred to as colonization resistance, protects the body from the challenge of exogenous and potentially pathogenic microbes. Colonization resistance is a constellation of tactics (e.g., competition for space in the mucus layer lining the intestinal lumen and intermicrobial chemical warfare). In recent years, excessive antibiotic use, poor diets (e.g., those high in fat and sugar and low in fiber), and chronic stress have contributed to a rise in disrupted gut microbiota, characterized most notably by low species diversity. Antibiotic treatment causes major alterations of the gut microbiota. Frequent antibiotic use can result in dysbiosis, a condition in which a severely eroded colonization resistance allows the overgrowth of pathogens. Poor diets can also cause dysbiosis since dietary factors play a significant role in shaping the microbiota. For example, in both humans and lab animals, the switch from a balanced diet to a high-fat diet causes the loss of beneficial bacteria, some of which are known to protect cells in the gut lining. In addition to GI tract diseases such as inflammatory bowel disease (IBS, a stress-related disorder now believed to be a contributing factor in depression and anxiety), dysbiosis has also been linked to numerous systemic disease states, including obesity, type 2 diabetes (pp. 615–17), metabolic syndrome (pp. 626), and several autoimmune diseases. Low-level chronic systemic inflammation, caused by the leakage of bacterial molecules such as lipopolysaccharide (also called endotoxin) across a gut wall compromised by the loss of protective bacteria, is now believed to be a significant feature of most metabolic diseases. Recent evidence has revealed that consumption of artificial sweeteners in food and beverages has detrimental health effects because their effects on certain gut microbes result in destabilized blood glucose control in lab animals and some humans. Overview CELLS ARE THE STRUCTURAL UNITS OF ALL LIVING ORGANISMS. ONE REMARKABLE FEATURE OF CELLS IS THEIR DIVERSITY: THE HUMAN BODY contains about 200 types of cells. This great variation reflects the variety of functions that cells can perform. However, no matter what their shape, size, or species, cells are also amazingly similar. They are all surrounded by a membrane that separates them from their environment. They are all composed of the same types of molecules. T he structural hierarchy of life on earth extends from the biosphere to biomolecules. Each level is inextricably linked to the levels above and below it. Cells, however, are considered the basic unit of life, since they are the smallest entities that are actually alive. Cells can sense and respond to their environment, transform matter and energy, and reproduce themselves. Living cells are classified as either prokaryotic or eukaryotic. Prokaryotes are single-celled organisms that lack a nucleus (pro = “before,” karyon = “nucleus” or “kernel”). Analysis of the RNA in prokaryotes has revealed that there are two distinct types of prokaryotes: the Bacteria and the Archaea. Some bacterial species cause disease (e.g., cholera, tuberculosis, syphilis, and tetanus), whereas others are of practical interest for humans (e.g., those used to make foods such as yogurt, cheese, and sourdough bread). A prominent feature of the Archaea is their unsurpassed capacity to occupy and even thrive in very challenging habitats. The eukaryotes (eu = “true”) are composed of cells that possess a nucleus, a membrane-bound compartment that contains the cell’s DNA. Animals, plants, fungi, and single-celled protists are examples of the eukaryotes. Eukaryotes also differ from prokaryotes in size and complexity. The volume of a typical eukaryotic cell such as a hepatocyte (liver cell) is between 6000 and 10,000 μm3. The volume of the bacterium Escherichia coli is significantly smaller at 2 to 4 μm3. Although the structural complexity of prokaryotes is significant, that of eukaryotes is greater by several orders of magnitude, largely because of subcellular compartments called organelles. Each organelle is specialized to perform specific tasks. The compartmentalization afforded by organelles creates microenvironments in which biochemical processes can be efficiently regulated. In multicellular eukaryotes, complexity is increased by cellular specialization and intercellular communication mechanisms. The common features of prokaryotic and eukaryotic cells include their similar chemical composition and the universal use of DNA as genetic material. This chapter provides an overview of cell structure. This review is a valuable exercise because biochemical reactions do not occur in isolation. Our understanding of living processes is incomplete without knowledge of their cellular context. After a brief discussion of some basic themes in cellular structure and function, the essential structural features of prokaryotic and eukaryotic cells are describe

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